In June 2017, a 4-year-old boy died 1 week after being knocked over and briefly submerged while playing in knee-deep water. This story was widely reported as a case of a rare occurrence called “dry” or “secondary” drowning, depending on the source.¹ The media accounts went viral, spreading fear in parents and others learning about these alleged conditions from the news and social media.

Many alleged cases of dry drowning are reported every year, but each has been found to have a recognized medical source that has a legitimate medically recognized diagnosis (which dry and secondary drowning are not).

Drowning is one of the most common causes of death in children, and so we ought to make sure that the information we share about it is accurate, as it is vital to effective prevention, rescue, and treatment.

Unfortunately, medical providers, medical journals, and the mass media continue to disseminate misinformation on drowning.² These reports often prevail over updated information and hinder accurate understanding of the drowning problem and its solutions.

Every death is tragic, especially the death of a child, and our heartfelt sympathies go out to the family in this alleged drowning case, as well as to all families suffering the loss of a loved one to drowning. However, in the 2017 case, the cause of death was found on autopsy to be myocarditis not related in any way to drowning. As often happens in such situations, this clarification did not receive any media attention, despite the wide reporting and penetration of the original, erroneous story.

We hope our review will reduce misunderstanding among the public and healthcare providers, contribute to improved data collection, and help to promote interventions aimed at prevention, rescue, and mitigation of drowning incidents.

WHAT IS DROWNING?

A consensus committee of the World Health Organization defined drowning as “the process of experiencing respiratory impairment from submersion/immersion in liquid.”³ The process begins when the victim’s airway goes below the surface of the liquid (submersion) or when water splashes over the face (immersion). If the victim is rescued at any time, the process is interrupted, and this is termed a nonfatal drowning. If the victim dies at any time, this is a fatal drowning. Any water-distress incident without evidence of respiratory impairment (ie, without aspiration) should be considered a water rescue and not a drowning.

Rarely do minimally symptomatic cases progress to death, just as most cases of chest pain do not progress to cardiac arrest.⁴ Nonetheless, rescued drowning victims can deteriorate, which is why we encourage people to seek medical care immediately upon warning signs, as we do with chest pain. For drowning, such warning signs are any water distress followed by difficulty breathing, excessive coughing, foam in the mouth, or abnormal behavior.

A SERIOUS PUBLIC HEALTH ISSUE

Drowning is a serious and neglected public health issue, claiming the lives of 372,000 people a year worldwide.⁵ It is a leading cause of death in children ages 1 to 14. The toll continues largely unabated, and in low- and middle-income nations it does not attract the levels of funding that go to other forms of injury prevention, such as road safety.

Nonfatal drowning—with symptoms ranging from mild cough to severe pulmonary edema, and complications ranging from none to severe neurologic impairment—is far more common than fatal drowning.⁶ For every fatal drowning, there are at least 5 nonfatal drowning incidents in which medical care is needed, and 200 rescues are performed.^7–10

In the United States, drowning accounts for almost 13,000 emergency department visits per year and about 3,500 deaths.^7,8

In Brazil, with two-thirds the population of the United States, drowning accounts for far fewer hospital visits but about twice as many deaths. In Rio de Janeiro, where a highly effective and specialized prehospital service is provided at 3 drowning resuscitation centers staffed by medical doctors, an analysis of the 46,060 cases of rescue in 10 years from 1991 to 2000 showed that medical assistance was needed in only 930 cases (2%).¹⁰ The preventive and rescue actions of parents, bystanders, lifeguards, and prehospital rescue services significantly reduce the number of drowning deaths, but these groups do not consistently gather data on nonfatal drowning that can be included in a comprehensive database.

DROWNING IS A PROCESS

When a person in the water can no longer keep the airway clear, water that enters the mouth is voluntarily spit out or swallowed. Within a few seconds to minutes, the person can no longer clear the airways and water is aspirated, stimulating the cough reflex. Laryngo­spasm, another myth concerning drowning, is presumed to protect the airways but does not, as it is rare, occurring in less than 2% of cases.^11,12

If the person is not rescued, aspiration of water continues, and hypoxemia leads to loss of consciousness and apnea within seconds to a few minutes, followed by cardiac arrest. As a consequence, hypoxemic cardiac arrest generally occurs after a period of tachycardia followed by bradycardia and pulseless electrical activity, usually leading to asystole.^13,14

The entire drowning process, from water distress to cardiac arrest, usually takes a few minutes, but in rare situations, such as rapid hypothermia, it can go on for up to an hour.¹⁵ Most drowning patients have an otherwise healthy heart, and the apnea and hypoxemia precede the cardiac arrest by only a few seconds to minutes; thus, cardiac arrest is caused by the hypoxemic insult and not by ventricular dysrhythmias.^6,16

Drowning can be interrupted at any point between distress and death. If the person is rescued early, the clinical picture is determined by the reactivity of the airway and the amount of water that has been aspirated, but not by the type of water (salt or fresh).

Another myth is that drowning in salt water is different from drowning in fresh water. Both salt water and fresh water cause similar surfactant destruction and washout and disrupt the alveolar-capillary membrane. Disruption of the alveolar-capillary membrane increases its permeability and exacerbates shifting of fluid, plasma, and electrolytes into the alveoli.¹³ The clinical picture of the damage is one of regional or generalized pulmonary edema, which interferes with gas exchange in the lungs.^6,13,17

Animal studies by Modell et al showed that aspiration of just 2.2 mL of water per kilogram of body weight is sufficient to cause severe disturbances in oxygen exchange,¹⁷ reflected in a rise in arterial pH and a drop in partial pressure of oxygen. The situation must be similar in humans. In a 70-kg person, this is only about 154 mL of water—about two-thirds of a cup.

The combined effects of fluid in the lungs, the loss of surfactant, and the increase in capillary-alveolar permeability can result in decreased lung compliance, increased right-to-left shunting in the lungs, atelectasis, alveolitis, hypoxemia, and cerebral hypoxia.¹³

If the victim needs cardiopulmonary resuscitation, the possibility of neurologic damage is similar to that in other cardiac arrest situations, but exceptions exist. For example, in rare cases, hypothermia provides a protective mechanism that allows victims to survive prolonged submersion.^4,15

The duration of submersion is the best predictor of death.¹⁸ Underwater, people are not taking in oxygen, and cerebral hypoxia causes both morbidity and death. For this reason, reversing cerebral hypoxia with effective ventilation, oxygen, and chest compression is the priority of treatment.

“Near drowning,” “dry drowning,” “wet drowning,” “delayed drowning,” and “secondary drowning” are not medically accepted diagnoses,^3,4,19 and many organizations and lifesaving institutions around the world discourage the use of these terms.^19,20 Unfortunately, these terms still slip past the editors of medical journals and are thus perpetuated. The terms are most pervasive in the nonmedical media, where drowning seems to be synonymous with death.^3,19,21 We urge all authors and stakeholders to abandon these terms in favor of understanding and communicating drowning as a process that can vary in severity and have a fatal or nonfatal outcome.

Near-drowning

Historically, drowning meant death, while near-drowning meant the victim survived, at least initially (usually for at least 24 hours).

Before 2002, there were 13 different published definitions of near-drowning.^21,22 This variability has caused a great deal of confusion when trying to describe and monitor drowning.

A person can drown and survive, just as a person can have cardiac arrest and survive.^4,21 Just as there is no recognized condition of “near-cardiac arrest,” there is also no condition of near-drowning. Using near-drowning as a medical diagnosis hides the true burden of drowning and consequently amplifies difficulties in developing effective prevention, rescue, and treatment programs.

Dry drowning

Dry drowning has never been an accepted medical term, although it has been used to describe different parts of the drowning process. While many authors use it as a synonym for secondary drowning (described below), in the past it was usually used in cases in which no water was found in the lungs at autopsy in persons who were found dead in the water.^2–4,21 This occurred in about 10% to 15% of cases and was also called drowning “without water aspiration.”

Perhaps some victims suffer sudden cardiac death. It happens on land—why not in the water? Modell et al stated, “In the absence of the common finding of significant pulmonary edema in the victim’s respiratory system, to conclude his or her death was caused by ‘drowning without aspiration’ is unwise.”²³

Laryngospasm is another proposed explanation. It could play a role in the fewer than 2% of cases in which no other cause of death is found on clinical examination or autopsy,^11,12,19,23 but it does not occur in most cases of drowning, or it is brief and is terminated by the respiratory movements that allow the air in the lung to escape and water to be inhaled.

The problem with the term dry drowning is the harm caused by misdiagnosing cases of sudden death as drowning, when an alternative cause is present. Most importantly, the management is the same if small amounts of water are present or not; therefore, no clinical distinction is made between wet and dry drowning.

Secondary drowning

Secondary drowning, sometimes called delayed drowning, is another term that is not medically accepted. The historical use of this term reflects the reality that some patients may worsen due to pulmonary edema after aspirating small amounts of water.

Drowning starts with aspiration, and few or only mild symptoms may be present as soon as the person is removed from the water. Either the small amount of water in the lungs is absorbed and causes no complications or, rarely, the patient’s condition becomes progressively worse over the next few hours as the alveoli become inflamed and the alveolar-capillary membrane is disrupted. But people do not unexpectedly die of drowning days or weeks later with no preceding symptoms. The lungs and heart do not “fill up with water,” and water does not need to be pumped out of the lungs.

There has never been a case published in the medical literature of a patient who underwent clinical evaluation, was initially without symptoms, and later deteriorated and died more than 8 hours after the incident.^6,10,21 People who have drowned and have minimal symptoms get better (usually) or worse (rarely) within 4 to 8 hours. In a study of more than 41,000 lifeguard rescues, only 0.5% of symptomatic patients died.⁶

Drowning secondary to injury or sudden illness

Any injury, trauma, or sudden illness that can cause loss of consciousness or mental or physical weakness can lead to drowning. Physicians need to recognize these situations to treat them appropriately. Drowning that is secondary to other primary insults can be classified as²⁴:

• Drowning caused by injury or trauma (eg, a surfing, boating, or a hang-gliding accident)
• Drowning caused by a sudden illness such as cardiac disease (eg, myocardial ischemia, arrhythmias, prolonged QT syndrome, hypertrophic cardiomyopathy) or neurologic disease (eg, epilepsy, stroke)
• Diving disease (eg, decompression sickness, pulmonary overpressurization syndrome, compression barotrauma, narcosis [“rapture of the deep”], shallow water blackout, immersion pulmonary edema).

PREVENTION IS BEST

Drowning is a leading and preventable cause of death worldwide and for people of all ages. The danger is real, not esoteric or rare, and healthcare providers should use any opportunity to discuss with patients, parents, and the media the most important tool for treating drowning: primary prevention.

For example, small children should be continuously and uninterruptedly supervised within arm’s reach while in the water, even if a lifeguard is present. Other preventive measures are lifejackets, fences completely enclosing pools or ponds, and swimming and water safety lessons. Drowning often occurs in a deceptively pleasant environment that may not seem dangerous.

When preventive measures fail, responders (usually a health professional is involved) need to be able to perform the necessary steps to interrupt the drowning process.

The first challenge is to recognize when someone in the water is at risk of drowning and needs to be rescued.²⁵ Early self-rescue or rescue by others may stop the drowning process and prevent most cases of initial and subsequent water aspiration, respiratory distress, and medical complications.

DON’T BECOME A VICTIM

Rescuers must take care not to become victims themselves. Panicked swimmers can thrash about and injure the rescuer or clutch at anything they encounter, dragging the rescuer under. And the rescuer can succumb to the same hazards that got the victim into trouble, such as strong currents, deep water, or underwater hazards.

Certified lifeguards are trained to get victims out of the water safely. The American Red Cross slogan “Reach or throw, don’t go” means “Reach out with a pole or other object or throw something that floats; don’t get in the water yourself.”

WHAT TO TELL THE PUBLIC

While some journalists acknowledge that the terms dry drowning and secondary drowning are medically discredited, they still use them in their reports. The novelty of this story—and its appeal to media outlets—is precisely the unfamiliarity of these terms to the general public and the perceived mysterious, looming threat.

We often hear that these terms are more familiar to the public, which is likely true. More concerning, some physicians continue to use them (and older definitions of drowning that equate it with death) in media interviews, clinical care, and publications. The paradox is that we, the medical community, invented these terms, not patients or the media.

As clinicians and researchers, we should drive popular culture definitions, not the other way around. Rather than dismiss these terms as “semantics” or “technicalities,” we should take the opportunity to highlight the dangers of drowning and the importance of prevention, and to promote simpler language that is easier for us and our patients to understand.^19,21

Healthcare providers should understand and share modern drowning science and best practices, which will reduce fear, improve resource utilization, and prevent potentially deadly consequences due to misunderstanding or misinterpretation of incorrect terminology.

WHEN PATIENTS SHOULD SEEK CARE

Anyone who experiences cough, breathless­ness, or other worrisome symptoms such as abnormal mentation within 8 hours of a drowning incident (using the modern definition above) should seek medical advice immediately.

We tell people to seek care if symptoms seem any worse than the experience of a drink “going down the wrong pipe” at the dinner table.²¹ But symptoms can be minimal. Careful attention should be given to mild symptoms that get progressively worse during that time. These cases can rarely progress to acute respiratory distress syndrome.

Table 1 explores who needs further medical help after being rescued from the water.²⁶

In most of these cases, it is most appropriate to call an ambulance, but care may involve seeing a doctor depending on the severity of the symptoms.^6,21 Usually, drowning patients are observed for 4 to 8 hours in an emergency department and are discharged if normal. Symptoms that are more significant include persistent cough, foam at the mouth or nose, confusion, or abnormal behavior, and these require further medical evaluation.

Patients should also seek medical care even if they are 100% normal upon exiting the water but develop worrisome symptoms more than 8 hours later, and providers should consider diagnoses other than primary drowning. Spontaneous pneumothorax, chemical pneumonitis, bacterial or viral pneumonia, head injury, asthma, chest trauma, and acute respiratory distress syndrome have been mislabeled as delayed, dry, or secondary drowning.^3,4,19,21

In June 2017, a 4-year-old boy died 1 week after being knocked over and briefly submerged while playing in knee-deep water. This story was widely reported as a case of a rare occurrence called “dry” or “secondary” drowning, depending on the source.¹ The media accounts went viral, spreading fear in parents and others learning about these alleged conditions from the news and social media.

Many alleged cases of dry drowning are reported every year, but each has been found to have a recognized medical source that has a legitimate medically recognized diagnosis (which dry and secondary drowning are not).

Drowning is one of the most common causes of death in children, and so we ought to make sure that the information we share about it is accurate, as it is vital to effective prevention, rescue, and treatment.

Unfortunately, medical providers, medical journals, and the mass media continue to disseminate misinformation on drowning.² These reports often prevail over updated information and hinder accurate understanding of the drowning problem and its solutions.

Every death is tragic, especially the death of a child, and our heartfelt sympathies go out to the family in this alleged drowning case, as well as to all families suffering the loss of a loved one to drowning. However, in the 2017 case, the cause of death was found on autopsy to be myocarditis not related in any way to drowning. As often happens in such situations, this clarification did not receive any media attention, despite the wide reporting and penetration of the original, erroneous story.

We hope our review will reduce misunderstanding among the public and healthcare providers, contribute to improved data collection, and help to promote interventions aimed at prevention, rescue, and mitigation of drowning incidents.

WHAT IS DROWNING?

A consensus committee of the World Health Organization defined drowning as “the process of experiencing respiratory impairment from submersion/immersion in liquid.”³ The process begins when the victim’s airway goes below the surface of the liquid (submersion) or when water splashes over the face (immersion). If the victim is rescued at any time, the process is interrupted, and this is termed a nonfatal drowning. If the victim dies at any time, this is a fatal drowning. Any water-distress incident without evidence of respiratory impairment (ie, without aspiration) should be considered a water rescue and not a drowning.

Rarely do minimally symptomatic cases progress to death, just as most cases of chest pain do not progress to cardiac arrest.⁴ Nonetheless, rescued drowning victims can deteriorate, which is why we encourage people to seek medical care immediately upon warning signs, as we do with chest pain. For drowning, such warning signs are any water distress followed by difficulty breathing, excessive coughing, foam in the mouth, or abnormal behavior.

A SERIOUS PUBLIC HEALTH ISSUE

Drowning is a serious and neglected public health issue, claiming the lives of 372,000 people a year worldwide.⁵ It is a leading cause of death in children ages 1 to 14. The toll continues largely unabated, and in low- and middle-income nations it does not attract the levels of funding that go to other forms of injury prevention, such as road safety.

Nonfatal drowning—with symptoms ranging from mild cough to severe pulmonary edema, and complications ranging from none to severe neurologic impairment—is far more common than fatal drowning.⁶ For every fatal drowning, there are at least 5 nonfatal drowning incidents in which medical care is needed, and 200 rescues are performed.^7–10

In the United States, drowning accounts for almost 13,000 emergency department visits per year and about 3,500 deaths.^7,8

In Brazil, with two-thirds the population of the United States, drowning accounts for far fewer hospital visits but about twice as many deaths. In Rio de Janeiro, where a highly effective and specialized prehospital service is provided at 3 drowning resuscitation centers staffed by medical doctors, an analysis of the 46,060 cases of rescue in 10 years from 1991 to 2000 showed that medical assistance was needed in only 930 cases (2%).¹⁰ The preventive and rescue actions of parents, bystanders, lifeguards, and prehospital rescue services significantly reduce the number of drowning deaths, but these groups do not consistently gather data on nonfatal drowning that can be included in a comprehensive database.

DROWNING IS A PROCESS

When a person in the water can no longer keep the airway clear, water that enters the mouth is voluntarily spit out or swallowed. Within a few seconds to minutes, the person can no longer clear the airways and water is aspirated, stimulating the cough reflex. Laryngo­spasm, another myth concerning drowning, is presumed to protect the airways but does not, as it is rare, occurring in less than 2% of cases.^11,12

If the person is not rescued, aspiration of water continues, and hypoxemia leads to loss of consciousness and apnea within seconds to a few minutes, followed by cardiac arrest. As a consequence, hypoxemic cardiac arrest generally occurs after a period of tachycardia followed by bradycardia and pulseless electrical activity, usually leading to asystole.^13,14

The entire drowning process, from water distress to cardiac arrest, usually takes a few minutes, but in rare situations, such as rapid hypothermia, it can go on for up to an hour.¹⁵ Most drowning patients have an otherwise healthy heart, and the apnea and hypoxemia precede the cardiac arrest by only a few seconds to minutes; thus, cardiac arrest is caused by the hypoxemic insult and not by ventricular dysrhythmias.^6,16

Drowning can be interrupted at any point between distress and death. If the person is rescued early, the clinical picture is determined by the reactivity of the airway and the amount of water that has been aspirated, but not by the type of water (salt or fresh).

Another myth is that drowning in salt water is different from drowning in fresh water. Both salt water and fresh water cause similar surfactant destruction and washout and disrupt the alveolar-capillary membrane. Disruption of the alveolar-capillary membrane increases its permeability and exacerbates shifting of fluid, plasma, and electrolytes into the alveoli.¹³ The clinical picture of the damage is one of regional or generalized pulmonary edema, which interferes with gas exchange in the lungs.^6,13,17

Animal studies by Modell et al showed that aspiration of just 2.2 mL of water per kilogram of body weight is sufficient to cause severe disturbances in oxygen exchange,¹⁷ reflected in a rise in arterial pH and a drop in partial pressure of oxygen. The situation must be similar in humans. In a 70-kg person, this is only about 154 mL of water—about two-thirds of a cup.

The combined effects of fluid in the lungs, the loss of surfactant, and the increase in capillary-alveolar permeability can result in decreased lung compliance, increased right-to-left shunting in the lungs, atelectasis, alveolitis, hypoxemia, and cerebral hypoxia.¹³

If the victim needs cardiopulmonary resuscitation, the possibility of neurologic damage is similar to that in other cardiac arrest situations, but exceptions exist. For example, in rare cases, hypothermia provides a protective mechanism that allows victims to survive prolonged submersion.^4,15

The duration of submersion is the best predictor of death.¹⁸ Underwater, people are not taking in oxygen, and cerebral hypoxia causes both morbidity and death. For this reason, reversing cerebral hypoxia with effective ventilation, oxygen, and chest compression is the priority of treatment.

“Near drowning,” “dry drowning,” “wet drowning,” “delayed drowning,” and “secondary drowning” are not medically accepted diagnoses,^3,4,19 and many organizations and lifesaving institutions around the world discourage the use of these terms.^19,20 Unfortunately, these terms still slip past the editors of medical journals and are thus perpetuated. The terms are most pervasive in the nonmedical media, where drowning seems to be synonymous with death.^3,19,21 We urge all authors and stakeholders to abandon these terms in favor of understanding and communicating drowning as a process that can vary in severity and have a fatal or nonfatal outcome.

Near-drowning

Historically, drowning meant death, while near-drowning meant the victim survived, at least initially (usually for at least 24 hours).

Before 2002, there were 13 different published definitions of near-drowning.^21,22 This variability has caused a great deal of confusion when trying to describe and monitor drowning.

A person can drown and survive, just as a person can have cardiac arrest and survive.^4,21 Just as there is no recognized condition of “near-cardiac arrest,” there is also no condition of near-drowning. Using near-drowning as a medical diagnosis hides the true burden of drowning and consequently amplifies difficulties in developing effective prevention, rescue, and treatment programs.

Dry drowning

Dry drowning has never been an accepted medical term, although it has been used to describe different parts of the drowning process. While many authors use it as a synonym for secondary drowning (described below), in the past it was usually used in cases in which no water was found in the lungs at autopsy in persons who were found dead in the water.^2–4,21 This occurred in about 10% to 15% of cases and was also called drowning “without water aspiration.”

Perhaps some victims suffer sudden cardiac death. It happens on land—why not in the water? Modell et al stated, “In the absence of the common finding of significant pulmonary edema in the victim’s respiratory system, to conclude his or her death was caused by ‘drowning without aspiration’ is unwise.”²³

Laryngospasm is another proposed explanation. It could play a role in the fewer than 2% of cases in which no other cause of death is found on clinical examination or autopsy,^11,12,19,23 but it does not occur in most cases of drowning, or it is brief and is terminated by the respiratory movements that allow the air in the lung to escape and water to be inhaled.

The problem with the term dry drowning is the harm caused by misdiagnosing cases of sudden death as drowning, when an alternative cause is present. Most importantly, the management is the same if small amounts of water are present or not; therefore, no clinical distinction is made between wet and dry drowning.

Secondary drowning

Secondary drowning, sometimes called delayed drowning, is another term that is not medically accepted. The historical use of this term reflects the reality that some patients may worsen due to pulmonary edema after aspirating small amounts of water.

Drowning starts with aspiration, and few or only mild symptoms may be present as soon as the person is removed from the water. Either the small amount of water in the lungs is absorbed and causes no complications or, rarely, the patient’s condition becomes progressively worse over the next few hours as the alveoli become inflamed and the alveolar-capillary membrane is disrupted. But people do not unexpectedly die of drowning days or weeks later with no preceding symptoms. The lungs and heart do not “fill up with water,” and water does not need to be pumped out of the lungs.

There has never been a case published in the medical literature of a patient who underwent clinical evaluation, was initially without symptoms, and later deteriorated and died more than 8 hours after the incident.^6,10,21 People who have drowned and have minimal symptoms get better (usually) or worse (rarely) within 4 to 8 hours. In a study of more than 41,000 lifeguard rescues, only 0.5% of symptomatic patients died.⁶

Drowning secondary to injury or sudden illness

Any injury, trauma, or sudden illness that can cause loss of consciousness or mental or physical weakness can lead to drowning. Physicians need to recognize these situations to treat them appropriately. Drowning that is secondary to other primary insults can be classified as²⁴:

• Drowning caused by injury or trauma (eg, a surfing, boating, or a hang-gliding accident)
• Drowning caused by a sudden illness such as cardiac disease (eg, myocardial ischemia, arrhythmias, prolonged QT syndrome, hypertrophic cardiomyopathy) or neurologic disease (eg, epilepsy, stroke)
• Diving disease (eg, decompression sickness, pulmonary overpressurization syndrome, compression barotrauma, narcosis [“rapture of the deep”], shallow water blackout, immersion pulmonary edema).

PREVENTION IS BEST

Drowning is a leading and preventable cause of death worldwide and for people of all ages. The danger is real, not esoteric or rare, and healthcare providers should use any opportunity to discuss with patients, parents, and the media the most important tool for treating drowning: primary prevention.

For example, small children should be continuously and uninterruptedly supervised within arm’s reach while in the water, even if a lifeguard is present. Other preventive measures are lifejackets, fences completely enclosing pools or ponds, and swimming and water safety lessons. Drowning often occurs in a deceptively pleasant environment that may not seem dangerous.

When preventive measures fail, responders (usually a health professional is involved) need to be able to perform the necessary steps to interrupt the drowning process.

The first challenge is to recognize when someone in the water is at risk of drowning and needs to be rescued.²⁵ Early self-rescue or rescue by others may stop the drowning process and prevent most cases of initial and subsequent water aspiration, respiratory distress, and medical complications.

DON’T BECOME A VICTIM

Rescuers must take care not to become victims themselves. Panicked swimmers can thrash about and injure the rescuer or clutch at anything they encounter, dragging the rescuer under. And the rescuer can succumb to the same hazards that got the victim into trouble, such as strong currents, deep water, or underwater hazards.

Certified lifeguards are trained to get victims out of the water safely. The American Red Cross slogan “Reach or throw, don’t go” means “Reach out with a pole or other object or throw something that floats; don’t get in the water yourself.”

WHAT TO TELL THE PUBLIC

While some journalists acknowledge that the terms dry drowning and secondary drowning are medically discredited, they still use them in their reports. The novelty of this story—and its appeal to media outlets—is precisely the unfamiliarity of these terms to the general public and the perceived mysterious, looming threat.

We often hear that these terms are more familiar to the public, which is likely true. More concerning, some physicians continue to use them (and older definitions of drowning that equate it with death) in media interviews, clinical care, and publications. The paradox is that we, the medical community, invented these terms, not patients or the media.

As clinicians and researchers, we should drive popular culture definitions, not the other way around. Rather than dismiss these terms as “semantics” or “technicalities,” we should take the opportunity to highlight the dangers of drowning and the importance of prevention, and to promote simpler language that is easier for us and our patients to understand.^19,21

Healthcare providers should understand and share modern drowning science and best practices, which will reduce fear, improve resource utilization, and prevent potentially deadly consequences due to misunderstanding or misinterpretation of incorrect terminology.

WHEN PATIENTS SHOULD SEEK CARE

Anyone who experiences cough, breathless­ness, or other worrisome symptoms such as abnormal mentation within 8 hours of a drowning incident (using the modern definition above) should seek medical advice immediately.

We tell people to seek care if symptoms seem any worse than the experience of a drink “going down the wrong pipe” at the dinner table.²¹ But symptoms can be minimal. Careful attention should be given to mild symptoms that get progressively worse during that time. These cases can rarely progress to acute respiratory distress syndrome.

Table 1 explores who needs further medical help after being rescued from the water.²⁶

In most of these cases, it is most appropriate to call an ambulance, but care may involve seeing a doctor depending on the severity of the symptoms.^6,21 Usually, drowning patients are observed for 4 to 8 hours in an emergency department and are discharged if normal. Symptoms that are more significant include persistent cough, foam at the mouth or nose, confusion, or abnormal behavior, and these require further medical evaluation.

Patients should also seek medical care even if they are 100% normal upon exiting the water but develop worrisome symptoms more than 8 hours later, and providers should consider diagnoses other than primary drowning. Spontaneous pneumothorax, chemical pneumonitis, bacterial or viral pneumonia, head injury, asthma, chest trauma, and acute respiratory distress syndrome have been mislabeled as delayed, dry, or secondary drowning.^3,4,19,21

In June 2017, a 4-year-old boy died 1 week after being knocked over and briefly submerged while playing in knee-deep water. This story was widely reported as a case of a rare occurrence called “dry” or “secondary” drowning, depending on the source.¹ The media accounts went viral, spreading fear in parents and others learning about these alleged conditions from the news and social media.

Many alleged cases of dry drowning are reported every year, but each has been found to have a recognized medical source that has a legitimate medically recognized diagnosis (which dry and secondary drowning are not).

Drowning is one of the most common causes of death in children, and so we ought to make sure that the information we share about it is accurate, as it is vital to effective prevention, rescue, and treatment.

Unfortunately, medical providers, medical journals, and the mass media continue to disseminate misinformation on drowning.² These reports often prevail over updated information and hinder accurate understanding of the drowning problem and its solutions.

Every death is tragic, especially the death of a child, and our heartfelt sympathies go out to the family in this alleged drowning case, as well as to all families suffering the loss of a loved one to drowning. However, in the 2017 case, the cause of death was found on autopsy to be myocarditis not related in any way to drowning. As often happens in such situations, this clarification did not receive any media attention, despite the wide reporting and penetration of the original, erroneous story.

We hope our review will reduce misunderstanding among the public and healthcare providers, contribute to improved data collection, and help to promote interventions aimed at prevention, rescue, and mitigation of drowning incidents.

WHAT IS DROWNING?

A consensus committee of the World Health Organization defined drowning as “the process of experiencing respiratory impairment from submersion/immersion in liquid.”³ The process begins when the victim’s airway goes below the surface of the liquid (submersion) or when water splashes over the face (immersion). If the victim is rescued at any time, the process is interrupted, and this is termed a nonfatal drowning. If the victim dies at any time, this is a fatal drowning. Any water-distress incident without evidence of respiratory impairment (ie, without aspiration) should be considered a water rescue and not a drowning.

Rarely do minimally symptomatic cases progress to death, just as most cases of chest pain do not progress to cardiac arrest.⁴ Nonetheless, rescued drowning victims can deteriorate, which is why we encourage people to seek medical care immediately upon warning signs, as we do with chest pain. For drowning, such warning signs are any water distress followed by difficulty breathing, excessive coughing, foam in the mouth, or abnormal behavior.

A SERIOUS PUBLIC HEALTH ISSUE

Drowning is a serious and neglected public health issue, claiming the lives of 372,000 people a year worldwide.⁵ It is a leading cause of death in children ages 1 to 14. The toll continues largely unabated, and in low- and middle-income nations it does not attract the levels of funding that go to other forms of injury prevention, such as road safety.

Nonfatal drowning—with symptoms ranging from mild cough to severe pulmonary edema, and complications ranging from none to severe neurologic impairment—is far more common than fatal drowning.⁶ For every fatal drowning, there are at least 5 nonfatal drowning incidents in which medical care is needed, and 200 rescues are performed.^7–10

In the United States, drowning accounts for almost 13,000 emergency department visits per year and about 3,500 deaths.^7,8

In Brazil, with two-thirds the population of the United States, drowning accounts for far fewer hospital visits but about twice as many deaths. In Rio de Janeiro, where a highly effective and specialized prehospital service is provided at 3 drowning resuscitation centers staffed by medical doctors, an analysis of the 46,060 cases of rescue in 10 years from 1991 to 2000 showed that medical assistance was needed in only 930 cases (2%).¹⁰ The preventive and rescue actions of parents, bystanders, lifeguards, and prehospital rescue services significantly reduce the number of drowning deaths, but these groups do not consistently gather data on nonfatal drowning that can be included in a comprehensive database.

DROWNING IS A PROCESS

When a person in the water can no longer keep the airway clear, water that enters the mouth is voluntarily spit out or swallowed. Within a few seconds to minutes, the person can no longer clear the airways and water is aspirated, stimulating the cough reflex. Laryngo­spasm, another myth concerning drowning, is presumed to protect the airways but does not, as it is rare, occurring in less than 2% of cases.^11,12

If the person is not rescued, aspiration of water continues, and hypoxemia leads to loss of consciousness and apnea within seconds to a few minutes, followed by cardiac arrest. As a consequence, hypoxemic cardiac arrest generally occurs after a period of tachycardia followed by bradycardia and pulseless electrical activity, usually leading to asystole.^13,14

The entire drowning process, from water distress to cardiac arrest, usually takes a few minutes, but in rare situations, such as rapid hypothermia, it can go on for up to an hour.¹⁵ Most drowning patients have an otherwise healthy heart, and the apnea and hypoxemia precede the cardiac arrest by only a few seconds to minutes; thus, cardiac arrest is caused by the hypoxemic insult and not by ventricular dysrhythmias.^6,16

Drowning can be interrupted at any point between distress and death. If the person is rescued early, the clinical picture is determined by the reactivity of the airway and the amount of water that has been aspirated, but not by the type of water (salt or fresh).

Another myth is that drowning in salt water is different from drowning in fresh water. Both salt water and fresh water cause similar surfactant destruction and washout and disrupt the alveolar-capillary membrane. Disruption of the alveolar-capillary membrane increases its permeability and exacerbates shifting of fluid, plasma, and electrolytes into the alveoli.¹³ The clinical picture of the damage is one of regional or generalized pulmonary edema, which interferes with gas exchange in the lungs.^6,13,17

Animal studies by Modell et al showed that aspiration of just 2.2 mL of water per kilogram of body weight is sufficient to cause severe disturbances in oxygen exchange,¹⁷ reflected in a rise in arterial pH and a drop in partial pressure of oxygen. The situation must be similar in humans. In a 70-kg person, this is only about 154 mL of water—about two-thirds of a cup.

The combined effects of fluid in the lungs, the loss of surfactant, and the increase in capillary-alveolar permeability can result in decreased lung compliance, increased right-to-left shunting in the lungs, atelectasis, alveolitis, hypoxemia, and cerebral hypoxia.¹³

If the victim needs cardiopulmonary resuscitation, the possibility of neurologic damage is similar to that in other cardiac arrest situations, but exceptions exist. For example, in rare cases, hypothermia provides a protective mechanism that allows victims to survive prolonged submersion.^4,15

The duration of submersion is the best predictor of death.¹⁸ Underwater, people are not taking in oxygen, and cerebral hypoxia causes both morbidity and death. For this reason, reversing cerebral hypoxia with effective ventilation, oxygen, and chest compression is the priority of treatment.

“Near drowning,” “dry drowning,” “wet drowning,” “delayed drowning,” and “secondary drowning” are not medically accepted diagnoses,^3,4,19 and many organizations and lifesaving institutions around the world discourage the use of these terms.^19,20 Unfortunately, these terms still slip past the editors of medical journals and are thus perpetuated. The terms are most pervasive in the nonmedical media, where drowning seems to be synonymous with death.^3,19,21 We urge all authors and stakeholders to abandon these terms in favor of understanding and communicating drowning as a process that can vary in severity and have a fatal or nonfatal outcome.

Near-drowning

Historically, drowning meant death, while near-drowning meant the victim survived, at least initially (usually for at least 24 hours).

Before 2002, there were 13 different published definitions of near-drowning.^21,22 This variability has caused a great deal of confusion when trying to describe and monitor drowning.

A person can drown and survive, just as a person can have cardiac arrest and survive.^4,21 Just as there is no recognized condition of “near-cardiac arrest,” there is also no condition of near-drowning. Using near-drowning as a medical diagnosis hides the true burden of drowning and consequently amplifies difficulties in developing effective prevention, rescue, and treatment programs.

Dry drowning

Dry drowning has never been an accepted medical term, although it has been used to describe different parts of the drowning process. While many authors use it as a synonym for secondary drowning (described below), in the past it was usually used in cases in which no water was found in the lungs at autopsy in persons who were found dead in the water.^2–4,21 This occurred in about 10% to 15% of cases and was also called drowning “without water aspiration.”

Perhaps some victims suffer sudden cardiac death. It happens on land—why not in the water? Modell et al stated, “In the absence of the common finding of significant pulmonary edema in the victim’s respiratory system, to conclude his or her death was caused by ‘drowning without aspiration’ is unwise.”²³

Laryngospasm is another proposed explanation. It could play a role in the fewer than 2% of cases in which no other cause of death is found on clinical examination or autopsy,^11,12,19,23 but it does not occur in most cases of drowning, or it is brief and is terminated by the respiratory movements that allow the air in the lung to escape and water to be inhaled.

The problem with the term dry drowning is the harm caused by misdiagnosing cases of sudden death as drowning, when an alternative cause is present. Most importantly, the management is the same if small amounts of water are present or not; therefore, no clinical distinction is made between wet and dry drowning.

Secondary drowning

Secondary drowning, sometimes called delayed drowning, is another term that is not medically accepted. The historical use of this term reflects the reality that some patients may worsen due to pulmonary edema after aspirating small amounts of water.

Drowning starts with aspiration, and few or only mild symptoms may be present as soon as the person is removed from the water. Either the small amount of water in the lungs is absorbed and causes no complications or, rarely, the patient’s condition becomes progressively worse over the next few hours as the alveoli become inflamed and the alveolar-capillary membrane is disrupted. But people do not unexpectedly die of drowning days or weeks later with no preceding symptoms. The lungs and heart do not “fill up with water,” and water does not need to be pumped out of the lungs.

There has never been a case published in the medical literature of a patient who underwent clinical evaluation, was initially without symptoms, and later deteriorated and died more than 8 hours after the incident.^6,10,21 People who have drowned and have minimal symptoms get better (usually) or worse (rarely) within 4 to 8 hours. In a study of more than 41,000 lifeguard rescues, only 0.5% of symptomatic patients died.⁶

Drowning secondary to injury or sudden illness

Any injury, trauma, or sudden illness that can cause loss of consciousness or mental or physical weakness can lead to drowning. Physicians need to recognize these situations to treat them appropriately. Drowning that is secondary to other primary insults can be classified as²⁴:

• Drowning caused by injury or trauma (eg, a surfing, boating, or a hang-gliding accident)
• Drowning caused by a sudden illness such as cardiac disease (eg, myocardial ischemia, arrhythmias, prolonged QT syndrome, hypertrophic cardiomyopathy) or neurologic disease (eg, epilepsy, stroke)
• Diving disease (eg, decompression sickness, pulmonary overpressurization syndrome, compression barotrauma, narcosis [“rapture of the deep”], shallow water blackout, immersion pulmonary edema).

PREVENTION IS BEST

Drowning is a leading and preventable cause of death worldwide and for people of all ages. The danger is real, not esoteric or rare, and healthcare providers should use any opportunity to discuss with patients, parents, and the media the most important tool for treating drowning: primary prevention.

For example, small children should be continuously and uninterruptedly supervised within arm’s reach while in the water, even if a lifeguard is present. Other preventive measures are lifejackets, fences completely enclosing pools or ponds, and swimming and water safety lessons. Drowning often occurs in a deceptively pleasant environment that may not seem dangerous.

When preventive measures fail, responders (usually a health professional is involved) need to be able to perform the necessary steps to interrupt the drowning process.

The first challenge is to recognize when someone in the water is at risk of drowning and needs to be rescued.²⁵ Early self-rescue or rescue by others may stop the drowning process and prevent most cases of initial and subsequent water aspiration, respiratory distress, and medical complications.

DON’T BECOME A VICTIM

Rescuers must take care not to become victims themselves. Panicked swimmers can thrash about and injure the rescuer or clutch at anything they encounter, dragging the rescuer under. And the rescuer can succumb to the same hazards that got the victim into trouble, such as strong currents, deep water, or underwater hazards.

Certified lifeguards are trained to get victims out of the water safely. The American Red Cross slogan “Reach or throw, don’t go” means “Reach out with a pole or other object or throw something that floats; don’t get in the water yourself.”

WHAT TO TELL THE PUBLIC

While some journalists acknowledge that the terms dry drowning and secondary drowning are medically discredited, they still use them in their reports. The novelty of this story—and its appeal to media outlets—is precisely the unfamiliarity of these terms to the general public and the perceived mysterious, looming threat.

We often hear that these terms are more familiar to the public, which is likely true. More concerning, some physicians continue to use them (and older definitions of drowning that equate it with death) in media interviews, clinical care, and publications. The paradox is that we, the medical community, invented these terms, not patients or the media.

As clinicians and researchers, we should drive popular culture definitions, not the other way around. Rather than dismiss these terms as “semantics” or “technicalities,” we should take the opportunity to highlight the dangers of drowning and the importance of prevention, and to promote simpler language that is easier for us and our patients to understand.^19,21

Healthcare providers should understand and share modern drowning science and best practices, which will reduce fear, improve resource utilization, and prevent potentially deadly consequences due to misunderstanding or misinterpretation of incorrect terminology.

WHEN PATIENTS SHOULD SEEK CARE

Anyone who experiences cough, breathless­ness, or other worrisome symptoms such as abnormal mentation within 8 hours of a drowning incident (using the modern definition above) should seek medical advice immediately.

We tell people to seek care if symptoms seem any worse than the experience of a drink “going down the wrong pipe” at the dinner table.²¹ But symptoms can be minimal. Careful attention should be given to mild symptoms that get progressively worse during that time. These cases can rarely progress to acute respiratory distress syndrome.

Table 1 explores who needs further medical help after being rescued from the water.²⁶

In most of these cases, it is most appropriate to call an ambulance, but care may involve seeing a doctor depending on the severity of the symptoms.^6,21 Usually, drowning patients are observed for 4 to 8 hours in an emergency department and are discharged if normal. Symptoms that are more significant include persistent cough, foam at the mouth or nose, confusion, or abnormal behavior, and these require further medical evaluation.

Patients should also seek medical care even if they are 100% normal upon exiting the water but develop worrisome symptoms more than 8 hours later, and providers should consider diagnoses other than primary drowning. Spontaneous pneumothorax, chemical pneumonitis, bacterial or viral pneumonia, head injury, asthma, chest trauma, and acute respiratory distress syndrome have been mislabeled as delayed, dry, or secondary drowning.^3,4,19,21

A 55-year-old man with no significant medical history presented to the emergency department with left-sided flank pain that had begun 3 days earlier. He described the pain as continuous, sharp, and aggravated by movement. He worked in construction, and before the pain started he had moved 8 sheets of drywall and lifted 5-gallon buckets of spackling compound. He denied any associated chest pain, palpitations, dyspnea, cough, or lightheadedness. His family history included sudden cardiac death in 2 second-degree relatives.

On arrival in the emergency department, his vital signs were normal, as were the rest of the findings on physical examination except for reproducible point tenderness below the left scapula.

Laboratory workup revealed normal blood cell counts, liver enzymes, and kidney function. His initial troponin test was negative.

The patient was referred to an electrophysiologist for further evaluation, but he returned to his home country (Haiti) after discharge and was lost to follow-up.

WOLFF-PARKINSON-WHITE PATTERN VS SYNDROME

WPW syndrome is a disorder of the conduction system leading to preexcitation of the ventricles by an accessory pathway between the atria and ventricles. It is characterized by preexcitation manifested on electrocardiography and by symptomatic arrhythmias.

In contrast, the WPW pattern is defined only by preexcitation findings on electrocardiography without symptomatic arrhythmias. Patients with WPW syndrome can present with palpitation, dizziness, and syncope resulting from underlying arrhythmia.¹ This is not seen in patients with the WPW pattern.

A short PR interval with or without delta waves can also be seen in the absence of an accessory pathway, eg, in hypoplastic left heart syndrome, atrioventricular canal defect, and Ebstein anomaly. These conditions are termed pseudopreexcitation syndrome.²

Our patient presented with severe musculoskeletal pain that precipitated the electrocardiographic changes of the WPW pattern and resolved with adequate pain control. The WPW pattern can be unmasked under different scenarios, including anesthesia, sympathomimetic drugs, and postoperatively.^3–5

Catecholamine challenge has been used to unmask high-risk features in WPW syndrome.³ Our patient may have had a transient spike in catecholamine levels because of severe musculoskeletal pain, leading to unmasking of accessory pathways and resulting in the WPW pattern on electrocardiography.

Most patients with the WPW pattern experience no symptoms, but a small percentage develop arrhythmias.

In rare cases, sudden cardiac death can be the presenting feature of WPW syndrome. The estimated risk of sudden cardiac death in patients with the WPW pattern is 1.25 per 1,000 person-years; ventricular fibrillation is the underlying mechanism.⁶ As our patient had a family history of sudden cardiac death, he was considered at high risk and was therefore referred to an electrophysiologist.

A 55-year-old man with no significant medical history presented to the emergency department with left-sided flank pain that had begun 3 days earlier. He described the pain as continuous, sharp, and aggravated by movement. He worked in construction, and before the pain started he had moved 8 sheets of drywall and lifted 5-gallon buckets of spackling compound. He denied any associated chest pain, palpitations, dyspnea, cough, or lightheadedness. His family history included sudden cardiac death in 2 second-degree relatives.

On arrival in the emergency department, his vital signs were normal, as were the rest of the findings on physical examination except for reproducible point tenderness below the left scapula.

Laboratory workup revealed normal blood cell counts, liver enzymes, and kidney function. His initial troponin test was negative.

The patient was referred to an electrophysiologist for further evaluation, but he returned to his home country (Haiti) after discharge and was lost to follow-up.

WOLFF-PARKINSON-WHITE PATTERN VS SYNDROME

WPW syndrome is a disorder of the conduction system leading to preexcitation of the ventricles by an accessory pathway between the atria and ventricles. It is characterized by preexcitation manifested on electrocardiography and by symptomatic arrhythmias.

In contrast, the WPW pattern is defined only by preexcitation findings on electrocardiography without symptomatic arrhythmias. Patients with WPW syndrome can present with palpitation, dizziness, and syncope resulting from underlying arrhythmia.¹ This is not seen in patients with the WPW pattern.

A short PR interval with or without delta waves can also be seen in the absence of an accessory pathway, eg, in hypoplastic left heart syndrome, atrioventricular canal defect, and Ebstein anomaly. These conditions are termed pseudopreexcitation syndrome.²

Our patient presented with severe musculoskeletal pain that precipitated the electrocardiographic changes of the WPW pattern and resolved with adequate pain control. The WPW pattern can be unmasked under different scenarios, including anesthesia, sympathomimetic drugs, and postoperatively.^3–5

Catecholamine challenge has been used to unmask high-risk features in WPW syndrome.³ Our patient may have had a transient spike in catecholamine levels because of severe musculoskeletal pain, leading to unmasking of accessory pathways and resulting in the WPW pattern on electrocardiography.

Most patients with the WPW pattern experience no symptoms, but a small percentage develop arrhythmias.

In rare cases, sudden cardiac death can be the presenting feature of WPW syndrome. The estimated risk of sudden cardiac death in patients with the WPW pattern is 1.25 per 1,000 person-years; ventricular fibrillation is the underlying mechanism.⁶ As our patient had a family history of sudden cardiac death, he was considered at high risk and was therefore referred to an electrophysiologist.

A 55-year-old man with no significant medical history presented to the emergency department with left-sided flank pain that had begun 3 days earlier. He described the pain as continuous, sharp, and aggravated by movement. He worked in construction, and before the pain started he had moved 8 sheets of drywall and lifted 5-gallon buckets of spackling compound. He denied any associated chest pain, palpitations, dyspnea, cough, or lightheadedness. His family history included sudden cardiac death in 2 second-degree relatives.

On arrival in the emergency department, his vital signs were normal, as were the rest of the findings on physical examination except for reproducible point tenderness below the left scapula.

Laboratory workup revealed normal blood cell counts, liver enzymes, and kidney function. His initial troponin test was negative.

The patient was referred to an electrophysiologist for further evaluation, but he returned to his home country (Haiti) after discharge and was lost to follow-up.

WOLFF-PARKINSON-WHITE PATTERN VS SYNDROME

WPW syndrome is a disorder of the conduction system leading to preexcitation of the ventricles by an accessory pathway between the atria and ventricles. It is characterized by preexcitation manifested on electrocardiography and by symptomatic arrhythmias.

In contrast, the WPW pattern is defined only by preexcitation findings on electrocardiography without symptomatic arrhythmias. Patients with WPW syndrome can present with palpitation, dizziness, and syncope resulting from underlying arrhythmia.¹ This is not seen in patients with the WPW pattern.

A short PR interval with or without delta waves can also be seen in the absence of an accessory pathway, eg, in hypoplastic left heart syndrome, atrioventricular canal defect, and Ebstein anomaly. These conditions are termed pseudopreexcitation syndrome.²

Our patient presented with severe musculoskeletal pain that precipitated the electrocardiographic changes of the WPW pattern and resolved with adequate pain control. The WPW pattern can be unmasked under different scenarios, including anesthesia, sympathomimetic drugs, and postoperatively.^3–5

Catecholamine challenge has been used to unmask high-risk features in WPW syndrome.³ Our patient may have had a transient spike in catecholamine levels because of severe musculoskeletal pain, leading to unmasking of accessory pathways and resulting in the WPW pattern on electrocardiography.

Most patients with the WPW pattern experience no symptoms, but a small percentage develop arrhythmias.

In rare cases, sudden cardiac death can be the presenting feature of WPW syndrome. The estimated risk of sudden cardiac death in patients with the WPW pattern is 1.25 per 1,000 person-years; ventricular fibrillation is the underlying mechanism.⁶ As our patient had a family history of sudden cardiac death, he was considered at high risk and was therefore referred to an electrophysiologist.

A 55-year-old man with a 20-year history of type 2 diabetes mellitus was admitted to the hospital after presenting to the emergency department with an acute change in mental status. Three days earlier, he had begun to feel abdominal discomfort and dizziness, which gradually worsened.

On presentation, his Glasgow Coma Scale score was 13 out of 15 (eye-opening response 3 of 4, verbal response 4 of 5, motor response 6 of 6), his blood pressure was 221/114 mm Hg, and other vital signs were normal. Physical examination including a neurologic examination was normal. No gait abnormality or ataxia was noted.

When asked about current medications, he said that 2 years earlier he had missed an appointment with his primary care physician and so had never obtained refills of his diabetes medications.

Results of laboratory testing were as follows:

• Blood glucose 1,011 mg/dL (reference range 65–110)
• Hemoglobin A_1c 17.8% (4%–5.6%)
• Sodium 126 mmol/L (135–145)
• Sodium corrected for serum glucose 141 mmol/L
• Potassium 3.2 mmol/L (3.5–5.0)
• Blood urea nitrogen 43.8 mg/dL (8–21)
• Calculated serum osmolality 324 mosm/kg (275–295).

Blood gas analysis showed no acidosis. Tests for urinary and serum ketones were negative. Computed tomography (CT) of the head without contrast was normal.

Based on the results of the evaluation, the patient’s condition was diagnosed as a hyperosmolar hyperglycemic state, presumably from dehydration and noncompliance with diabetes medications. His altered mental status was also attributed to this diagnosis. He was started on aggressive hydration and insulin infusion to correct the blood glucose level. Repeat laboratory testing 7 hours after admission revealed a blood glucose of 49 mg/dL, sodium 148 mmol/L, blood urea nitrogen 43 mg/dL, and calculated serum osmolality 290 mosm/kg.

The insulin infusion was suspended, and glucose infusion was started. With this treatment, his blood glucose level stabilized, but his Glasgow Coma Scale score was unchanged from the time of presentation. A neurologic examination at this time showed bilateral dysmetria. Cranial nerves were normal. Motor examination showed normal tone with a Medical Research Council score of 5 of 5 in all extremities. Sensory examination revealed a glove-and-stocking pattern of loss of vibratory sensation. Tendon reflexes were normal except for diminished bilateral knee-jerk and ankle-jerk responses.

OSMOTIC DEMYELINATION SYNDROME

Central pontine myelinolysis is a pivotal manifestation of the syndrome and is characterized by progressive lethargy, quadriparesis, dysarthria, ophthalmoplegia, dysphasia, ataxia, and reflex changes. Clinical symptoms of extrapontine myelinolysis are variable.⁴

Although CT may underestimate osmotic demyelination syndrome, the typical radiologic findings on brain MRI are hyperintense lesions in the central pons or associated extrapontine structures on T2-weighted and fluid-attenuated inversion recovery sequences.⁴

A precise definition of hyperosmolar hyperglycemia does not exist. The Joint British Diabetes Societies for Inpatient Care suggested the following features: a measured osmolality of 320 mosm/kg or higher, a blood glucose level of 541 mg/dL or higher, severe dehydration, and feeling unwell.⁵

Our patient’s clinical course and high hemoglobin A_1c suggested prolonged hyperglycemia and high serum osmolality before his admission. After his admission, aggressive hydration and insulin therapy corrected the hyperglycemia and serum osmolality too rapidly for his brain cells to adjust to the change. It was reasonable to suspect a hyperosmolar hyperglycemic state as one of the main causes of his mental status change and ataxia. This, along with lack of improvement in his impaired metal status and new-onset ataxia despite treatment, led to suspicion of osmotic demyelination syndrome. His diminished bilateral knee-jerk and ankle-jerk responses more likely represented diabetic neuropathy rather than osmotic demyelination syndrome.

Osmotic demyelination syndrome has seldom been reported as a complication of hyperosmolar hyperglycemia.^6–13 And extrapontine myelinolysis with hyperosmolar hyperglycemia is extremely rare, with only 2 reports to date to the best of our knowledge.^6,10

There is no specific treatment for osmotic demyelination syndrome except for supportive care and treatment of coexisting conditions. Once an osmotic derangement is identified, we recommend correcting chronically elevated serum glucose values gradually to avoid overtreatment, just as we would do with elevated serum sodium levels. Changes in neurologic findings, serum blood glucose level, and serum osmolality should be followed closely. A review showed that a favorable recovery from osmotic demyelination syndrome is possible even with severe neurologic deficits.⁴

TAKE-AWAY POINTS

• Osmotic demyelination syndrome is a rare but severe complication of a hyperosmolar hyperglycemic state.
• Physicians should be aware not only of changes in serum sodium, but also of changes in serum osmolality and serum glucose.
• When a new-onset neurologic deficit is found during treatment of a hyperosmolar hyperglycemic state, suspect osmotic demyelination syndrome, monitor changes in serum osmolality, and consider brain MRI.

A 55-year-old man with a 20-year history of type 2 diabetes mellitus was admitted to the hospital after presenting to the emergency department with an acute change in mental status. Three days earlier, he had begun to feel abdominal discomfort and dizziness, which gradually worsened.

On presentation, his Glasgow Coma Scale score was 13 out of 15 (eye-opening response 3 of 4, verbal response 4 of 5, motor response 6 of 6), his blood pressure was 221/114 mm Hg, and other vital signs were normal. Physical examination including a neurologic examination was normal. No gait abnormality or ataxia was noted.

When asked about current medications, he said that 2 years earlier he had missed an appointment with his primary care physician and so had never obtained refills of his diabetes medications.

Results of laboratory testing were as follows:

• Blood glucose 1,011 mg/dL (reference range 65–110)
• Hemoglobin A_1c 17.8% (4%–5.6%)
• Sodium 126 mmol/L (135–145)
• Sodium corrected for serum glucose 141 mmol/L
• Potassium 3.2 mmol/L (3.5–5.0)
• Blood urea nitrogen 43.8 mg/dL (8–21)
• Calculated serum osmolality 324 mosm/kg (275–295).

Blood gas analysis showed no acidosis. Tests for urinary and serum ketones were negative. Computed tomography (CT) of the head without contrast was normal.

Based on the results of the evaluation, the patient’s condition was diagnosed as a hyperosmolar hyperglycemic state, presumably from dehydration and noncompliance with diabetes medications. His altered mental status was also attributed to this diagnosis. He was started on aggressive hydration and insulin infusion to correct the blood glucose level. Repeat laboratory testing 7 hours after admission revealed a blood glucose of 49 mg/dL, sodium 148 mmol/L, blood urea nitrogen 43 mg/dL, and calculated serum osmolality 290 mosm/kg.

The insulin infusion was suspended, and glucose infusion was started. With this treatment, his blood glucose level stabilized, but his Glasgow Coma Scale score was unchanged from the time of presentation. A neurologic examination at this time showed bilateral dysmetria. Cranial nerves were normal. Motor examination showed normal tone with a Medical Research Council score of 5 of 5 in all extremities. Sensory examination revealed a glove-and-stocking pattern of loss of vibratory sensation. Tendon reflexes were normal except for diminished bilateral knee-jerk and ankle-jerk responses.

OSMOTIC DEMYELINATION SYNDROME

Central pontine myelinolysis is a pivotal manifestation of the syndrome and is characterized by progressive lethargy, quadriparesis, dysarthria, ophthalmoplegia, dysphasia, ataxia, and reflex changes. Clinical symptoms of extrapontine myelinolysis are variable.⁴

Although CT may underestimate osmotic demyelination syndrome, the typical radiologic findings on brain MRI are hyperintense lesions in the central pons or associated extrapontine structures on T2-weighted and fluid-attenuated inversion recovery sequences.⁴

A precise definition of hyperosmolar hyperglycemia does not exist. The Joint British Diabetes Societies for Inpatient Care suggested the following features: a measured osmolality of 320 mosm/kg or higher, a blood glucose level of 541 mg/dL or higher, severe dehydration, and feeling unwell.⁵

Our patient’s clinical course and high hemoglobin A_1c suggested prolonged hyperglycemia and high serum osmolality before his admission. After his admission, aggressive hydration and insulin therapy corrected the hyperglycemia and serum osmolality too rapidly for his brain cells to adjust to the change. It was reasonable to suspect a hyperosmolar hyperglycemic state as one of the main causes of his mental status change and ataxia. This, along with lack of improvement in his impaired metal status and new-onset ataxia despite treatment, led to suspicion of osmotic demyelination syndrome. His diminished bilateral knee-jerk and ankle-jerk responses more likely represented diabetic neuropathy rather than osmotic demyelination syndrome.

Osmotic demyelination syndrome has seldom been reported as a complication of hyperosmolar hyperglycemia.^6–13 And extrapontine myelinolysis with hyperosmolar hyperglycemia is extremely rare, with only 2 reports to date to the best of our knowledge.^6,10

There is no specific treatment for osmotic demyelination syndrome except for supportive care and treatment of coexisting conditions. Once an osmotic derangement is identified, we recommend correcting chronically elevated serum glucose values gradually to avoid overtreatment, just as we would do with elevated serum sodium levels. Changes in neurologic findings, serum blood glucose level, and serum osmolality should be followed closely. A review showed that a favorable recovery from osmotic demyelination syndrome is possible even with severe neurologic deficits.⁴

TAKE-AWAY POINTS

• Osmotic demyelination syndrome is a rare but severe complication of a hyperosmolar hyperglycemic state.
• Physicians should be aware not only of changes in serum sodium, but also of changes in serum osmolality and serum glucose.
• When a new-onset neurologic deficit is found during treatment of a hyperosmolar hyperglycemic state, suspect osmotic demyelination syndrome, monitor changes in serum osmolality, and consider brain MRI.

A 55-year-old man with a 20-year history of type 2 diabetes mellitus was admitted to the hospital after presenting to the emergency department with an acute change in mental status. Three days earlier, he had begun to feel abdominal discomfort and dizziness, which gradually worsened.

On presentation, his Glasgow Coma Scale score was 13 out of 15 (eye-opening response 3 of 4, verbal response 4 of 5, motor response 6 of 6), his blood pressure was 221/114 mm Hg, and other vital signs were normal. Physical examination including a neurologic examination was normal. No gait abnormality or ataxia was noted.

When asked about current medications, he said that 2 years earlier he had missed an appointment with his primary care physician and so had never obtained refills of his diabetes medications.

Results of laboratory testing were as follows:

• Blood glucose 1,011 mg/dL (reference range 65–110)
• Hemoglobin A_1c 17.8% (4%–5.6%)
• Sodium 126 mmol/L (135–145)
• Sodium corrected for serum glucose 141 mmol/L
• Potassium 3.2 mmol/L (3.5–5.0)
• Blood urea nitrogen 43.8 mg/dL (8–21)
• Calculated serum osmolality 324 mosm/kg (275–295).

Blood gas analysis showed no acidosis. Tests for urinary and serum ketones were negative. Computed tomography (CT) of the head without contrast was normal.

Based on the results of the evaluation, the patient’s condition was diagnosed as a hyperosmolar hyperglycemic state, presumably from dehydration and noncompliance with diabetes medications. His altered mental status was also attributed to this diagnosis. He was started on aggressive hydration and insulin infusion to correct the blood glucose level. Repeat laboratory testing 7 hours after admission revealed a blood glucose of 49 mg/dL, sodium 148 mmol/L, blood urea nitrogen 43 mg/dL, and calculated serum osmolality 290 mosm/kg.

The insulin infusion was suspended, and glucose infusion was started. With this treatment, his blood glucose level stabilized, but his Glasgow Coma Scale score was unchanged from the time of presentation. A neurologic examination at this time showed bilateral dysmetria. Cranial nerves were normal. Motor examination showed normal tone with a Medical Research Council score of 5 of 5 in all extremities. Sensory examination revealed a glove-and-stocking pattern of loss of vibratory sensation. Tendon reflexes were normal except for diminished bilateral knee-jerk and ankle-jerk responses.

OSMOTIC DEMYELINATION SYNDROME

Central pontine myelinolysis is a pivotal manifestation of the syndrome and is characterized by progressive lethargy, quadriparesis, dysarthria, ophthalmoplegia, dysphasia, ataxia, and reflex changes. Clinical symptoms of extrapontine myelinolysis are variable.⁴

Although CT may underestimate osmotic demyelination syndrome, the typical radiologic findings on brain MRI are hyperintense lesions in the central pons or associated extrapontine structures on T2-weighted and fluid-attenuated inversion recovery sequences.⁴

A precise definition of hyperosmolar hyperglycemia does not exist. The Joint British Diabetes Societies for Inpatient Care suggested the following features: a measured osmolality of 320 mosm/kg or higher, a blood glucose level of 541 mg/dL or higher, severe dehydration, and feeling unwell.⁵

Our patient’s clinical course and high hemoglobin A_1c suggested prolonged hyperglycemia and high serum osmolality before his admission. After his admission, aggressive hydration and insulin therapy corrected the hyperglycemia and serum osmolality too rapidly for his brain cells to adjust to the change. It was reasonable to suspect a hyperosmolar hyperglycemic state as one of the main causes of his mental status change and ataxia. This, along with lack of improvement in his impaired metal status and new-onset ataxia despite treatment, led to suspicion of osmotic demyelination syndrome. His diminished bilateral knee-jerk and ankle-jerk responses more likely represented diabetic neuropathy rather than osmotic demyelination syndrome.

Osmotic demyelination syndrome has seldom been reported as a complication of hyperosmolar hyperglycemia.^6–13 And extrapontine myelinolysis with hyperosmolar hyperglycemia is extremely rare, with only 2 reports to date to the best of our knowledge.^6,10

There is no specific treatment for osmotic demyelination syndrome except for supportive care and treatment of coexisting conditions. Once an osmotic derangement is identified, we recommend correcting chronically elevated serum glucose values gradually to avoid overtreatment, just as we would do with elevated serum sodium levels. Changes in neurologic findings, serum blood glucose level, and serum osmolality should be followed closely. A review showed that a favorable recovery from osmotic demyelination syndrome is possible even with severe neurologic deficits.⁴

TAKE-AWAY POINTS

• Osmotic demyelination syndrome is a rare but severe complication of a hyperosmolar hyperglycemic state.
• Physicians should be aware not only of changes in serum sodium, but also of changes in serum osmolality and serum glucose.
• When a new-onset neurologic deficit is found during treatment of a hyperosmolar hyperglycemic state, suspect osmotic demyelination syndrome, monitor changes in serum osmolality, and consider brain MRI.

We recommend the following combination treatment:

Normal saline (0.9% NaCl) 1 to 2 L by intravenous (IV) infusion over 2 to 4 hours.  This can be repeated every 6 to 12 hours.

Ketorolac 30-mg IV bolus, which can be repeated every 6 hours. However, patients with coronary artery disease, uncontrolled hypertension, acute renal failure, or cerebrovascular disease should instead receive aceta­minophen 1,000 mg, naproxen sodium 550 mg, or aspirin 325 mg by mouth.

Prochlorperazine or metoclopramide 10-mg IV infusion. This can be repeated every 6 hours. However, to reduce the extrapyramidal adverse effects of these drugs, patients should first receive diphenhydramine 25- to 50-mg IV bolus, which can be repeated every 6 to 8 hours.

Sodium valproate 500 to 1,000 mg by IV infusion over 20 minutes. This can be repeated after 8 hours.

Dexamethasone 4-mg IV bolus every 6 hours, or 10-mg IV bolus once in 24 hours.

Magnesium sulfate 500 to 1,000 mg by IV infusion over 1 hour. This can be repeated every 6 to 12 hours.

If the migraine has not improved after 3 cycles of this regimen, a neurologic consultation should be considered. Other options include dihydroergotamine and occipital nerve blocks¹ performed at the bedside.

GENERAL PRINCIPLES

Managing acute intractable migraine can be frustrating for both the practitioner and the patient. Some general principles are helpful.

Use a combination of drugs. Aborting a severe migraine attack often requires a combination of medications that work synergistically.

Use IV and intramuscular formulations rather than oral formulations: they are more rapidly absorbed, provide faster pain relief, and can be given when the nausea that often accompanies migraine precludes oral treatments.

Rule out secondary causes. The mnemonic SNOOP—systemic signs, neurologic signs, onset, older age, progression of existing headache disorder—is useful for assessing underlying causes.² Any patient presenting with intractable migraine should also have a thorough neuro­logic examination.

Screening electrocardiography may be helpful, as the pretreatment QTc interval may direct the choice of intravenous treatment. If the patient has a prolonged QTc or is taking another drug that could prolong the QTc, certain medications, specifically dopamine receptor antagonists and diphenhydra­mine, should be avoided.

Ask the patient what has worked previously. A particular agent may have been effective in aborting the migraine; thus, a single dose of it could abort the headache, expediting discharge.

Establish if a triptan or ergot derivative has been used during the 24 hours before presentation, as repeated dosing within this interval is not recommended.³

Establish the baseline headache severity. Complete headache relief is difficult to achieve in a patient with chronic daily headache, and establishing a more realistic goal (eg, 50% relief) from the outset is useful.

Antiemetics

Dopamine receptor antagonists are assumed to merely treat nausea in patients with migraine; however, they act independently to abort migraine and thus should be considered, irrespective of the presence of nausea.

The two most commonly used agents are prochlorperazine and metoclopramide. The American Academy of Neurology guidelines recommend prochlorperazine as first-line therapy for acute migraine. Metoclopramide is rated slightly lower and is considered to have moderate benefit.⁴ The Canadian Headache Society cites a high level of evidence supporting prochlorperazine and a moderate level of evidence supporting metoclopramide.⁵ The American Headache Society assessment of parenteral pharmacotherapies gives prochlorperazine and metoclopramide a level B recommendation of “should offer” (a recommendation only additionally assigned to subcutaneous sumatriptan).³ Hence, either agent can be used.

To reduce the risk of posttreatment akathisia, diphenhydramine or benztropine may be given before starting a dopamine receptor antagonist. Diphenhydramine may be independently effective in migraine treatment,^6,7 but  data on this are limited.

Ketorolac, ibuprofen

Ketorolac and ibuprofen are the only available nonsteroidal antiinflammatory drugs (NSAIDs) for IV administration. The Canadian Headache Society guidelines strongly recommend ketorolac for the treatment of migraine in emergency settings.⁵ Doses range from 30 mg to 60 mg.¹ Ibuprofen 400 to 800 mg by IV infusion is an acceptable alternative. These medications should be avoided in patients with renal failure or severe coronary artery disease.

Oral naproxen sodium is a possible alternative in patients with cardiovascular disease, as it has been shown to carry a lower cardiovascular risk than other NSAIDs.⁸

The same concerns in patients with renal dysfunction apply to any NSAID, as the enzyme cyclooxygenase plays a constitutive role in glomerular function.

Antiepileptic drugs

The antiepileptic drugs sodium valproate and levetiracetam are available in IV formulations that have demonstrated efficacy in the treatment of status migrainosus¹ (ie, migraine lasting more than 72 hours). Valproate has the strongest track record, is well tolerated, and is effective in rapidly aborting migraine.⁹

Volume repletion

Although its use is anecdotal and to date no trial has measured its efficacy, IV volume repletion is often used in acute migraine, as most headache experts surmise it to be highly effective, especially in patients with prolonged nausea or vomiting.¹

Magnesium

IV magnesium is effective, particularly for migraine with aura.¹⁰ Hypotension is a common side effect, and pretreatment or concurrent treatment with IV fluids is advised. Doses from 500 mg to 1,000 mg have demonstrated efficacy.¹⁰

Corticosteroids

Corticosteroids can be used in the treatment of status migrainosus. Most studies have shown benefit in preventing recurrences rather than merely aborting migraine.¹¹ A systematic review suggested that recurrent headaches are milder with corticosteroid treatment; 19 of 25 studies indicated favorable benefit, and 6 of 19 studies indicated noninferior outcomes.¹²

Both IV methylprednisolone and IV dexamethasone may be considered.¹² Dexamethasone appears to be particularly effective in preventing headache recurrence when combined with other IV therapies.¹³ It can be given as a single dose of 10 mg, or as repeated doses of 4 mg up to 16 mg/day.¹ Patients with active psychosis or uncontrolled diabetes should be closely monitored for these conditions, which corticosteroids can worsen.

Serotoninergic agents

Serotonin agonists including subcutaneous sumatriptan and IV dihydroergotamine are highly effective, with proven statistical and clinical benefit.⁴ They should be considered in patients with no known history of coronary artery disease or other vaso-occlusive vascular disorder.¹

Ideally, IV dihydroergotamine should be administered after consultation with a neurologist or headache specialist, given the pretreatment and cotreatment requirements often necessary to suppress its side effects. Careful titration is important to prevent transient headache exacerbations during infusion, as well as abdominal cramping, nausea, and diarrhea.

Avoid opioids

Opioids should be avoided. Evidence supporting their use in acute migraine is extremely limited,³ and the risks of migraine becoming chronic and of addiction are high.¹⁴ Safer, more effective alternatives have been detailed above.

A detailed algorithm for the management of patients with acute migraine has been published¹⁴ and is aimed at decreasing acute treatment with opioids and barbiturates.

We recommend the following combination treatment:

Normal saline (0.9% NaCl) 1 to 2 L by intravenous (IV) infusion over 2 to 4 hours.  This can be repeated every 6 to 12 hours.

Ketorolac 30-mg IV bolus, which can be repeated every 6 hours. However, patients with coronary artery disease, uncontrolled hypertension, acute renal failure, or cerebrovascular disease should instead receive aceta­minophen 1,000 mg, naproxen sodium 550 mg, or aspirin 325 mg by mouth.

Prochlorperazine or metoclopramide 10-mg IV infusion. This can be repeated every 6 hours. However, to reduce the extrapyramidal adverse effects of these drugs, patients should first receive diphenhydramine 25- to 50-mg IV bolus, which can be repeated every 6 to 8 hours.

Sodium valproate 500 to 1,000 mg by IV infusion over 20 minutes. This can be repeated after 8 hours.

Dexamethasone 4-mg IV bolus every 6 hours, or 10-mg IV bolus once in 24 hours.

Magnesium sulfate 500 to 1,000 mg by IV infusion over 1 hour. This can be repeated every 6 to 12 hours.

If the migraine has not improved after 3 cycles of this regimen, a neurologic consultation should be considered. Other options include dihydroergotamine and occipital nerve blocks¹ performed at the bedside.

GENERAL PRINCIPLES

Managing acute intractable migraine can be frustrating for both the practitioner and the patient. Some general principles are helpful.

Use a combination of drugs. Aborting a severe migraine attack often requires a combination of medications that work synergistically.

Use IV and intramuscular formulations rather than oral formulations: they are more rapidly absorbed, provide faster pain relief, and can be given when the nausea that often accompanies migraine precludes oral treatments.

Rule out secondary causes. The mnemonic SNOOP—systemic signs, neurologic signs, onset, older age, progression of existing headache disorder—is useful for assessing underlying causes.² Any patient presenting with intractable migraine should also have a thorough neuro­logic examination.

Screening electrocardiography may be helpful, as the pretreatment QTc interval may direct the choice of intravenous treatment. If the patient has a prolonged QTc or is taking another drug that could prolong the QTc, certain medications, specifically dopamine receptor antagonists and diphenhydra­mine, should be avoided.

Ask the patient what has worked previously. A particular agent may have been effective in aborting the migraine; thus, a single dose of it could abort the headache, expediting discharge.

Establish if a triptan or ergot derivative has been used during the 24 hours before presentation, as repeated dosing within this interval is not recommended.³

Establish the baseline headache severity. Complete headache relief is difficult to achieve in a patient with chronic daily headache, and establishing a more realistic goal (eg, 50% relief) from the outset is useful.

Antiemetics

Dopamine receptor antagonists are assumed to merely treat nausea in patients with migraine; however, they act independently to abort migraine and thus should be considered, irrespective of the presence of nausea.

The two most commonly used agents are prochlorperazine and metoclopramide. The American Academy of Neurology guidelines recommend prochlorperazine as first-line therapy for acute migraine. Metoclopramide is rated slightly lower and is considered to have moderate benefit.⁴ The Canadian Headache Society cites a high level of evidence supporting prochlorperazine and a moderate level of evidence supporting metoclopramide.⁵ The American Headache Society assessment of parenteral pharmacotherapies gives prochlorperazine and metoclopramide a level B recommendation of “should offer” (a recommendation only additionally assigned to subcutaneous sumatriptan).³ Hence, either agent can be used.

To reduce the risk of posttreatment akathisia, diphenhydramine or benztropine may be given before starting a dopamine receptor antagonist. Diphenhydramine may be independently effective in migraine treatment,^6,7 but  data on this are limited.

Ketorolac, ibuprofen

Ketorolac and ibuprofen are the only available nonsteroidal antiinflammatory drugs (NSAIDs) for IV administration. The Canadian Headache Society guidelines strongly recommend ketorolac for the treatment of migraine in emergency settings.⁵ Doses range from 30 mg to 60 mg.¹ Ibuprofen 400 to 800 mg by IV infusion is an acceptable alternative. These medications should be avoided in patients with renal failure or severe coronary artery disease.

Oral naproxen sodium is a possible alternative in patients with cardiovascular disease, as it has been shown to carry a lower cardiovascular risk than other NSAIDs.⁸

The same concerns in patients with renal dysfunction apply to any NSAID, as the enzyme cyclooxygenase plays a constitutive role in glomerular function.

Antiepileptic drugs

The antiepileptic drugs sodium valproate and levetiracetam are available in IV formulations that have demonstrated efficacy in the treatment of status migrainosus¹ (ie, migraine lasting more than 72 hours). Valproate has the strongest track record, is well tolerated, and is effective in rapidly aborting migraine.⁹

Volume repletion

Although its use is anecdotal and to date no trial has measured its efficacy, IV volume repletion is often used in acute migraine, as most headache experts surmise it to be highly effective, especially in patients with prolonged nausea or vomiting.¹

Magnesium

IV magnesium is effective, particularly for migraine with aura.¹⁰ Hypotension is a common side effect, and pretreatment or concurrent treatment with IV fluids is advised. Doses from 500 mg to 1,000 mg have demonstrated efficacy.¹⁰

Corticosteroids

Corticosteroids can be used in the treatment of status migrainosus. Most studies have shown benefit in preventing recurrences rather than merely aborting migraine.¹¹ A systematic review suggested that recurrent headaches are milder with corticosteroid treatment; 19 of 25 studies indicated favorable benefit, and 6 of 19 studies indicated noninferior outcomes.¹²

Both IV methylprednisolone and IV dexamethasone may be considered.¹² Dexamethasone appears to be particularly effective in preventing headache recurrence when combined with other IV therapies.¹³ It can be given as a single dose of 10 mg, or as repeated doses of 4 mg up to 16 mg/day.¹ Patients with active psychosis or uncontrolled diabetes should be closely monitored for these conditions, which corticosteroids can worsen.

Serotoninergic agents

Serotonin agonists including subcutaneous sumatriptan and IV dihydroergotamine are highly effective, with proven statistical and clinical benefit.⁴ They should be considered in patients with no known history of coronary artery disease or other vaso-occlusive vascular disorder.¹

Ideally, IV dihydroergotamine should be administered after consultation with a neurologist or headache specialist, given the pretreatment and cotreatment requirements often necessary to suppress its side effects. Careful titration is important to prevent transient headache exacerbations during infusion, as well as abdominal cramping, nausea, and diarrhea.

Avoid opioids

Opioids should be avoided. Evidence supporting their use in acute migraine is extremely limited,³ and the risks of migraine becoming chronic and of addiction are high.¹⁴ Safer, more effective alternatives have been detailed above.

A detailed algorithm for the management of patients with acute migraine has been published¹⁴ and is aimed at decreasing acute treatment with opioids and barbiturates.

We recommend the following combination treatment:

Normal saline (0.9% NaCl) 1 to 2 L by intravenous (IV) infusion over 2 to 4 hours.  This can be repeated every 6 to 12 hours.

Ketorolac 30-mg IV bolus, which can be repeated every 6 hours. However, patients with coronary artery disease, uncontrolled hypertension, acute renal failure, or cerebrovascular disease should instead receive aceta­minophen 1,000 mg, naproxen sodium 550 mg, or aspirin 325 mg by mouth.

Prochlorperazine or metoclopramide 10-mg IV infusion. This can be repeated every 6 hours. However, to reduce the extrapyramidal adverse effects of these drugs, patients should first receive diphenhydramine 25- to 50-mg IV bolus, which can be repeated every 6 to 8 hours.

Sodium valproate 500 to 1,000 mg by IV infusion over 20 minutes. This can be repeated after 8 hours.

Dexamethasone 4-mg IV bolus every 6 hours, or 10-mg IV bolus once in 24 hours.

Magnesium sulfate 500 to 1,000 mg by IV infusion over 1 hour. This can be repeated every 6 to 12 hours.

If the migraine has not improved after 3 cycles of this regimen, a neurologic consultation should be considered. Other options include dihydroergotamine and occipital nerve blocks¹ performed at the bedside.

GENERAL PRINCIPLES

Managing acute intractable migraine can be frustrating for both the practitioner and the patient. Some general principles are helpful.

Use a combination of drugs. Aborting a severe migraine attack often requires a combination of medications that work synergistically.

Use IV and intramuscular formulations rather than oral formulations: they are more rapidly absorbed, provide faster pain relief, and can be given when the nausea that often accompanies migraine precludes oral treatments.

Rule out secondary causes. The mnemonic SNOOP—systemic signs, neurologic signs, onset, older age, progression of existing headache disorder—is useful for assessing underlying causes.² Any patient presenting with intractable migraine should also have a thorough neuro­logic examination.

Screening electrocardiography may be helpful, as the pretreatment QTc interval may direct the choice of intravenous treatment. If the patient has a prolonged QTc or is taking another drug that could prolong the QTc, certain medications, specifically dopamine receptor antagonists and diphenhydra­mine, should be avoided.

Ask the patient what has worked previously. A particular agent may have been effective in aborting the migraine; thus, a single dose of it could abort the headache, expediting discharge.

Establish if a triptan or ergot derivative has been used during the 24 hours before presentation, as repeated dosing within this interval is not recommended.³

Establish the baseline headache severity. Complete headache relief is difficult to achieve in a patient with chronic daily headache, and establishing a more realistic goal (eg, 50% relief) from the outset is useful.

Antiemetics

Dopamine receptor antagonists are assumed to merely treat nausea in patients with migraine; however, they act independently to abort migraine and thus should be considered, irrespective of the presence of nausea.

The two most commonly used agents are prochlorperazine and metoclopramide. The American Academy of Neurology guidelines recommend prochlorperazine as first-line therapy for acute migraine. Metoclopramide is rated slightly lower and is considered to have moderate benefit.⁴ The Canadian Headache Society cites a high level of evidence supporting prochlorperazine and a moderate level of evidence supporting metoclopramide.⁵ The American Headache Society assessment of parenteral pharmacotherapies gives prochlorperazine and metoclopramide a level B recommendation of “should offer” (a recommendation only additionally assigned to subcutaneous sumatriptan).³ Hence, either agent can be used.

To reduce the risk of posttreatment akathisia, diphenhydramine or benztropine may be given before starting a dopamine receptor antagonist. Diphenhydramine may be independently effective in migraine treatment,^6,7 but  data on this are limited.

Ketorolac, ibuprofen

Ketorolac and ibuprofen are the only available nonsteroidal antiinflammatory drugs (NSAIDs) for IV administration. The Canadian Headache Society guidelines strongly recommend ketorolac for the treatment of migraine in emergency settings.⁵ Doses range from 30 mg to 60 mg.¹ Ibuprofen 400 to 800 mg by IV infusion is an acceptable alternative. These medications should be avoided in patients with renal failure or severe coronary artery disease.

Oral naproxen sodium is a possible alternative in patients with cardiovascular disease, as it has been shown to carry a lower cardiovascular risk than other NSAIDs.⁸

The same concerns in patients with renal dysfunction apply to any NSAID, as the enzyme cyclooxygenase plays a constitutive role in glomerular function.

Antiepileptic drugs

The antiepileptic drugs sodium valproate and levetiracetam are available in IV formulations that have demonstrated efficacy in the treatment of status migrainosus¹ (ie, migraine lasting more than 72 hours). Valproate has the strongest track record, is well tolerated, and is effective in rapidly aborting migraine.⁹

Volume repletion

Although its use is anecdotal and to date no trial has measured its efficacy, IV volume repletion is often used in acute migraine, as most headache experts surmise it to be highly effective, especially in patients with prolonged nausea or vomiting.¹

Magnesium

IV magnesium is effective, particularly for migraine with aura.¹⁰ Hypotension is a common side effect, and pretreatment or concurrent treatment with IV fluids is advised. Doses from 500 mg to 1,000 mg have demonstrated efficacy.¹⁰

Corticosteroids

Corticosteroids can be used in the treatment of status migrainosus. Most studies have shown benefit in preventing recurrences rather than merely aborting migraine.¹¹ A systematic review suggested that recurrent headaches are milder with corticosteroid treatment; 19 of 25 studies indicated favorable benefit, and 6 of 19 studies indicated noninferior outcomes.¹²

Both IV methylprednisolone and IV dexamethasone may be considered.¹² Dexamethasone appears to be particularly effective in preventing headache recurrence when combined with other IV therapies.¹³ It can be given as a single dose of 10 mg, or as repeated doses of 4 mg up to 16 mg/day.¹ Patients with active psychosis or uncontrolled diabetes should be closely monitored for these conditions, which corticosteroids can worsen.

Serotoninergic agents

Serotonin agonists including subcutaneous sumatriptan and IV dihydroergotamine are highly effective, with proven statistical and clinical benefit.⁴ They should be considered in patients with no known history of coronary artery disease or other vaso-occlusive vascular disorder.¹

Ideally, IV dihydroergotamine should be administered after consultation with a neurologist or headache specialist, given the pretreatment and cotreatment requirements often necessary to suppress its side effects. Careful titration is important to prevent transient headache exacerbations during infusion, as well as abdominal cramping, nausea, and diarrhea.

Avoid opioids

Opioids should be avoided. Evidence supporting their use in acute migraine is extremely limited,³ and the risks of migraine becoming chronic and of addiction are high.¹⁴ Safer, more effective alternatives have been detailed above.

A detailed algorithm for the management of patients with acute migraine has been published¹⁴ and is aimed at decreasing acute treatment with opioids and barbiturates.

Staphylococcus aureus is the most common infective agent in native and prosthetic valve endocarditis, and 13% to 22% of patients with S aureus bacteremia have infective endocarditis.¹

See related editorial

Transthoracic echocardiography (TTE) is a good starting point in the workup of suspected infective endocarditis, but transesophageal echocardiography (TEE) plays a key role in diagnosis and is indicated in patients with a high pretest probability of infective endocarditis, as in the following scenarios:

• Clinical picture consistent with infective endocarditis
• Presence of previously placed port or other indwelling vascular device
• Presence of a prosthetic valve or other prosthetic material 
• Presence of a pacemaker
• History of valve disease
• Injection drug use
• Positive blood cultures after 72 hours despite appropriate antibiotic treatment
• Abnormal TTE result requiring better visualization of valvular anatomy and function and confirmation of local complications
• Absence of another reasonable explanation for S aureus bacteremia.

Forgoing TEE is reasonable in patients with normal results on TTE, no predisposing risk factors, a reasonable alternative explanation for S aureus bacteremia, and a low pretest probability of infective endocarditis.¹ TEE may also be unnecessary if there is another disease focus requiring extended treatment (eg, vertebral infection) and there are no findings suggesting complicated infective endocarditis, eg, persistent bacteremia, symptoms of heart failure, and conduction abnormality.¹

TEE also may be unnecessary in patients at low risk who have identifiable foci of bacteremia due to soft-tissue infection or a newly placed vascular catheter and whose bacteremia clears within 72 hours of the start of antibiotic therapy. These patients may be followed clinically for the development of new findings such as metastatic foci of infection (eg, septic pulmonary emboli, renal infarction, splenic abscess or infarction), the new onset of heart failure or cardiac conduction abnormality, or recurrence of previously cleared S aureus bacteremia. If these should develop, then a more invasive study such as TEE may be warranted.

INFECTIVE ENDOCARDITIS: EPIDEMIOLOGY AND MICROBIOLOGY

The US incidence rate of infective endocarditis has steadily increased, with an estimated 457,052 hospitalizations from 2000 to 2011. During that period, from 2000 to 2007, there was a marked increase in valve replacement surgeries.² This trend is likely explained by an increase in the at-risk population—eg, elderly patients, patients with opiate dependence or diabetes, and patients on hemodialysis.

Although S aureus is the predominant pathogen in infective endocarditis,^2–5S aureus bacteremia is often observed in patients with skin or soft-tissue infection, prosthetic device infection, vascular graft or catheter infection, and bone and joint infections. S aureus bacteremia necessitates a search for the source of infection.

S aureus is a major pathogen in bloodstream infections, and up to 14% of patients with S aureus bacteremia have infective endocarditis as the primary source of infection.³ The pathogenesis of S aureus infective endocarditis is thought to be mediated by cell-wall factors that promote adhesion to the extracellular matrix of intravascular structures.³

A new localizing symptom such as back pain, joint pain, or swelling in a patient with S aureus bacteremia should trigger an investigation for metastatic infection.

Infectious disease consultation in patients with S aureus bacteremia is associated with improved outcomes and, thus, should be pursued.³

A cardiac surgery consult is recommended early on in cases of infective endocarditis caused by vancomycin-resistant enterococci, Pseudomonas aeruginosa, and fungi, as well as in patients with complications such as valvular insufficiency, perivalvular abscess, conduction abnormalities, persistent bacteremia, and metastatic foci of infection.⁶

Risk factors for infective endocarditis include injection drug abuse, valvular heart disease, congenital heart disease (unrepaired, repaired with residual defects, or fully repaired within the past 6 months), previous infective endocarditis, prosthetic heart valve, and cardiac transplant.^2–4,6 Other risk factors are poor dentition, hemodialysis, ventriculoatrial shunts, intravascular devices including vascular grafts, and pacemakers.^2,3 Many risk factors for infective endocarditis and S aureus bacteremia overlap.³

DIAGNOSTIC PRINCIPLES

The clinical presentation of infective endocarditis can vary from a nonspecific infectious syndrome, to overt organ failure (heart failure, kidney failure), to an acute vascular catastrophe (arterial ischemia, cerebrovascular accidents, myocardial infarction). Patients may present with indolent symptoms such as fever, fatigue, and weight loss,⁶ or they may present at an advanced stage, with fulminant acute heart failure due to valvular insufficiency or with arrhythmias due to a perivalvular abscess infiltrating the conduction system. Extracardiac clinical manifestations may be related to direct infective metastatic foci such as septic emboli or to immunologic phenomena such as glomerulonephritis or Osler nodes.

ECHOCARDIOGRAPHY’S ROLE IN DIAGNOSIS

TTE plays an important role in diagnosis and risk stratification of infective endocarditis.⁶ TTE is usually done first because of its low cost, wide availability, and safety; it has a sensitivity of 70% and a specificity over 95%.⁸ While a normal result on TTE does not completely rule out infective endocarditis, completely normal valvular morphology and function on TTE make the diagnosis less likely.^8,9

If suspicion remains high despite a normal study, repeating TTE at a later time may result in a higher diagnostic yield because of growth of the suspected vegetation. Otherwise, TEE should be considered.

TEE provides a higher spatial resolution and diagnostic yield than TTE, especially for detecting complex pathology such as pseudoaneurysm, valve perforation, or valvular abscess. TEE has a sensitivity and specificity of approximately 95% for infective endocarditis.⁸ It should be performed early in patients with preexisting valve disease, prosthetic cardiac material (eg, valves), or a pacemaker or implantable cardioverter-defibrillator.^6,7

Detecting valve vegetation provides answers about the cause of S aureus bacteremia with its complications (eg, septic emboli, mycotic aneurysm) and informs decisions about the duration of antibiotic therapy and the need for surgery.^3,6

As with any diagnostic test, it is important to compare the results of any recent study with those of previous studies whenever possible to differentiate new from old findings.

WHEN TO FORGO TEE IN S AUREUS BACTEREMIA

Because TEE is invasive and requires the patient to swallow an endoscopic probe,¹⁰ it is important to screen patients for esophageal disease, cervical spine conditions, and baseline respiratory insufficiency. Complications are rare but include esophageal perforation, esophageal bleeding, pharyngeal hematoma, and reactions to anesthesia.¹⁰

As with any diagnostic test, the clinician first needs to consider the patient’s pretest probability of the disease, the diagnostic accuracy, the associated risks and costs, and the implications of the results.

While TEE provides better diagnostic images than TTE, a normal TEE study does not exclude the diagnosis of infective endocarditis: small lesions and complications such as paravalvular abscess of a prosthetic aortic valve may still be missed. In such patients, a repeat TEE examination or additional imaging study (eg, gated computed tomographic angiography) should be considered.⁶

Noninfective sterile echodensities, valvular tumors such as papillary fibroelastomas, Lambl excrescences, and suture lines of prosthetic valves are among the conditions and factors that can cause a false-positive result on TEE. 

Staphylococcus aureus is the most common infective agent in native and prosthetic valve endocarditis, and 13% to 22% of patients with S aureus bacteremia have infective endocarditis.¹

See related editorial

Transthoracic echocardiography (TTE) is a good starting point in the workup of suspected infective endocarditis, but transesophageal echocardiography (TEE) plays a key role in diagnosis and is indicated in patients with a high pretest probability of infective endocarditis, as in the following scenarios:

• Clinical picture consistent with infective endocarditis
• Presence of previously placed port or other indwelling vascular device
• Presence of a prosthetic valve or other prosthetic material 
• Presence of a pacemaker
• History of valve disease
• Injection drug use
• Positive blood cultures after 72 hours despite appropriate antibiotic treatment
• Abnormal TTE result requiring better visualization of valvular anatomy and function and confirmation of local complications
• Absence of another reasonable explanation for S aureus bacteremia.

Forgoing TEE is reasonable in patients with normal results on TTE, no predisposing risk factors, a reasonable alternative explanation for S aureus bacteremia, and a low pretest probability of infective endocarditis.¹ TEE may also be unnecessary if there is another disease focus requiring extended treatment (eg, vertebral infection) and there are no findings suggesting complicated infective endocarditis, eg, persistent bacteremia, symptoms of heart failure, and conduction abnormality.¹

TEE also may be unnecessary in patients at low risk who have identifiable foci of bacteremia due to soft-tissue infection or a newly placed vascular catheter and whose bacteremia clears within 72 hours of the start of antibiotic therapy. These patients may be followed clinically for the development of new findings such as metastatic foci of infection (eg, septic pulmonary emboli, renal infarction, splenic abscess or infarction), the new onset of heart failure or cardiac conduction abnormality, or recurrence of previously cleared S aureus bacteremia. If these should develop, then a more invasive study such as TEE may be warranted.

INFECTIVE ENDOCARDITIS: EPIDEMIOLOGY AND MICROBIOLOGY

The US incidence rate of infective endocarditis has steadily increased, with an estimated 457,052 hospitalizations from 2000 to 2011. During that period, from 2000 to 2007, there was a marked increase in valve replacement surgeries.² This trend is likely explained by an increase in the at-risk population—eg, elderly patients, patients with opiate dependence or diabetes, and patients on hemodialysis.

Although S aureus is the predominant pathogen in infective endocarditis,^2–5S aureus bacteremia is often observed in patients with skin or soft-tissue infection, prosthetic device infection, vascular graft or catheter infection, and bone and joint infections. S aureus bacteremia necessitates a search for the source of infection.

S aureus is a major pathogen in bloodstream infections, and up to 14% of patients with S aureus bacteremia have infective endocarditis as the primary source of infection.³ The pathogenesis of S aureus infective endocarditis is thought to be mediated by cell-wall factors that promote adhesion to the extracellular matrix of intravascular structures.³

A new localizing symptom such as back pain, joint pain, or swelling in a patient with S aureus bacteremia should trigger an investigation for metastatic infection.

Infectious disease consultation in patients with S aureus bacteremia is associated with improved outcomes and, thus, should be pursued.³

A cardiac surgery consult is recommended early on in cases of infective endocarditis caused by vancomycin-resistant enterococci, Pseudomonas aeruginosa, and fungi, as well as in patients with complications such as valvular insufficiency, perivalvular abscess, conduction abnormalities, persistent bacteremia, and metastatic foci of infection.⁶

Risk factors for infective endocarditis include injection drug abuse, valvular heart disease, congenital heart disease (unrepaired, repaired with residual defects, or fully repaired within the past 6 months), previous infective endocarditis, prosthetic heart valve, and cardiac transplant.^2–4,6 Other risk factors are poor dentition, hemodialysis, ventriculoatrial shunts, intravascular devices including vascular grafts, and pacemakers.^2,3 Many risk factors for infective endocarditis and S aureus bacteremia overlap.³

DIAGNOSTIC PRINCIPLES

The clinical presentation of infective endocarditis can vary from a nonspecific infectious syndrome, to overt organ failure (heart failure, kidney failure), to an acute vascular catastrophe (arterial ischemia, cerebrovascular accidents, myocardial infarction). Patients may present with indolent symptoms such as fever, fatigue, and weight loss,⁶ or they may present at an advanced stage, with fulminant acute heart failure due to valvular insufficiency or with arrhythmias due to a perivalvular abscess infiltrating the conduction system. Extracardiac clinical manifestations may be related to direct infective metastatic foci such as septic emboli or to immunologic phenomena such as glomerulonephritis or Osler nodes.

ECHOCARDIOGRAPHY’S ROLE IN DIAGNOSIS

TTE plays an important role in diagnosis and risk stratification of infective endocarditis.⁶ TTE is usually done first because of its low cost, wide availability, and safety; it has a sensitivity of 70% and a specificity over 95%.⁸ While a normal result on TTE does not completely rule out infective endocarditis, completely normal valvular morphology and function on TTE make the diagnosis less likely.^8,9

If suspicion remains high despite a normal study, repeating TTE at a later time may result in a higher diagnostic yield because of growth of the suspected vegetation. Otherwise, TEE should be considered.

TEE provides a higher spatial resolution and diagnostic yield than TTE, especially for detecting complex pathology such as pseudoaneurysm, valve perforation, or valvular abscess. TEE has a sensitivity and specificity of approximately 95% for infective endocarditis.⁸ It should be performed early in patients with preexisting valve disease, prosthetic cardiac material (eg, valves), or a pacemaker or implantable cardioverter-defibrillator.^6,7

Detecting valve vegetation provides answers about the cause of S aureus bacteremia with its complications (eg, septic emboli, mycotic aneurysm) and informs decisions about the duration of antibiotic therapy and the need for surgery.^3,6

As with any diagnostic test, it is important to compare the results of any recent study with those of previous studies whenever possible to differentiate new from old findings.

WHEN TO FORGO TEE IN S AUREUS BACTEREMIA

Because TEE is invasive and requires the patient to swallow an endoscopic probe,¹⁰ it is important to screen patients for esophageal disease, cervical spine conditions, and baseline respiratory insufficiency. Complications are rare but include esophageal perforation, esophageal bleeding, pharyngeal hematoma, and reactions to anesthesia.¹⁰

As with any diagnostic test, the clinician first needs to consider the patient’s pretest probability of the disease, the diagnostic accuracy, the associated risks and costs, and the implications of the results.

While TEE provides better diagnostic images than TTE, a normal TEE study does not exclude the diagnosis of infective endocarditis: small lesions and complications such as paravalvular abscess of a prosthetic aortic valve may still be missed. In such patients, a repeat TEE examination or additional imaging study (eg, gated computed tomographic angiography) should be considered.⁶

Noninfective sterile echodensities, valvular tumors such as papillary fibroelastomas, Lambl excrescences, and suture lines of prosthetic valves are among the conditions and factors that can cause a false-positive result on TEE. 

Staphylococcus aureus is the most common infective agent in native and prosthetic valve endocarditis, and 13% to 22% of patients with S aureus bacteremia have infective endocarditis.¹

See related editorial

Transthoracic echocardiography (TTE) is a good starting point in the workup of suspected infective endocarditis, but transesophageal echocardiography (TEE) plays a key role in diagnosis and is indicated in patients with a high pretest probability of infective endocarditis, as in the following scenarios:

• Clinical picture consistent with infective endocarditis
• Presence of previously placed port or other indwelling vascular device
• Presence of a prosthetic valve or other prosthetic material 
• Presence of a pacemaker
• History of valve disease
• Injection drug use
• Positive blood cultures after 72 hours despite appropriate antibiotic treatment
• Abnormal TTE result requiring better visualization of valvular anatomy and function and confirmation of local complications
• Absence of another reasonable explanation for S aureus bacteremia.

Forgoing TEE is reasonable in patients with normal results on TTE, no predisposing risk factors, a reasonable alternative explanation for S aureus bacteremia, and a low pretest probability of infective endocarditis.¹ TEE may also be unnecessary if there is another disease focus requiring extended treatment (eg, vertebral infection) and there are no findings suggesting complicated infective endocarditis, eg, persistent bacteremia, symptoms of heart failure, and conduction abnormality.¹

TEE also may be unnecessary in patients at low risk who have identifiable foci of bacteremia due to soft-tissue infection or a newly placed vascular catheter and whose bacteremia clears within 72 hours of the start of antibiotic therapy. These patients may be followed clinically for the development of new findings such as metastatic foci of infection (eg, septic pulmonary emboli, renal infarction, splenic abscess or infarction), the new onset of heart failure or cardiac conduction abnormality, or recurrence of previously cleared S aureus bacteremia. If these should develop, then a more invasive study such as TEE may be warranted.

INFECTIVE ENDOCARDITIS: EPIDEMIOLOGY AND MICROBIOLOGY

The US incidence rate of infective endocarditis has steadily increased, with an estimated 457,052 hospitalizations from 2000 to 2011. During that period, from 2000 to 2007, there was a marked increase in valve replacement surgeries.² This trend is likely explained by an increase in the at-risk population—eg, elderly patients, patients with opiate dependence or diabetes, and patients on hemodialysis.

Although S aureus is the predominant pathogen in infective endocarditis,^2–5S aureus bacteremia is often observed in patients with skin or soft-tissue infection, prosthetic device infection, vascular graft or catheter infection, and bone and joint infections. S aureus bacteremia necessitates a search for the source of infection.

S aureus is a major pathogen in bloodstream infections, and up to 14% of patients with S aureus bacteremia have infective endocarditis as the primary source of infection.³ The pathogenesis of S aureus infective endocarditis is thought to be mediated by cell-wall factors that promote adhesion to the extracellular matrix of intravascular structures.³

A new localizing symptom such as back pain, joint pain, or swelling in a patient with S aureus bacteremia should trigger an investigation for metastatic infection.

Infectious disease consultation in patients with S aureus bacteremia is associated with improved outcomes and, thus, should be pursued.³

A cardiac surgery consult is recommended early on in cases of infective endocarditis caused by vancomycin-resistant enterococci, Pseudomonas aeruginosa, and fungi, as well as in patients with complications such as valvular insufficiency, perivalvular abscess, conduction abnormalities, persistent bacteremia, and metastatic foci of infection.⁶

Risk factors for infective endocarditis include injection drug abuse, valvular heart disease, congenital heart disease (unrepaired, repaired with residual defects, or fully repaired within the past 6 months), previous infective endocarditis, prosthetic heart valve, and cardiac transplant.^2–4,6 Other risk factors are poor dentition, hemodialysis, ventriculoatrial shunts, intravascular devices including vascular grafts, and pacemakers.^2,3 Many risk factors for infective endocarditis and S aureus bacteremia overlap.³

DIAGNOSTIC PRINCIPLES

The clinical presentation of infective endocarditis can vary from a nonspecific infectious syndrome, to overt organ failure (heart failure, kidney failure), to an acute vascular catastrophe (arterial ischemia, cerebrovascular accidents, myocardial infarction). Patients may present with indolent symptoms such as fever, fatigue, and weight loss,⁶ or they may present at an advanced stage, with fulminant acute heart failure due to valvular insufficiency or with arrhythmias due to a perivalvular abscess infiltrating the conduction system. Extracardiac clinical manifestations may be related to direct infective metastatic foci such as septic emboli or to immunologic phenomena such as glomerulonephritis or Osler nodes.

ECHOCARDIOGRAPHY’S ROLE IN DIAGNOSIS

TTE plays an important role in diagnosis and risk stratification of infective endocarditis.⁶ TTE is usually done first because of its low cost, wide availability, and safety; it has a sensitivity of 70% and a specificity over 95%.⁸ While a normal result on TTE does not completely rule out infective endocarditis, completely normal valvular morphology and function on TTE make the diagnosis less likely.^8,9

If suspicion remains high despite a normal study, repeating TTE at a later time may result in a higher diagnostic yield because of growth of the suspected vegetation. Otherwise, TEE should be considered.

TEE provides a higher spatial resolution and diagnostic yield than TTE, especially for detecting complex pathology such as pseudoaneurysm, valve perforation, or valvular abscess. TEE has a sensitivity and specificity of approximately 95% for infective endocarditis.⁸ It should be performed early in patients with preexisting valve disease, prosthetic cardiac material (eg, valves), or a pacemaker or implantable cardioverter-defibrillator.^6,7

Detecting valve vegetation provides answers about the cause of S aureus bacteremia with its complications (eg, septic emboli, mycotic aneurysm) and informs decisions about the duration of antibiotic therapy and the need for surgery.^3,6

As with any diagnostic test, it is important to compare the results of any recent study with those of previous studies whenever possible to differentiate new from old findings.

WHEN TO FORGO TEE IN S AUREUS BACTEREMIA

Because TEE is invasive and requires the patient to swallow an endoscopic probe,¹⁰ it is important to screen patients for esophageal disease, cervical spine conditions, and baseline respiratory insufficiency. Complications are rare but include esophageal perforation, esophageal bleeding, pharyngeal hematoma, and reactions to anesthesia.¹⁰

As with any diagnostic test, the clinician first needs to consider the patient’s pretest probability of the disease, the diagnostic accuracy, the associated risks and costs, and the implications of the results.

While TEE provides better diagnostic images than TTE, a normal TEE study does not exclude the diagnosis of infective endocarditis: small lesions and complications such as paravalvular abscess of a prosthetic aortic valve may still be missed. In such patients, a repeat TEE examination or additional imaging study (eg, gated computed tomographic angiography) should be considered.⁶

Noninfective sterile echodensities, valvular tumors such as papillary fibroelastomas, Lambl excrescences, and suture lines of prosthetic valves are among the conditions and factors that can cause a false-positive result on TEE. 

Morbidity and mortality rates in patients with Staphylococcus aureus bacteremia remain high even though diagnostic tests have improved and antibiotic therapy is effective. Diagnosis and management are made more complex by difficulties in finding the source of bacteremia and sites of metastatic infection.

See related article

S aureus bacteremia is a finding that demands further investigation, since up to 25% of people who have it may have endocarditis, a condition with even worse consequences.¹ The ability of S aureus to infect normal valves^2,3 adds to the challenge. In the mid-20th century, Wilson and Hamburger⁴ demonstrated that 64% of patients with S aureus bacteremia had evidence of valvular infection at autopsy. In a more recent case series of patients with S aureus endocarditis, the diagnosis was established at autopsy in 32%.⁵

Specific clinical findings in patients with complicated S aureus bacteremia—those who have a site of infection remote from or extended beyond the primary focus—may be useful in determining the need for additional diagnostic and therapeutic measures.

In a prospective cohort study, Fowler et al⁶ identified several factors that predicted complicated S aureus bacteremia (including but not limited to endocarditis):

• Prolonged bacteremia (> 48–72 hours after initiation of therapy)
• Community onset
• Fever persisting more than 72 hours
• Skin findings suggesting systemic infection.

THE ROLE OF ECHOCARDIOGRAPHY

Infective endocarditis may be difficult to detect in patients with S aureus bacteremia; experts recommend routine use of echocardiography in this process.^7,8 Transesophageal echocardiography (TEE) detects more cases of endocarditis than transthoracic echocardiography (TTE),^9,10 but access, cost, and risks lead to questions about its utility.

Guidance for the use of echocardiography in S aureus bacteremia^1,10–14 continues to evolve. Consensus seems to be emerging that the risk of endocarditis is lower in patients with S aureus bacteremia who:

• Do not have a prosthetic valve or other permanent intracardiac device
• Have sterile blood cultures within 96 hours after the initial set
• Are not hemodialysis-dependent
• Developed the bacteremia in a healthcare setting
• Have no secondary focus of infection
• Have no clinical signs of infective endocarditis.

Heriot et al¹⁴ point out that studies of risk-stratification approaches to echocardiography in patients with S aureus bacteremia are difficult to interpret, as there are questions regarding the validity of the studies and the balance of the risks and benefits.¹ The question of timing of TEE remains largely unexplored, both in initial screening and in follow-up of previously undiagnosed cases of S aureus endocarditis.

In this issue of the Journal, Mirrakhimov et al¹⁵ weigh in on use of a risk-stratification model to guide use of TEE in patients with S aureus bacteremia. Their comments about avoiding TEE in patients who have an alternative explanation for S aureus bacteremia and a low pretest probability for infectious endocarditis and in patients with a disease focus that requires extended treatment are derived from a survey of infectious disease physicians.¹⁶

ROLE OF INFECTIOUS DISEASE CONSULTATION

Infectious disease consultation reduces mortality rates and healthcare costs for a variety of infections, with endocarditis as a prime example.¹⁷ For S aureus bacteremia, a large and growing body of literature demonstrates the impact of infectious disease consultation, including improved adherence to guidelines and quality measures,^18–20 lower in-hospital mortality rates^18–21 and earlier hospital discharge.¹⁸ In the era of “curbside consults” and “e-consultation,” it is interesting to note the enduring value of bedside, in-person consultation in the management of S aureus bacteremia.²⁰

Many people with S aureus bacteremia should undergo TEE. Until the evidence becomes more robust, the decision to forgo TEE must be made with caution. The expertise of infectious disease physicians in the diagnosis and management of endocarditis can assist clinicians working with the often-complex patients who develop S aureus bacteremia. If the goal is to improve outcomes, infectious disease consultation may be at least as important as appropriate selection of patients for TEE.

Morbidity and mortality rates in patients with Staphylococcus aureus bacteremia remain high even though diagnostic tests have improved and antibiotic therapy is effective. Diagnosis and management are made more complex by difficulties in finding the source of bacteremia and sites of metastatic infection.

See related article

S aureus bacteremia is a finding that demands further investigation, since up to 25% of people who have it may have endocarditis, a condition with even worse consequences.¹ The ability of S aureus to infect normal valves^2,3 adds to the challenge. In the mid-20th century, Wilson and Hamburger⁴ demonstrated that 64% of patients with S aureus bacteremia had evidence of valvular infection at autopsy. In a more recent case series of patients with S aureus endocarditis, the diagnosis was established at autopsy in 32%.⁵

Specific clinical findings in patients with complicated S aureus bacteremia—those who have a site of infection remote from or extended beyond the primary focus—may be useful in determining the need for additional diagnostic and therapeutic measures.

In a prospective cohort study, Fowler et al⁶ identified several factors that predicted complicated S aureus bacteremia (including but not limited to endocarditis):

• Prolonged bacteremia (> 48–72 hours after initiation of therapy)
• Community onset
• Fever persisting more than 72 hours
• Skin findings suggesting systemic infection.

THE ROLE OF ECHOCARDIOGRAPHY

Infective endocarditis may be difficult to detect in patients with S aureus bacteremia; experts recommend routine use of echocardiography in this process.^7,8 Transesophageal echocardiography (TEE) detects more cases of endocarditis than transthoracic echocardiography (TTE),^9,10 but access, cost, and risks lead to questions about its utility.

Guidance for the use of echocardiography in S aureus bacteremia^1,10–14 continues to evolve. Consensus seems to be emerging that the risk of endocarditis is lower in patients with S aureus bacteremia who:

• Do not have a prosthetic valve or other permanent intracardiac device
• Have sterile blood cultures within 96 hours after the initial set
• Are not hemodialysis-dependent
• Developed the bacteremia in a healthcare setting
• Have no secondary focus of infection
• Have no clinical signs of infective endocarditis.

Heriot et al¹⁴ point out that studies of risk-stratification approaches to echocardiography in patients with S aureus bacteremia are difficult to interpret, as there are questions regarding the validity of the studies and the balance of the risks and benefits.¹ The question of timing of TEE remains largely unexplored, both in initial screening and in follow-up of previously undiagnosed cases of S aureus endocarditis.

In this issue of the Journal, Mirrakhimov et al¹⁵ weigh in on use of a risk-stratification model to guide use of TEE in patients with S aureus bacteremia. Their comments about avoiding TEE in patients who have an alternative explanation for S aureus bacteremia and a low pretest probability for infectious endocarditis and in patients with a disease focus that requires extended treatment are derived from a survey of infectious disease physicians.¹⁶

ROLE OF INFECTIOUS DISEASE CONSULTATION

Infectious disease consultation reduces mortality rates and healthcare costs for a variety of infections, with endocarditis as a prime example.¹⁷ For S aureus bacteremia, a large and growing body of literature demonstrates the impact of infectious disease consultation, including improved adherence to guidelines and quality measures,^18–20 lower in-hospital mortality rates^18–21 and earlier hospital discharge.¹⁸ In the era of “curbside consults” and “e-consultation,” it is interesting to note the enduring value of bedside, in-person consultation in the management of S aureus bacteremia.²⁰

Many people with S aureus bacteremia should undergo TEE. Until the evidence becomes more robust, the decision to forgo TEE must be made with caution. The expertise of infectious disease physicians in the diagnosis and management of endocarditis can assist clinicians working with the often-complex patients who develop S aureus bacteremia. If the goal is to improve outcomes, infectious disease consultation may be at least as important as appropriate selection of patients for TEE.

Morbidity and mortality rates in patients with Staphylococcus aureus bacteremia remain high even though diagnostic tests have improved and antibiotic therapy is effective. Diagnosis and management are made more complex by difficulties in finding the source of bacteremia and sites of metastatic infection.

See related article

S aureus bacteremia is a finding that demands further investigation, since up to 25% of people who have it may have endocarditis, a condition with even worse consequences.¹ The ability of S aureus to infect normal valves^2,3 adds to the challenge. In the mid-20th century, Wilson and Hamburger⁴ demonstrated that 64% of patients with S aureus bacteremia had evidence of valvular infection at autopsy. In a more recent case series of patients with S aureus endocarditis, the diagnosis was established at autopsy in 32%.⁵

Specific clinical findings in patients with complicated S aureus bacteremia—those who have a site of infection remote from or extended beyond the primary focus—may be useful in determining the need for additional diagnostic and therapeutic measures.

In a prospective cohort study, Fowler et al⁶ identified several factors that predicted complicated S aureus bacteremia (including but not limited to endocarditis):

• Prolonged bacteremia (> 48–72 hours after initiation of therapy)
• Community onset
• Fever persisting more than 72 hours
• Skin findings suggesting systemic infection.

THE ROLE OF ECHOCARDIOGRAPHY

Infective endocarditis may be difficult to detect in patients with S aureus bacteremia; experts recommend routine use of echocardiography in this process.^7,8 Transesophageal echocardiography (TEE) detects more cases of endocarditis than transthoracic echocardiography (TTE),^9,10 but access, cost, and risks lead to questions about its utility.

Guidance for the use of echocardiography in S aureus bacteremia^1,10–14 continues to evolve. Consensus seems to be emerging that the risk of endocarditis is lower in patients with S aureus bacteremia who:

• Do not have a prosthetic valve or other permanent intracardiac device
• Have sterile blood cultures within 96 hours after the initial set
• Are not hemodialysis-dependent
• Developed the bacteremia in a healthcare setting
• Have no secondary focus of infection
• Have no clinical signs of infective endocarditis.

Heriot et al¹⁴ point out that studies of risk-stratification approaches to echocardiography in patients with S aureus bacteremia are difficult to interpret, as there are questions regarding the validity of the studies and the balance of the risks and benefits.¹ The question of timing of TEE remains largely unexplored, both in initial screening and in follow-up of previously undiagnosed cases of S aureus endocarditis.

In this issue of the Journal, Mirrakhimov et al¹⁵ weigh in on use of a risk-stratification model to guide use of TEE in patients with S aureus bacteremia. Their comments about avoiding TEE in patients who have an alternative explanation for S aureus bacteremia and a low pretest probability for infectious endocarditis and in patients with a disease focus that requires extended treatment are derived from a survey of infectious disease physicians.¹⁶

ROLE OF INFECTIOUS DISEASE CONSULTATION

Infectious disease consultation reduces mortality rates and healthcare costs for a variety of infections, with endocarditis as a prime example.¹⁷ For S aureus bacteremia, a large and growing body of literature demonstrates the impact of infectious disease consultation, including improved adherence to guidelines and quality measures,^18–20 lower in-hospital mortality rates^18–21 and earlier hospital discharge.¹⁸ In the era of “curbside consults” and “e-consultation,” it is interesting to note the enduring value of bedside, in-person consultation in the management of S aureus bacteremia.²⁰

Many people with S aureus bacteremia should undergo TEE. Until the evidence becomes more robust, the decision to forgo TEE must be made with caution. The expertise of infectious disease physicians in the diagnosis and management of endocarditis can assist clinicians working with the often-complex patients who develop S aureus bacteremia. If the goal is to improve outcomes, infectious disease consultation may be at least as important as appropriate selection of patients for TEE.

Patients who survive critical illness such as shock or respiratory failure warranting admission to an intensive care unit (ICU) often develop a constellation of chronic symptoms including cognitive decline, psychiatric disturbances, and physical weakness. These changes can prevent patients from returning to their former level of function and often necessitate significant support for patients and their caregivers.¹

See related editorial

With growing awareness of the unique needs of ICU survivors, multidisciplinary PICS clinics have emerged. However, access to these clinics is limited, and most patients discharged from the ICU eventually follow up with their primary care provider. Primary care physicians who recognize PICS, understand its prognosis and its burden on caregivers, and are aware of tools that have shown promise in its management will be well prepared to address the needs of these patients.

COGNITIVE DECLINE

Several studies have shown that survivors of critical illness suffer from long-term impairment of multiple domains of cognition, including executive function. In one study, 40% of ICU survivors had global cognition scores at 1 year after discharge that were worse than those seen in moderate traumatic brain injury, and over 25% had scores similar to those seen in Alzheimer dementia.² Age had poor correlation with the incidence of long-term cognitive impairment. Cognitive impairment may not be recognized in younger patients without a high index of suspicion and directed cognitive screening. Well-known cognitive impairment screening tests such as the Montreal Cognitive Assessment may help in the evaluation of PICS.

No treatment has been shown to improve long-term cognitive impairment from any cause. The most important intervention is to recognize it and to consider how impaired executive function may interfere with other aspects of treatment, such as participation in physical therapy and adherence to medication regimens.

Evidence is also emerging that patients are often inappropriately discharged on psychoactive medications (including atypical antipsychotic drugs and sedatives) that were started in the inpatient setting.⁷ These medications increase the risk of accidents, arrhythmia, and infection, as well as add to the overall cost of postdischarge care, and they do not improve the prolonged confusion and cognitive impairment associated with PICS.⁸ Psychoactive medications should be discontinued once delirium-associated behavior has resolved, as recommended in the American Geriatrics Society guideline on postoperative delirium.⁹ Further, patients and caregivers should be counseled so that they have reasonable expectations regarding the timing of cognitive recovery, which may be prolonged and incomplete.

PHYSICAL WEAKNESS

Prolonged physical weakness may affect up to one-third of patients who survive critical illness, and it may persist for years, severely compromising quality of life.¹⁰ In addition to deconditioning due to bedrest and illness, ICU patients often develop critical illness myopathy and critical illness polyneuropathy.

Although the mechanisms and risk factors for injury to muscles and peripheral nerves are  not completely understood, the severity has been well described and ranges from proximal muscle weakness to complete quadriparesis, with inability to wean from mechanical ventilation. There is also an association with the severity of sepsis and the use of glucocorticoids and paralytics.¹⁰

Physical weakness can be readily apparent on routine history and physical examination. Differentiating critical illness myopathy from critical illness polyneuropathy requires invasive testing, including electromyography, but the results may not change management in the outpatient setting, making it unnecessary for most patients.

Physical weakness places a heavy burden on patients and their family and caregivers. As a result, most ICU patients suffer loss of employment and require supportive services on discharge, including home health aides and even institutionalization.

Physical therapy and occupational therapy are effective in reducing weakness and improving physical functioning; starting physical therapy in the outpatient setting may be as effective as early intervention in the ICU.¹¹ Given the high prevalence of respiratory and cardiovascular disease in patients after ICU discharge, referral for pulmonary or cardiovascular rehabilitation is recommended. Because of the possible link between glucocorticoids and critical illness myopathy, these drugs should be decreased or discontinued as soon as possible.

Mental health impairments in ICU survivors are common, severe, debilitating, and unfortunately, commonly overlooked. A recent study found a 37% incidence of depression and a 40% incidence of anxiety; further, 22% of patients met criteria for posttraumatic stress disorder.¹² Patients with critical illness are also more likely to have had untreated mental health illness before hospitalization. Anxiety may present with poor sleep, irritability, and fatigue. Posttraumatic stress disorder may manifest as flashbacks or as a severe cognitive or behavioral response to provocation. All of these may be assessed using standard screening questionnaires, including the Posttraumatic Stress Disorder Checklist, the 2-item Patient Health Questionnaire (PHQ-2) for depression, and the 7-item Generalized Anxiety Disorder Screen (GAD-7).

Many primary care physicians are comfortable treating some of the psychiatric disturbances associated with PICS, such as depression, but may be challenged by the spectrum and complexity of mental illness of ICU survivors. Early referral to a mental health professional ensures optimal psychiatric care and allows more time to focus on the patient’s medical comorbidities.

SOCIAL SUPPORT

The cognitive, physical, and mental health complications coupled with other medical and psychiatric comorbidities result in serious social and financial stress on patients and their families. Long-term follow-up studies show that only half of patients return to work within 1 year of critical illness and that nearly one-fourth require continued assistance with activities of daily living.¹³ Reassuringly, however, most patients in 1 study had returned to work by 2 years from discharge.³

The immense burden on caregivers, the decrease in income, and increased expenditures in providing care result in increased stress on families. The incidence of depression, anxiety, and posttraumatic stress disorder is similar among patients and their caregivers.¹¹ The frequency of emotional morbidity and the severity of the caregiver burden associated with caring for ICU survivors led to the description of a new entity: post-intensive care syndrome-family, or PICS-F.

Because of these stresses, patients often benefit from referral to a social worker. Patients should also be encouraged to bring their caregivers to physician appointments, and family members should be encouraged to discuss their perspectives in the context of a dedicated appointment. Family members should also be screened and treated for their own medical and mental health challenges. A dedicated ICU survivorship clinic may help facilitate this holistic approach and provide complementary services to the primary care provider.

CRITICAL CARE RECOVERY

As survival rates after critical illness continue to improve and clinicians encounter more patients with PICS, it is essential to appreciate the extent of associated physical, emotional, and financial hardship and to recognize when cognitive impairment may interfere with treatment. Early and accurate recognition of these challenges can help the primary care physician arrange and coordinate recovery services that ICU survivors require. Including family members in follow-up appointments can help overcome challenges in adherence to treatment plans, uncover gaps in social support, and identify signs of caregiver distress.

A thorough physical assessment and a thoughtful reconciliation of medications are critical, as is engaging the assistance of physical and occupational therapists, mental health professionals, and social workers.

Risk factors for the illness that necessitated the ICU stay such as uncontrolled diabetes, chronic obstructive pulmonary disease, and substance abuse, as well as medical sequelae such as chronic respiratory failure and heart failure, must be considered and addressed by the primary care physician, with referral to medical specialists if necessary.

Referral to an ICU survivorship center, if locally available, could help the physician manage the patient’s complex and multidisciplinary physical and neuropsychiatric needs. The Society of Critical Care Medicine maintains a resource for survivors and families at www.myicucare.org/thrive/pages/find-in-person-support-groups.aspx.

Patients who survive critical illness such as shock or respiratory failure warranting admission to an intensive care unit (ICU) often develop a constellation of chronic symptoms including cognitive decline, psychiatric disturbances, and physical weakness. These changes can prevent patients from returning to their former level of function and often necessitate significant support for patients and their caregivers.¹

See related editorial

With growing awareness of the unique needs of ICU survivors, multidisciplinary PICS clinics have emerged. However, access to these clinics is limited, and most patients discharged from the ICU eventually follow up with their primary care provider. Primary care physicians who recognize PICS, understand its prognosis and its burden on caregivers, and are aware of tools that have shown promise in its management will be well prepared to address the needs of these patients.

COGNITIVE DECLINE

Several studies have shown that survivors of critical illness suffer from long-term impairment of multiple domains of cognition, including executive function. In one study, 40% of ICU survivors had global cognition scores at 1 year after discharge that were worse than those seen in moderate traumatic brain injury, and over 25% had scores similar to those seen in Alzheimer dementia.² Age had poor correlation with the incidence of long-term cognitive impairment. Cognitive impairment may not be recognized in younger patients without a high index of suspicion and directed cognitive screening. Well-known cognitive impairment screening tests such as the Montreal Cognitive Assessment may help in the evaluation of PICS.

No treatment has been shown to improve long-term cognitive impairment from any cause. The most important intervention is to recognize it and to consider how impaired executive function may interfere with other aspects of treatment, such as participation in physical therapy and adherence to medication regimens.

Evidence is also emerging that patients are often inappropriately discharged on psychoactive medications (including atypical antipsychotic drugs and sedatives) that were started in the inpatient setting.⁷ These medications increase the risk of accidents, arrhythmia, and infection, as well as add to the overall cost of postdischarge care, and they do not improve the prolonged confusion and cognitive impairment associated with PICS.⁸ Psychoactive medications should be discontinued once delirium-associated behavior has resolved, as recommended in the American Geriatrics Society guideline on postoperative delirium.⁹ Further, patients and caregivers should be counseled so that they have reasonable expectations regarding the timing of cognitive recovery, which may be prolonged and incomplete.

PHYSICAL WEAKNESS

Prolonged physical weakness may affect up to one-third of patients who survive critical illness, and it may persist for years, severely compromising quality of life.¹⁰ In addition to deconditioning due to bedrest and illness, ICU patients often develop critical illness myopathy and critical illness polyneuropathy.

Although the mechanisms and risk factors for injury to muscles and peripheral nerves are  not completely understood, the severity has been well described and ranges from proximal muscle weakness to complete quadriparesis, with inability to wean from mechanical ventilation. There is also an association with the severity of sepsis and the use of glucocorticoids and paralytics.¹⁰

Physical weakness can be readily apparent on routine history and physical examination. Differentiating critical illness myopathy from critical illness polyneuropathy requires invasive testing, including electromyography, but the results may not change management in the outpatient setting, making it unnecessary for most patients.

Physical weakness places a heavy burden on patients and their family and caregivers. As a result, most ICU patients suffer loss of employment and require supportive services on discharge, including home health aides and even institutionalization.

Physical therapy and occupational therapy are effective in reducing weakness and improving physical functioning; starting physical therapy in the outpatient setting may be as effective as early intervention in the ICU.¹¹ Given the high prevalence of respiratory and cardiovascular disease in patients after ICU discharge, referral for pulmonary or cardiovascular rehabilitation is recommended. Because of the possible link between glucocorticoids and critical illness myopathy, these drugs should be decreased or discontinued as soon as possible.

Mental health impairments in ICU survivors are common, severe, debilitating, and unfortunately, commonly overlooked. A recent study found a 37% incidence of depression and a 40% incidence of anxiety; further, 22% of patients met criteria for posttraumatic stress disorder.¹² Patients with critical illness are also more likely to have had untreated mental health illness before hospitalization. Anxiety may present with poor sleep, irritability, and fatigue. Posttraumatic stress disorder may manifest as flashbacks or as a severe cognitive or behavioral response to provocation. All of these may be assessed using standard screening questionnaires, including the Posttraumatic Stress Disorder Checklist, the 2-item Patient Health Questionnaire (PHQ-2) for depression, and the 7-item Generalized Anxiety Disorder Screen (GAD-7).

Many primary care physicians are comfortable treating some of the psychiatric disturbances associated with PICS, such as depression, but may be challenged by the spectrum and complexity of mental illness of ICU survivors. Early referral to a mental health professional ensures optimal psychiatric care and allows more time to focus on the patient’s medical comorbidities.

SOCIAL SUPPORT

The cognitive, physical, and mental health complications coupled with other medical and psychiatric comorbidities result in serious social and financial stress on patients and their families. Long-term follow-up studies show that only half of patients return to work within 1 year of critical illness and that nearly one-fourth require continued assistance with activities of daily living.¹³ Reassuringly, however, most patients in 1 study had returned to work by 2 years from discharge.³

The immense burden on caregivers, the decrease in income, and increased expenditures in providing care result in increased stress on families. The incidence of depression, anxiety, and posttraumatic stress disorder is similar among patients and their caregivers.¹¹ The frequency of emotional morbidity and the severity of the caregiver burden associated with caring for ICU survivors led to the description of a new entity: post-intensive care syndrome-family, or PICS-F.

Because of these stresses, patients often benefit from referral to a social worker. Patients should also be encouraged to bring their caregivers to physician appointments, and family members should be encouraged to discuss their perspectives in the context of a dedicated appointment. Family members should also be screened and treated for their own medical and mental health challenges. A dedicated ICU survivorship clinic may help facilitate this holistic approach and provide complementary services to the primary care provider.

CRITICAL CARE RECOVERY

As survival rates after critical illness continue to improve and clinicians encounter more patients with PICS, it is essential to appreciate the extent of associated physical, emotional, and financial hardship and to recognize when cognitive impairment may interfere with treatment. Early and accurate recognition of these challenges can help the primary care physician arrange and coordinate recovery services that ICU survivors require. Including family members in follow-up appointments can help overcome challenges in adherence to treatment plans, uncover gaps in social support, and identify signs of caregiver distress.

A thorough physical assessment and a thoughtful reconciliation of medications are critical, as is engaging the assistance of physical and occupational therapists, mental health professionals, and social workers.

Risk factors for the illness that necessitated the ICU stay such as uncontrolled diabetes, chronic obstructive pulmonary disease, and substance abuse, as well as medical sequelae such as chronic respiratory failure and heart failure, must be considered and addressed by the primary care physician, with referral to medical specialists if necessary.

Referral to an ICU survivorship center, if locally available, could help the physician manage the patient’s complex and multidisciplinary physical and neuropsychiatric needs. The Society of Critical Care Medicine maintains a resource for survivors and families at www.myicucare.org/thrive/pages/find-in-person-support-groups.aspx.

Patients who survive critical illness such as shock or respiratory failure warranting admission to an intensive care unit (ICU) often develop a constellation of chronic symptoms including cognitive decline, psychiatric disturbances, and physical weakness. These changes can prevent patients from returning to their former level of function and often necessitate significant support for patients and their caregivers.¹

See related editorial

With growing awareness of the unique needs of ICU survivors, multidisciplinary PICS clinics have emerged. However, access to these clinics is limited, and most patients discharged from the ICU eventually follow up with their primary care provider. Primary care physicians who recognize PICS, understand its prognosis and its burden on caregivers, and are aware of tools that have shown promise in its management will be well prepared to address the needs of these patients.

COGNITIVE DECLINE

Several studies have shown that survivors of critical illness suffer from long-term impairment of multiple domains of cognition, including executive function. In one study, 40% of ICU survivors had global cognition scores at 1 year after discharge that were worse than those seen in moderate traumatic brain injury, and over 25% had scores similar to those seen in Alzheimer dementia.² Age had poor correlation with the incidence of long-term cognitive impairment. Cognitive impairment may not be recognized in younger patients without a high index of suspicion and directed cognitive screening. Well-known cognitive impairment screening tests such as the Montreal Cognitive Assessment may help in the evaluation of PICS.

No treatment has been shown to improve long-term cognitive impairment from any cause. The most important intervention is to recognize it and to consider how impaired executive function may interfere with other aspects of treatment, such as participation in physical therapy and adherence to medication regimens.

Evidence is also emerging that patients are often inappropriately discharged on psychoactive medications (including atypical antipsychotic drugs and sedatives) that were started in the inpatient setting.⁷ These medications increase the risk of accidents, arrhythmia, and infection, as well as add to the overall cost of postdischarge care, and they do not improve the prolonged confusion and cognitive impairment associated with PICS.⁸ Psychoactive medications should be discontinued once delirium-associated behavior has resolved, as recommended in the American Geriatrics Society guideline on postoperative delirium.⁹ Further, patients and caregivers should be counseled so that they have reasonable expectations regarding the timing of cognitive recovery, which may be prolonged and incomplete.

PHYSICAL WEAKNESS

Prolonged physical weakness may affect up to one-third of patients who survive critical illness, and it may persist for years, severely compromising quality of life.¹⁰ In addition to deconditioning due to bedrest and illness, ICU patients often develop critical illness myopathy and critical illness polyneuropathy.

Although the mechanisms and risk factors for injury to muscles and peripheral nerves are  not completely understood, the severity has been well described and ranges from proximal muscle weakness to complete quadriparesis, with inability to wean from mechanical ventilation. There is also an association with the severity of sepsis and the use of glucocorticoids and paralytics.¹⁰

Physical weakness can be readily apparent on routine history and physical examination. Differentiating critical illness myopathy from critical illness polyneuropathy requires invasive testing, including electromyography, but the results may not change management in the outpatient setting, making it unnecessary for most patients.

Physical weakness places a heavy burden on patients and their family and caregivers. As a result, most ICU patients suffer loss of employment and require supportive services on discharge, including home health aides and even institutionalization.

Physical therapy and occupational therapy are effective in reducing weakness and improving physical functioning; starting physical therapy in the outpatient setting may be as effective as early intervention in the ICU.¹¹ Given the high prevalence of respiratory and cardiovascular disease in patients after ICU discharge, referral for pulmonary or cardiovascular rehabilitation is recommended. Because of the possible link between glucocorticoids and critical illness myopathy, these drugs should be decreased or discontinued as soon as possible.

Mental health impairments in ICU survivors are common, severe, debilitating, and unfortunately, commonly overlooked. A recent study found a 37% incidence of depression and a 40% incidence of anxiety; further, 22% of patients met criteria for posttraumatic stress disorder.¹² Patients with critical illness are also more likely to have had untreated mental health illness before hospitalization. Anxiety may present with poor sleep, irritability, and fatigue. Posttraumatic stress disorder may manifest as flashbacks or as a severe cognitive or behavioral response to provocation. All of these may be assessed using standard screening questionnaires, including the Posttraumatic Stress Disorder Checklist, the 2-item Patient Health Questionnaire (PHQ-2) for depression, and the 7-item Generalized Anxiety Disorder Screen (GAD-7).

Many primary care physicians are comfortable treating some of the psychiatric disturbances associated with PICS, such as depression, but may be challenged by the spectrum and complexity of mental illness of ICU survivors. Early referral to a mental health professional ensures optimal psychiatric care and allows more time to focus on the patient’s medical comorbidities.

SOCIAL SUPPORT

The cognitive, physical, and mental health complications coupled with other medical and psychiatric comorbidities result in serious social and financial stress on patients and their families. Long-term follow-up studies show that only half of patients return to work within 1 year of critical illness and that nearly one-fourth require continued assistance with activities of daily living.¹³ Reassuringly, however, most patients in 1 study had returned to work by 2 years from discharge.³

The immense burden on caregivers, the decrease in income, and increased expenditures in providing care result in increased stress on families. The incidence of depression, anxiety, and posttraumatic stress disorder is similar among patients and their caregivers.¹¹ The frequency of emotional morbidity and the severity of the caregiver burden associated with caring for ICU survivors led to the description of a new entity: post-intensive care syndrome-family, or PICS-F.

Because of these stresses, patients often benefit from referral to a social worker. Patients should also be encouraged to bring their caregivers to physician appointments, and family members should be encouraged to discuss their perspectives in the context of a dedicated appointment. Family members should also be screened and treated for their own medical and mental health challenges. A dedicated ICU survivorship clinic may help facilitate this holistic approach and provide complementary services to the primary care provider.

CRITICAL CARE RECOVERY

As survival rates after critical illness continue to improve and clinicians encounter more patients with PICS, it is essential to appreciate the extent of associated physical, emotional, and financial hardship and to recognize when cognitive impairment may interfere with treatment. Early and accurate recognition of these challenges can help the primary care physician arrange and coordinate recovery services that ICU survivors require. Including family members in follow-up appointments can help overcome challenges in adherence to treatment plans, uncover gaps in social support, and identify signs of caregiver distress.

A thorough physical assessment and a thoughtful reconciliation of medications are critical, as is engaging the assistance of physical and occupational therapists, mental health professionals, and social workers.

Risk factors for the illness that necessitated the ICU stay such as uncontrolled diabetes, chronic obstructive pulmonary disease, and substance abuse, as well as medical sequelae such as chronic respiratory failure and heart failure, must be considered and addressed by the primary care physician, with referral to medical specialists if necessary.

Referral to an ICU survivorship center, if locally available, could help the physician manage the patient’s complex and multidisciplinary physical and neuropsychiatric needs. The Society of Critical Care Medicine maintains a resource for survivors and families at www.myicucare.org/thrive/pages/find-in-person-support-groups.aspx.

My introduction to critical care medicine came about during the summer between my third and fourth years of medical school. During that brief break, I, like most of my classmates, was drawn to the classic medical satire The House of God by Samuel Shem,¹ which had become a cult classic in the medical field for its ghoulish medical wisdom and dark humor. In “the house,” the intensive care unit (ICU) is “that mausoleum down the hall,” its patients “perched precariously on the edge of that slick bobsled ride down to death.”¹ This sentiment persisted even as I began my critical care medicine fellowship in the mid-1990s.

See related article

The science and practice of critical care medicine have changed, evolved, and advanced over the past several decades reflecting newer technology, but also an aging population with higher acuity.² Critical care medicine has established itself as a specialty in its own right, and the importance of the physician intensivist-led multidisciplinary care teams in optimizing outcome has been demonstrated.^3,4 These teams have been associated with improved quality of care, reduced length of stay, improved resource utilization, and reduced rates of complications, morbidity, and death.

While there have been few medical miracles and limited advances in therapeutics over the last 30 years, advances in patient management, adherence to processes of care, better use of technology, and more timely diagnosis and treatment have facilitated improved outcomes.⁵ Collaboration with nurses, respiratory therapists, pharmacists, and other healthcare personnel is invaluable, as these providers are responsible for executing management protocols such as weaning sedation and mechanical ventilation, nutrition, glucose control, vasopressor and electrolyte titration, positioning, and early ambulation.

Unfortunately, as an increasing number of patients are being discharged from the ICU, evidence is accumulating that ICU survivors may develop persistent organ dysfunction requiring prolonged stays in the ICU and resulting in chronic critical illness. A 2015 study estimated 380,000 cases of chronic critical illness annually, particularly among the elderly population, with attendant hospital costs of up to $26 billion.⁶ While 70% of these patients may survive their hospitalization, the Society of Critical Care Medicine (SCCM) estimates that the 1-year post-discharge mortality rate may exceed 50%.⁷

We can take pride and comfort in knowing that the past several decades have seen growth in critical care training, more engaged practice, and heightened communication resulting in lower mortality rates.⁸ However, a majority of survivors suffer significant morbidities that may be severe and persist for a prolonged period after hospital discharge. These worsening impairments after discharge are termed postintensive care syndrome (PICS), which manifests as a new or worsening mental, cognitive, and physical condition and may affect up to 50% of ICU survivors.⁶

The impact on daily functioning and quality of life can be devastating, and primary care physicians will be increasingly called on to diagnose and participate in ongoing post-discharge management. Additionally, the impact of critical illness on relatives and informal caregivers can be long-lasting and profound, increasing their own risk of depression, posttraumatic stress disorder, and financial hardship.

In this issue of the Journal, Golovyan and colleagues identify several potential complications and sequelae of critical illness after discharge from the ICU.⁹ Primary care providers will see these patients in outpatient settings and need to be prepared to triage and treat the new-onset and chronic conditions for which these patients are at high risk.

In addition, as the authors point out, family members and informal caregivers need to be counseled about the proper care of these patients as well as themselves.

The current healthcare system does not appropriately address these survivors and their families. In 2015, the Society of Critical Care Medicine announced the THRIVE initiative, designed to improve support for the patient and family after critical illness. Given the many survivors and caregivers touched by critical illness, the Society has invested in THRIVE with the intent of helping those affected to work together with clinicians to advance recovery. Through peer support groups, post-ICU clinics, and continuing research into quality improvement, THRIVE may help to reduce readmissions and improve quality of life for critical care survivors and their loved ones.

Things have changed since the days of The House of God. Critical care medicine has become a vibrant medical specialty and an integral part of our healthcare system. Dedicated critical care physicians and the multidisciplinary teams they lead have improved outcomes and resource utilization.^2–5

The demand for ICU care will continue to increase as our population ages and the need for medical and surgical services increases commensurately. The ratio of ICU beds to hospital beds continues to escalate, and it is feared that the demand for critical care professionals may outstrip the supply.

While we no longer see that mournful shaking of the head when a patient is admitted to the ICU, we need to have the proper vision and use the most up-to-date scientific knowledge and research in treating underlying illness to ensure that once these patients are discharged, communication continues between critical care and primary care providers. This ongoing support will ensure these patients the best possible quality of life.

My introduction to critical care medicine came about during the summer between my third and fourth years of medical school. During that brief break, I, like most of my classmates, was drawn to the classic medical satire The House of God by Samuel Shem,¹ which had become a cult classic in the medical field for its ghoulish medical wisdom and dark humor. In “the house,” the intensive care unit (ICU) is “that mausoleum down the hall,” its patients “perched precariously on the edge of that slick bobsled ride down to death.”¹ This sentiment persisted even as I began my critical care medicine fellowship in the mid-1990s.

See related article

The science and practice of critical care medicine have changed, evolved, and advanced over the past several decades reflecting newer technology, but also an aging population with higher acuity.² Critical care medicine has established itself as a specialty in its own right, and the importance of the physician intensivist-led multidisciplinary care teams in optimizing outcome has been demonstrated.^3,4 These teams have been associated with improved quality of care, reduced length of stay, improved resource utilization, and reduced rates of complications, morbidity, and death.

While there have been few medical miracles and limited advances in therapeutics over the last 30 years, advances in patient management, adherence to processes of care, better use of technology, and more timely diagnosis and treatment have facilitated improved outcomes.⁵ Collaboration with nurses, respiratory therapists, pharmacists, and other healthcare personnel is invaluable, as these providers are responsible for executing management protocols such as weaning sedation and mechanical ventilation, nutrition, glucose control, vasopressor and electrolyte titration, positioning, and early ambulation.

Unfortunately, as an increasing number of patients are being discharged from the ICU, evidence is accumulating that ICU survivors may develop persistent organ dysfunction requiring prolonged stays in the ICU and resulting in chronic critical illness. A 2015 study estimated 380,000 cases of chronic critical illness annually, particularly among the elderly population, with attendant hospital costs of up to $26 billion.⁶ While 70% of these patients may survive their hospitalization, the Society of Critical Care Medicine (SCCM) estimates that the 1-year post-discharge mortality rate may exceed 50%.⁷

We can take pride and comfort in knowing that the past several decades have seen growth in critical care training, more engaged practice, and heightened communication resulting in lower mortality rates.⁸ However, a majority of survivors suffer significant morbidities that may be severe and persist for a prolonged period after hospital discharge. These worsening impairments after discharge are termed postintensive care syndrome (PICS), which manifests as a new or worsening mental, cognitive, and physical condition and may affect up to 50% of ICU survivors.⁶

The impact on daily functioning and quality of life can be devastating, and primary care physicians will be increasingly called on to diagnose and participate in ongoing post-discharge management. Additionally, the impact of critical illness on relatives and informal caregivers can be long-lasting and profound, increasing their own risk of depression, posttraumatic stress disorder, and financial hardship.

In this issue of the Journal, Golovyan and colleagues identify several potential complications and sequelae of critical illness after discharge from the ICU.⁹ Primary care providers will see these patients in outpatient settings and need to be prepared to triage and treat the new-onset and chronic conditions for which these patients are at high risk.

In addition, as the authors point out, family members and informal caregivers need to be counseled about the proper care of these patients as well as themselves.

The current healthcare system does not appropriately address these survivors and their families. In 2015, the Society of Critical Care Medicine announced the THRIVE initiative, designed to improve support for the patient and family after critical illness. Given the many survivors and caregivers touched by critical illness, the Society has invested in THRIVE with the intent of helping those affected to work together with clinicians to advance recovery. Through peer support groups, post-ICU clinics, and continuing research into quality improvement, THRIVE may help to reduce readmissions and improve quality of life for critical care survivors and their loved ones.

Things have changed since the days of The House of God. Critical care medicine has become a vibrant medical specialty and an integral part of our healthcare system. Dedicated critical care physicians and the multidisciplinary teams they lead have improved outcomes and resource utilization.^2–5

The demand for ICU care will continue to increase as our population ages and the need for medical and surgical services increases commensurately. The ratio of ICU beds to hospital beds continues to escalate, and it is feared that the demand for critical care professionals may outstrip the supply.

While we no longer see that mournful shaking of the head when a patient is admitted to the ICU, we need to have the proper vision and use the most up-to-date scientific knowledge and research in treating underlying illness to ensure that once these patients are discharged, communication continues between critical care and primary care providers. This ongoing support will ensure these patients the best possible quality of life.

My introduction to critical care medicine came about during the summer between my third and fourth years of medical school. During that brief break, I, like most of my classmates, was drawn to the classic medical satire The House of God by Samuel Shem,¹ which had become a cult classic in the medical field for its ghoulish medical wisdom and dark humor. In “the house,” the intensive care unit (ICU) is “that mausoleum down the hall,” its patients “perched precariously on the edge of that slick bobsled ride down to death.”¹ This sentiment persisted even as I began my critical care medicine fellowship in the mid-1990s.

See related article

The science and practice of critical care medicine have changed, evolved, and advanced over the past several decades reflecting newer technology, but also an aging population with higher acuity.² Critical care medicine has established itself as a specialty in its own right, and the importance of the physician intensivist-led multidisciplinary care teams in optimizing outcome has been demonstrated.^3,4 These teams have been associated with improved quality of care, reduced length of stay, improved resource utilization, and reduced rates of complications, morbidity, and death.

While there have been few medical miracles and limited advances in therapeutics over the last 30 years, advances in patient management, adherence to processes of care, better use of technology, and more timely diagnosis and treatment have facilitated improved outcomes.⁵ Collaboration with nurses, respiratory therapists, pharmacists, and other healthcare personnel is invaluable, as these providers are responsible for executing management protocols such as weaning sedation and mechanical ventilation, nutrition, glucose control, vasopressor and electrolyte titration, positioning, and early ambulation.

Unfortunately, as an increasing number of patients are being discharged from the ICU, evidence is accumulating that ICU survivors may develop persistent organ dysfunction requiring prolonged stays in the ICU and resulting in chronic critical illness. A 2015 study estimated 380,000 cases of chronic critical illness annually, particularly among the elderly population, with attendant hospital costs of up to $26 billion.⁶ While 70% of these patients may survive their hospitalization, the Society of Critical Care Medicine (SCCM) estimates that the 1-year post-discharge mortality rate may exceed 50%.⁷

We can take pride and comfort in knowing that the past several decades have seen growth in critical care training, more engaged practice, and heightened communication resulting in lower mortality rates.⁸ However, a majority of survivors suffer significant morbidities that may be severe and persist for a prolonged period after hospital discharge. These worsening impairments after discharge are termed postintensive care syndrome (PICS), which manifests as a new or worsening mental, cognitive, and physical condition and may affect up to 50% of ICU survivors.⁶

The impact on daily functioning and quality of life can be devastating, and primary care physicians will be increasingly called on to diagnose and participate in ongoing post-discharge management. Additionally, the impact of critical illness on relatives and informal caregivers can be long-lasting and profound, increasing their own risk of depression, posttraumatic stress disorder, and financial hardship.

In this issue of the Journal, Golovyan and colleagues identify several potential complications and sequelae of critical illness after discharge from the ICU.⁹ Primary care providers will see these patients in outpatient settings and need to be prepared to triage and treat the new-onset and chronic conditions for which these patients are at high risk.

In addition, as the authors point out, family members and informal caregivers need to be counseled about the proper care of these patients as well as themselves.

The current healthcare system does not appropriately address these survivors and their families. In 2015, the Society of Critical Care Medicine announced the THRIVE initiative, designed to improve support for the patient and family after critical illness. Given the many survivors and caregivers touched by critical illness, the Society has invested in THRIVE with the intent of helping those affected to work together with clinicians to advance recovery. Through peer support groups, post-ICU clinics, and continuing research into quality improvement, THRIVE may help to reduce readmissions and improve quality of life for critical care survivors and their loved ones.

Things have changed since the days of The House of God. Critical care medicine has become a vibrant medical specialty and an integral part of our healthcare system. Dedicated critical care physicians and the multidisciplinary teams they lead have improved outcomes and resource utilization.^2–5

The demand for ICU care will continue to increase as our population ages and the need for medical and surgical services increases commensurately. The ratio of ICU beds to hospital beds continues to escalate, and it is feared that the demand for critical care professionals may outstrip the supply.

While we no longer see that mournful shaking of the head when a patient is admitted to the ICU, we need to have the proper vision and use the most up-to-date scientific knowledge and research in treating underlying illness to ensure that once these patients are discharged, communication continues between critical care and primary care providers. This ongoing support will ensure these patients the best possible quality of life.

Although calcium and vitamin D are often recommended for prevention and treatment of osteoporosis, considerable controversy exists in terms of their safety and efficacy.¹ This article highlights the issues, referring  readers to reviews and meta-analyses for details and providing some practical advice for patients requiring supplementation.

CALCIUM INTAKE AND BONE DENSITY

Calcium enters the body through diet and supplementation. If intake is low, blood calcium levels fall, resulting in secondary hyperparathyroidism, which has 3 main effects:

• Increased fractional absorption of the calcium that is consumed
• Reduced urinary excretion of calcium
• Increased bone resorption, which releases calcium into the blood,² which explains the potential for the deleterious effect of deficient intake of calcium on bone.³

Based on the simple physiology outlined above, it seems logical that insufficient intake of calcium over time could lead to mobilization of calcium from bone, lower bone mineral density, and higher fracture risk.³ This topic has been reviewed by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases and the International Foundation for Osteoporosis.¹

Many lines of evidence suggest that low calcium intake adversely affects bone mineral density.¹ Low calcium intake has been associated with lower bone density in some cross-sectional studies,^4–6 though not all.⁷ Interventions to increase calcium intake in postmenopausal women have shown beneficial effects on bone density,^8–10 though in some studies the benefit was small and nonprogressive.¹¹ The question is whether this improvement in bone mineral density translates into fewer fractures.

Results from individual studies looking at fracture prevention through calcium supplementation have been conflicting,^10,12–14 and reviews and meta-analyses have summarized the data.^1,3,15 A recent review of these meta-analyses showed a small but significant reduction in some types of fracture.¹

Some speculate that the difficulty in demonstrating fracture efficacy might be due to imperfect compliance with calcium intake, and that the participants in the placebo groups often had fairly robust calcium intake from diet and off-study supplemental intake, which could reduce the sensitivity of studies to demonstrate the fracture benefit.^1,16

The US Preventive Services Task Force¹⁷ recommends that the general public not take supplemental calcium for skeletal health, but emphasizes that this recommendation does not apply to patients with osteoporosis. Most other official guidelines (eg, those of the Endocrine Society,¹⁸ American Association of Clinical Endocrinologists,¹⁹ Institute of Medicine,²⁰ and National Osteoporosis Foundation²¹) recommend adequate calcium intake to optimize skeletal health.

CALCIUM INTAKE AND CORONARY ARTERY DISEASE

Patients often wonder if the calcium in their supplements ends up in their coronary arteries rather than their bones. Although we once dismissed such concerns, several studies and meta-analyses have reported higher rates of cardiovascular disease with supplemental calcium use.^22–24 A proposed mechanism to explain this increased risk is that taking calcium supplements transiently raises the serum calcium level, resulting in calcium deposition in coronary arteries, accelerating atherosclerosis formation.²⁵

On the other hand, some studies and meta-analyses have not shown any increased risk of cardiovascular disease with calcium and vitamin D supplementation.^26,27 This subject has been reviewed by Harvey et al.¹

Our conclusions are as follows:

Patients should be told that the National Osteoporosis Foundation and the American Society for Preventive Cardiology released a statement in 2016 adopting the position that calcium intake from food and supplements should be considered safe from a cardiovascular perspective.²⁸

If patients want to avoid the possible increase in risk of cardiovascular disease due to calcium supplementation, they can optimize their calcium intake with dietary calcium. Observational studies that showed increased risk with supplemental calcium found no such increase in cardiovascular disease with a robust dietary intake of calcium.²⁹

This is not to say that patients should be encouraged to boost their dietary calcium intake and avoid heart disease by eating more cheese and ice cream, as these foods are high in saturated fats and cholesterol. Many dairy and nondairy sources of calcium do not contain these undesirable nutrients.

CALCIUM SUPPLEMENTATION AND NEPHROLITHIASIS

High dietary calcium intake has not been shown to increase the risk of kidney stones.

In the Nurses’ Health Study, the multivariate relative risk of stone formation was 0.65 (95% confidence interval [CI] 0.5–0.83) in those in the highest vs the lowest quintiles of dietary calcium intake.³⁰ In contrast, the relative risk of stones in those taking calcium supplements was 1.2 (CI 1.02–1.41),³⁰ although this higher risk was not seen in younger women (ages 27 to 44).³¹  

Similar results were seen in the Women’s Health Initiative, in which calcium carbonate and vitamin D supplements resulted in a relative increased risk of stone formation of 1.17 (95% CI 1.02–1.34) compared with women on placebo.¹²

Data from male stone-formers also suggests that high dietary calcium intake does not increase the risk of stones.³²

A theory to explain the difference between dietary and supplemental calcium with respect to stone formation is that dietary calcium binds to oxalate in the gut and reduces its absorption. The most common type of kidney stones are composed of calcium oxalate, and the oxalate, not the calcium, may be the real culprit. In contrast, calcium supplements are often taken between meals and therefore do not exert this protective effect and may be absorbed more rapidly and raise the serum calcium level more, which could lead to higher urinary calcium excretion.³³

CALCIUM INTAKE IN PATIENTS TAKING ANTIRESORPTIVE DRUGS

Patients often mistakenly think that calcium and vitamin D supplements are given for mild cases of bone loss, and that if their bone loss is significant enough to require a medication, then they no longer need calcium and vitamin D supplements. Most clinical trials showing bone mineral density and fracture benefit from antiresorptive therapy were in patients who were taking enough calcium and vitamin D, so the efficacy of antiresorptive therapy is most clear only when taking enough calcium and vitamin D.^34,35

Furthermore, patients with inadequate calcium and vitamin D intake essentially maintain their serum calcium levels by mobilizing calcium from bone; the combination of insufficient calcium intake and administration of agents that interfere with the ability to mobilize calcium from bone may put patients at risk of hypocalcemia.³⁶

OPTIMIZING INTAKE OF CALCIUM AND VITAMIN D

Diet is key to calcium intake. People should consume adequate amounts of calcium-rich foods regardless of whether they have a history of kidney stones, since robust dietary intake of calcium does not increase the risk of cardiovascular disease or kidney stones and may actually have a protective effect. We also remain skeptical of the concern that supplemental calcium increases the risk of cardiovascular disease.

We recommend a target total calcium intake from diet, and if necessary, supplements, of 1,000 to 1,200 mg daily, and not to worry about cardiovascular disease or kidney stones. A patient or clinician reluctant to push calcium intake that high with supplements might opt for a more conservative goal of 800 mg of calcium daily. This recommendation is based on data suggesting that in the presence of vitamin D sufficiency, calcium supplementation with 500 mg of calcium citrate does little for patients whose calcium intake is above 400 mg/day.³⁷

Vitamin D: How much do we need?

Regarding vitamin D intake, the Institute of Medicine recommends 600 to 800 IU to achieve a 25-hydroxyvitamin D level of 20 to 40 ng/mL.²⁰

The Endocrine Society recommends “at least” 600 to 800 IU, but says that 1,500 to 2,000 IU may be needed to get the 25-hydroxyvitamin D level to 30 to 60 ng/mL.¹⁸

The Institute of Medicine based its recommendation on randomized controlled trials that showed fewer fractures with vitamin D intakes of 600 to 800 IU/day.^13,14 Also, observational studies show little further reduction in fracture risk when the 25-hydroxyvitamin D levels rise above 20 ng/mL.³⁸ A case-control study found an association between 25-hydroxyvitamin D levels higher than 40 ng/mL and pancreatic cancer.³⁹

The Endocrine Society guidelines recommended higher intakes and levels of vitamin D because there are data suggesting that vitamin D levels higher than 30 ng/mL suppress parathyroid hormone levels further, which should favor less mobilization of bone.⁴⁰

Levels of 25-hydroxyvitamin D in people exposed to plenty of sunlight rarely go above 60 ng/mL, suggesting 60 ng/mL should be the upper limit of levels to target, and it is unlikely that such levels are harmful.⁴¹

Implementing either recommendation—a target 25-hydroxyvitamin D level of 20 to 40 ng/mL or 30 to 60 ng/mL—is reasonable.

CALCULATING A PATIENT’S DIETARY CALCIUM INTAKE

A detailed dietary history can be obtained by a dietitian, or by using the Calcium Calculator app supported by the International Osteoporosis Foundation.⁴³ However, dietary calcium intake can be assessed quickly. To approximate a patient’s total dietary calcium intake (in milligrams), we multiply the number of servings of dietary calcium by 300. A serving of dietary calcium is found in:

• 1 cup of milk, yogurt, calcium-fortified juice, almonds, cooked spinach, or collard greens
• 1.5 ounces of hard cheese
• 2 cups of ice cream, cottage cheese, or beans
• 4 ounces of tofu or canned fish with bones such as salmon or sardines.

Therefore, if a patient consumes 1 cup of milk daily and 1 cup of yogurt 3 times a week, she takes in an estimated 1.5 servings of dietary calcium daily, or 450 mg. What the patient does not receive in the diet should be made up with supplemental calcium.

CALCIUM SUPPLEMENTS

Calcium citrate has certain advantages as a supplement. Calcium carbonate requires gastric acidity to be absorbed and is therefore better absorbed if taken with meals; however, calcium citrate is equally well absorbed in the fasting or fed state and so can be taken without regard for achlorhydria or timing of meals.⁴⁴

Another potential advantage of calcium citrate is that it has never been shown to increase the risk of kidney stones the way calcium carbonate has.¹² Further, potassium citrate is a treatment for certain types of kidney stones,⁴⁵ and it is possible that when calcium is given as citrate there is less danger of kidney stones.⁴⁶ For these reasons, we generally recommend calcium citrate over other forms of calcium.

The brand of calcium citrate most readily available is Citracal, but any version of calcium citrate is acceptable.

SOURCES OF CONFUSION

Labels that describe calcium content of supplements are often misleading, and this lack of clarity can interfere with the patient’s ability to correctly identify how much calcium is in each pill.

Serving size. Whereas 1 serving of Caltrate is 1 pill, 1 serving of Tums or Citracal is 2 pills; for other brands a serving may be 3 or 4 pills.

Calcium salt vs elemental calcium. The amount of elemental calcium contained in different calcium salts varies according to the molecular weight of the salt: 1,000 mg of calcium carbonate has 400 mg of elemental calcium, while 1,000 mg of calcium citrate has 200 mg of elemental calcium.

When we recommend 1,000 to 1,200 mg of calcium daily, we mean the amount of elemental calcium. The label on calcium supplements usually indicates the amount of elemental calcium, but some have confusing information about the amount of calcium salt they contain. For instance, Tums lists the amount of calcium carbonate per pill on the top of the label, but elsewhere lists the amount of elemental calcium.

Same brand, different preparation. Some brands of calcium have more than 1 formulation, each with a different amount of calcium. For instance, Citracal has a maximum-strength 315-mg tablet and a “petite” 200-mg tablet. Careful reading of the label is required to make sure that the patient is getting the amount of calcium she thinks she is getting.

OPTIONS FOR THOSE WITH DIFFICULTY SWALLOWING LARGE PILLS

Many calcium pills are large and difficult to swallow. Patients often ask if calcium pills can be crushed, and the answer is that they certainly can, but this approach is cumbersome and usually results in patients eventually stopping calcium in frustration.

CALCIUM SUPPLEMENTS AND CONSTIPATION

Constipation is a common side effect of calcium supplementation.⁴⁷ Many patients report that they cannot take a calcium supplement because of constipation, or ask if there are calcium preparations that are less constipating than others.

There are ways of overcoming the constipating effects of calcium. Osmotic laxatives and stool softeners such as polyethylene glycol, magnesium citrate, and docusate sodium are safe and effective, although patients are often reluctant to take a medicine to combat the side effects from another medicine.

In such circumstances patients are often amenable to taking a combination product such as calcium with magnesium, since the cathartic effects of magnesium nicely counteract the constipating effects of calcium. This idea is exploited in antacids such as Rolaids, which are combinations of calcium carbonate and magnesium oxide that usually have no net effect on stool consistency.⁴⁷

Many patients believe that calcium must be combined with magnesium to be absorbed. Although there are no data to support this idea, a patient already harboring this misconception may be more amenable to calcium-magnesium combinations for the purpose of avoiding constipation.

If a patient cannot find a calcium preparation that she can take at the full recommended doses, we often suggest starting with a very small dose for 2 weeks, and then adjusting the dose upward every 2 weeks until reaching the maximum dose that the patient can tolerate. Even if the dose is well below recommended doses, most of the benefit of calcium is obtained by bringing total intake to more than 500 mg daily,³⁷ so continued use should be encouraged even when optimal targets cannot be sustained.

For patients who cannot tolerate enough calcium, we recommend being especially sure to optimize the vitamin D levels, since there are studies that suggest that secondary hyperparathyroidism mostly occurs in states of low calcium intake if vitamin D levels are insufficient.⁴⁸

If the patient has secondary hyperpara­thyroidism despite best attempts at supplementation with calcium and vitamin D, consider prescribing calcitriol (activated vitamin D), which stimulates gut absorption of whatever calcium is taken.⁴⁹ If calcitriol is given, the patient must undergo cumbersome monitoring for hypercalcemia and hypercalciuria. Fortunately, it is unusual to require calcitriol unless the patient has significant structural gastrointestinal abnormalities such as gastric bypass or Crohn disease.

Although calcium and vitamin D are often recommended for prevention and treatment of osteoporosis, considerable controversy exists in terms of their safety and efficacy.¹ This article highlights the issues, referring  readers to reviews and meta-analyses for details and providing some practical advice for patients requiring supplementation.

CALCIUM INTAKE AND BONE DENSITY

Calcium enters the body through diet and supplementation. If intake is low, blood calcium levels fall, resulting in secondary hyperparathyroidism, which has 3 main effects:

• Increased fractional absorption of the calcium that is consumed
• Reduced urinary excretion of calcium
• Increased bone resorption, which releases calcium into the blood,² which explains the potential for the deleterious effect of deficient intake of calcium on bone.³

Based on the simple physiology outlined above, it seems logical that insufficient intake of calcium over time could lead to mobilization of calcium from bone, lower bone mineral density, and higher fracture risk.³ This topic has been reviewed by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases and the International Foundation for Osteoporosis.¹

Many lines of evidence suggest that low calcium intake adversely affects bone mineral density.¹ Low calcium intake has been associated with lower bone density in some cross-sectional studies,^4–6 though not all.⁷ Interventions to increase calcium intake in postmenopausal women have shown beneficial effects on bone density,^8–10 though in some studies the benefit was small and nonprogressive.¹¹ The question is whether this improvement in bone mineral density translates into fewer fractures.

Results from individual studies looking at fracture prevention through calcium supplementation have been conflicting,^10,12–14 and reviews and meta-analyses have summarized the data.^1,3,15 A recent review of these meta-analyses showed a small but significant reduction in some types of fracture.¹

Some speculate that the difficulty in demonstrating fracture efficacy might be due to imperfect compliance with calcium intake, and that the participants in the placebo groups often had fairly robust calcium intake from diet and off-study supplemental intake, which could reduce the sensitivity of studies to demonstrate the fracture benefit.^1,16

The US Preventive Services Task Force¹⁷ recommends that the general public not take supplemental calcium for skeletal health, but emphasizes that this recommendation does not apply to patients with osteoporosis. Most other official guidelines (eg, those of the Endocrine Society,¹⁸ American Association of Clinical Endocrinologists,¹⁹ Institute of Medicine,²⁰ and National Osteoporosis Foundation²¹) recommend adequate calcium intake to optimize skeletal health.

CALCIUM INTAKE AND CORONARY ARTERY DISEASE

Patients often wonder if the calcium in their supplements ends up in their coronary arteries rather than their bones. Although we once dismissed such concerns, several studies and meta-analyses have reported higher rates of cardiovascular disease with supplemental calcium use.^22–24 A proposed mechanism to explain this increased risk is that taking calcium supplements transiently raises the serum calcium level, resulting in calcium deposition in coronary arteries, accelerating atherosclerosis formation.²⁵

On the other hand, some studies and meta-analyses have not shown any increased risk of cardiovascular disease with calcium and vitamin D supplementation.^26,27 This subject has been reviewed by Harvey et al.¹

Our conclusions are as follows:

Patients should be told that the National Osteoporosis Foundation and the American Society for Preventive Cardiology released a statement in 2016 adopting the position that calcium intake from food and supplements should be considered safe from a cardiovascular perspective.²⁸

If patients want to avoid the possible increase in risk of cardiovascular disease due to calcium supplementation, they can optimize their calcium intake with dietary calcium. Observational studies that showed increased risk with supplemental calcium found no such increase in cardiovascular disease with a robust dietary intake of calcium.²⁹

This is not to say that patients should be encouraged to boost their dietary calcium intake and avoid heart disease by eating more cheese and ice cream, as these foods are high in saturated fats and cholesterol. Many dairy and nondairy sources of calcium do not contain these undesirable nutrients.

CALCIUM SUPPLEMENTATION AND NEPHROLITHIASIS

High dietary calcium intake has not been shown to increase the risk of kidney stones.

In the Nurses’ Health Study, the multivariate relative risk of stone formation was 0.65 (95% confidence interval [CI] 0.5–0.83) in those in the highest vs the lowest quintiles of dietary calcium intake.³⁰ In contrast, the relative risk of stones in those taking calcium supplements was 1.2 (CI 1.02–1.41),³⁰ although this higher risk was not seen in younger women (ages 27 to 44).³¹  

Similar results were seen in the Women’s Health Initiative, in which calcium carbonate and vitamin D supplements resulted in a relative increased risk of stone formation of 1.17 (95% CI 1.02–1.34) compared with women on placebo.¹²

Data from male stone-formers also suggests that high dietary calcium intake does not increase the risk of stones.³²

A theory to explain the difference between dietary and supplemental calcium with respect to stone formation is that dietary calcium binds to oxalate in the gut and reduces its absorption. The most common type of kidney stones are composed of calcium oxalate, and the oxalate, not the calcium, may be the real culprit. In contrast, calcium supplements are often taken between meals and therefore do not exert this protective effect and may be absorbed more rapidly and raise the serum calcium level more, which could lead to higher urinary calcium excretion.³³

CALCIUM INTAKE IN PATIENTS TAKING ANTIRESORPTIVE DRUGS

Patients often mistakenly think that calcium and vitamin D supplements are given for mild cases of bone loss, and that if their bone loss is significant enough to require a medication, then they no longer need calcium and vitamin D supplements. Most clinical trials showing bone mineral density and fracture benefit from antiresorptive therapy were in patients who were taking enough calcium and vitamin D, so the efficacy of antiresorptive therapy is most clear only when taking enough calcium and vitamin D.^34,35

Furthermore, patients with inadequate calcium and vitamin D intake essentially maintain their serum calcium levels by mobilizing calcium from bone; the combination of insufficient calcium intake and administration of agents that interfere with the ability to mobilize calcium from bone may put patients at risk of hypocalcemia.³⁶

OPTIMIZING INTAKE OF CALCIUM AND VITAMIN D

Diet is key to calcium intake. People should consume adequate amounts of calcium-rich foods regardless of whether they have a history of kidney stones, since robust dietary intake of calcium does not increase the risk of cardiovascular disease or kidney stones and may actually have a protective effect. We also remain skeptical of the concern that supplemental calcium increases the risk of cardiovascular disease.

We recommend a target total calcium intake from diet, and if necessary, supplements, of 1,000 to 1,200 mg daily, and not to worry about cardiovascular disease or kidney stones. A patient or clinician reluctant to push calcium intake that high with supplements might opt for a more conservative goal of 800 mg of calcium daily. This recommendation is based on data suggesting that in the presence of vitamin D sufficiency, calcium supplementation with 500 mg of calcium citrate does little for patients whose calcium intake is above 400 mg/day.³⁷

Vitamin D: How much do we need?

Regarding vitamin D intake, the Institute of Medicine recommends 600 to 800 IU to achieve a 25-hydroxyvitamin D level of 20 to 40 ng/mL.²⁰

The Endocrine Society recommends “at least” 600 to 800 IU, but says that 1,500 to 2,000 IU may be needed to get the 25-hydroxyvitamin D level to 30 to 60 ng/mL.¹⁸

The Institute of Medicine based its recommendation on randomized controlled trials that showed fewer fractures with vitamin D intakes of 600 to 800 IU/day.^13,14 Also, observational studies show little further reduction in fracture risk when the 25-hydroxyvitamin D levels rise above 20 ng/mL.³⁸ A case-control study found an association between 25-hydroxyvitamin D levels higher than 40 ng/mL and pancreatic cancer.³⁹

The Endocrine Society guidelines recommended higher intakes and levels of vitamin D because there are data suggesting that vitamin D levels higher than 30 ng/mL suppress parathyroid hormone levels further, which should favor less mobilization of bone.⁴⁰

Levels of 25-hydroxyvitamin D in people exposed to plenty of sunlight rarely go above 60 ng/mL, suggesting 60 ng/mL should be the upper limit of levels to target, and it is unlikely that such levels are harmful.⁴¹

Implementing either recommendation—a target 25-hydroxyvitamin D level of 20 to 40 ng/mL or 30 to 60 ng/mL—is reasonable.

CALCULATING A PATIENT’S DIETARY CALCIUM INTAKE

A detailed dietary history can be obtained by a dietitian, or by using the Calcium Calculator app supported by the International Osteoporosis Foundation.⁴³ However, dietary calcium intake can be assessed quickly. To approximate a patient’s total dietary calcium intake (in milligrams), we multiply the number of servings of dietary calcium by 300. A serving of dietary calcium is found in:

• 1 cup of milk, yogurt, calcium-fortified juice, almonds, cooked spinach, or collard greens
• 1.5 ounces of hard cheese
• 2 cups of ice cream, cottage cheese, or beans
• 4 ounces of tofu or canned fish with bones such as salmon or sardines.

Therefore, if a patient consumes 1 cup of milk daily and 1 cup of yogurt 3 times a week, she takes in an estimated 1.5 servings of dietary calcium daily, or 450 mg. What the patient does not receive in the diet should be made up with supplemental calcium.

CALCIUM SUPPLEMENTS

Calcium citrate has certain advantages as a supplement. Calcium carbonate requires gastric acidity to be absorbed and is therefore better absorbed if taken with meals; however, calcium citrate is equally well absorbed in the fasting or fed state and so can be taken without regard for achlorhydria or timing of meals.⁴⁴

Another potential advantage of calcium citrate is that it has never been shown to increase the risk of kidney stones the way calcium carbonate has.¹² Further, potassium citrate is a treatment for certain types of kidney stones,⁴⁵ and it is possible that when calcium is given as citrate there is less danger of kidney stones.⁴⁶ For these reasons, we generally recommend calcium citrate over other forms of calcium.

The brand of calcium citrate most readily available is Citracal, but any version of calcium citrate is acceptable.

SOURCES OF CONFUSION

Labels that describe calcium content of supplements are often misleading, and this lack of clarity can interfere with the patient’s ability to correctly identify how much calcium is in each pill.

Serving size. Whereas 1 serving of Caltrate is 1 pill, 1 serving of Tums or Citracal is 2 pills; for other brands a serving may be 3 or 4 pills.

Calcium salt vs elemental calcium. The amount of elemental calcium contained in different calcium salts varies according to the molecular weight of the salt: 1,000 mg of calcium carbonate has 400 mg of elemental calcium, while 1,000 mg of calcium citrate has 200 mg of elemental calcium.

When we recommend 1,000 to 1,200 mg of calcium daily, we mean the amount of elemental calcium. The label on calcium supplements usually indicates the amount of elemental calcium, but some have confusing information about the amount of calcium salt they contain. For instance, Tums lists the amount of calcium carbonate per pill on the top of the label, but elsewhere lists the amount of elemental calcium.

Same brand, different preparation. Some brands of calcium have more than 1 formulation, each with a different amount of calcium. For instance, Citracal has a maximum-strength 315-mg tablet and a “petite” 200-mg tablet. Careful reading of the label is required to make sure that the patient is getting the amount of calcium she thinks she is getting.

OPTIONS FOR THOSE WITH DIFFICULTY SWALLOWING LARGE PILLS

Many calcium pills are large and difficult to swallow. Patients often ask if calcium pills can be crushed, and the answer is that they certainly can, but this approach is cumbersome and usually results in patients eventually stopping calcium in frustration.

CALCIUM SUPPLEMENTS AND CONSTIPATION

Constipation is a common side effect of calcium supplementation.⁴⁷ Many patients report that they cannot take a calcium supplement because of constipation, or ask if there are calcium preparations that are less constipating than others.

There are ways of overcoming the constipating effects of calcium. Osmotic laxatives and stool softeners such as polyethylene glycol, magnesium citrate, and docusate sodium are safe and effective, although patients are often reluctant to take a medicine to combat the side effects from another medicine.

In such circumstances patients are often amenable to taking a combination product such as calcium with magnesium, since the cathartic effects of magnesium nicely counteract the constipating effects of calcium. This idea is exploited in antacids such as Rolaids, which are combinations of calcium carbonate and magnesium oxide that usually have no net effect on stool consistency.⁴⁷

Many patients believe that calcium must be combined with magnesium to be absorbed. Although there are no data to support this idea, a patient already harboring this misconception may be more amenable to calcium-magnesium combinations for the purpose of avoiding constipation.

If a patient cannot find a calcium preparation that she can take at the full recommended doses, we often suggest starting with a very small dose for 2 weeks, and then adjusting the dose upward every 2 weeks until reaching the maximum dose that the patient can tolerate. Even if the dose is well below recommended doses, most of the benefit of calcium is obtained by bringing total intake to more than 500 mg daily,³⁷ so continued use should be encouraged even when optimal targets cannot be sustained.

For patients who cannot tolerate enough calcium, we recommend being especially sure to optimize the vitamin D levels, since there are studies that suggest that secondary hyperparathyroidism mostly occurs in states of low calcium intake if vitamin D levels are insufficient.⁴⁸

If the patient has secondary hyperpara­thyroidism despite best attempts at supplementation with calcium and vitamin D, consider prescribing calcitriol (activated vitamin D), which stimulates gut absorption of whatever calcium is taken.⁴⁹ If calcitriol is given, the patient must undergo cumbersome monitoring for hypercalcemia and hypercalciuria. Fortunately, it is unusual to require calcitriol unless the patient has significant structural gastrointestinal abnormalities such as gastric bypass or Crohn disease.

Although calcium and vitamin D are often recommended for prevention and treatment of osteoporosis, considerable controversy exists in terms of their safety and efficacy.¹ This article highlights the issues, referring  readers to reviews and meta-analyses for details and providing some practical advice for patients requiring supplementation.

CALCIUM INTAKE AND BONE DENSITY

Calcium enters the body through diet and supplementation. If intake is low, blood calcium levels fall, resulting in secondary hyperparathyroidism, which has 3 main effects:

• Increased fractional absorption of the calcium that is consumed
• Reduced urinary excretion of calcium
• Increased bone resorption, which releases calcium into the blood,² which explains the potential for the deleterious effect of deficient intake of calcium on bone.³

Based on the simple physiology outlined above, it seems logical that insufficient intake of calcium over time could lead to mobilization of calcium from bone, lower bone mineral density, and higher fracture risk.³ This topic has been reviewed by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases and the International Foundation for Osteoporosis.¹

Many lines of evidence suggest that low calcium intake adversely affects bone mineral density.¹ Low calcium intake has been associated with lower bone density in some cross-sectional studies,^4–6 though not all.⁷ Interventions to increase calcium intake in postmenopausal women have shown beneficial effects on bone density,^8–10 though in some studies the benefit was small and nonprogressive.¹¹ The question is whether this improvement in bone mineral density translates into fewer fractures.

Results from individual studies looking at fracture prevention through calcium supplementation have been conflicting,^10,12–14 and reviews and meta-analyses have summarized the data.^1,3,15 A recent review of these meta-analyses showed a small but significant reduction in some types of fracture.¹

Some speculate that the difficulty in demonstrating fracture efficacy might be due to imperfect compliance with calcium intake, and that the participants in the placebo groups often had fairly robust calcium intake from diet and off-study supplemental intake, which could reduce the sensitivity of studies to demonstrate the fracture benefit.^1,16

The US Preventive Services Task Force¹⁷ recommends that the general public not take supplemental calcium for skeletal health, but emphasizes that this recommendation does not apply to patients with osteoporosis. Most other official guidelines (eg, those of the Endocrine Society,¹⁸ American Association of Clinical Endocrinologists,¹⁹ Institute of Medicine,²⁰ and National Osteoporosis Foundation²¹) recommend adequate calcium intake to optimize skeletal health.

CALCIUM INTAKE AND CORONARY ARTERY DISEASE

Patients often wonder if the calcium in their supplements ends up in their coronary arteries rather than their bones. Although we once dismissed such concerns, several studies and meta-analyses have reported higher rates of cardiovascular disease with supplemental calcium use.^22–24 A proposed mechanism to explain this increased risk is that taking calcium supplements transiently raises the serum calcium level, resulting in calcium deposition in coronary arteries, accelerating atherosclerosis formation.²⁵

On the other hand, some studies and meta-analyses have not shown any increased risk of cardiovascular disease with calcium and vitamin D supplementation.^26,27 This subject has been reviewed by Harvey et al.¹

Our conclusions are as follows:

Patients should be told that the National Osteoporosis Foundation and the American Society for Preventive Cardiology released a statement in 2016 adopting the position that calcium intake from food and supplements should be considered safe from a cardiovascular perspective.²⁸

If patients want to avoid the possible increase in risk of cardiovascular disease due to calcium supplementation, they can optimize their calcium intake with dietary calcium. Observational studies that showed increased risk with supplemental calcium found no such increase in cardiovascular disease with a robust dietary intake of calcium.²⁹

This is not to say that patients should be encouraged to boost their dietary calcium intake and avoid heart disease by eating more cheese and ice cream, as these foods are high in saturated fats and cholesterol. Many dairy and nondairy sources of calcium do not contain these undesirable nutrients.

CALCIUM SUPPLEMENTATION AND NEPHROLITHIASIS

High dietary calcium intake has not been shown to increase the risk of kidney stones.

In the Nurses’ Health Study, the multivariate relative risk of stone formation was 0.65 (95% confidence interval [CI] 0.5–0.83) in those in the highest vs the lowest quintiles of dietary calcium intake.³⁰ In contrast, the relative risk of stones in those taking calcium supplements was 1.2 (CI 1.02–1.41),³⁰ although this higher risk was not seen in younger women (ages 27 to 44).³¹  

Similar results were seen in the Women’s Health Initiative, in which calcium carbonate and vitamin D supplements resulted in a relative increased risk of stone formation of 1.17 (95% CI 1.02–1.34) compared with women on placebo.¹²

Data from male stone-formers also suggests that high dietary calcium intake does not increase the risk of stones.³²

A theory to explain the difference between dietary and supplemental calcium with respect to stone formation is that dietary calcium binds to oxalate in the gut and reduces its absorption. The most common type of kidney stones are composed of calcium oxalate, and the oxalate, not the calcium, may be the real culprit. In contrast, calcium supplements are often taken between meals and therefore do not exert this protective effect and may be absorbed more rapidly and raise the serum calcium level more, which could lead to higher urinary calcium excretion.³³

CALCIUM INTAKE IN PATIENTS TAKING ANTIRESORPTIVE DRUGS

Patients often mistakenly think that calcium and vitamin D supplements are given for mild cases of bone loss, and that if their bone loss is significant enough to require a medication, then they no longer need calcium and vitamin D supplements. Most clinical trials showing bone mineral density and fracture benefit from antiresorptive therapy were in patients who were taking enough calcium and vitamin D, so the efficacy of antiresorptive therapy is most clear only when taking enough calcium and vitamin D.^34,35

Furthermore, patients with inadequate calcium and vitamin D intake essentially maintain their serum calcium levels by mobilizing calcium from bone; the combination of insufficient calcium intake and administration of agents that interfere with the ability to mobilize calcium from bone may put patients at risk of hypocalcemia.³⁶

OPTIMIZING INTAKE OF CALCIUM AND VITAMIN D

Diet is key to calcium intake. People should consume adequate amounts of calcium-rich foods regardless of whether they have a history of kidney stones, since robust dietary intake of calcium does not increase the risk of cardiovascular disease or kidney stones and may actually have a protective effect. We also remain skeptical of the concern that supplemental calcium increases the risk of cardiovascular disease.

We recommend a target total calcium intake from diet, and if necessary, supplements, of 1,000 to 1,200 mg daily, and not to worry about cardiovascular disease or kidney stones. A patient or clinician reluctant to push calcium intake that high with supplements might opt for a more conservative goal of 800 mg of calcium daily. This recommendation is based on data suggesting that in the presence of vitamin D sufficiency, calcium supplementation with 500 mg of calcium citrate does little for patients whose calcium intake is above 400 mg/day.³⁷

Vitamin D: How much do we need?

Regarding vitamin D intake, the Institute of Medicine recommends 600 to 800 IU to achieve a 25-hydroxyvitamin D level of 20 to 40 ng/mL.²⁰

The Endocrine Society recommends “at least” 600 to 800 IU, but says that 1,500 to 2,000 IU may be needed to get the 25-hydroxyvitamin D level to 30 to 60 ng/mL.¹⁸

The Institute of Medicine based its recommendation on randomized controlled trials that showed fewer fractures with vitamin D intakes of 600 to 800 IU/day.^13,14 Also, observational studies show little further reduction in fracture risk when the 25-hydroxyvitamin D levels rise above 20 ng/mL.³⁸ A case-control study found an association between 25-hydroxyvitamin D levels higher than 40 ng/mL and pancreatic cancer.³⁹

The Endocrine Society guidelines recommended higher intakes and levels of vitamin D because there are data suggesting that vitamin D levels higher than 30 ng/mL suppress parathyroid hormone levels further, which should favor less mobilization of bone.⁴⁰

Levels of 25-hydroxyvitamin D in people exposed to plenty of sunlight rarely go above 60 ng/mL, suggesting 60 ng/mL should be the upper limit of levels to target, and it is unlikely that such levels are harmful.⁴¹

Implementing either recommendation—a target 25-hydroxyvitamin D level of 20 to 40 ng/mL or 30 to 60 ng/mL—is reasonable.

CALCULATING A PATIENT’S DIETARY CALCIUM INTAKE

A detailed dietary history can be obtained by a dietitian, or by using the Calcium Calculator app supported by the International Osteoporosis Foundation.⁴³ However, dietary calcium intake can be assessed quickly. To approximate a patient’s total dietary calcium intake (in milligrams), we multiply the number of servings of dietary calcium by 300. A serving of dietary calcium is found in:

• 1 cup of milk, yogurt, calcium-fortified juice, almonds, cooked spinach, or collard greens
• 1.5 ounces of hard cheese
• 2 cups of ice cream, cottage cheese, or beans
• 4 ounces of tofu or canned fish with bones such as salmon or sardines.

Therefore, if a patient consumes 1 cup of milk daily and 1 cup of yogurt 3 times a week, she takes in an estimated 1.5 servings of dietary calcium daily, or 450 mg. What the patient does not receive in the diet should be made up with supplemental calcium.

CALCIUM SUPPLEMENTS

Calcium citrate has certain advantages as a supplement. Calcium carbonate requires gastric acidity to be absorbed and is therefore better absorbed if taken with meals; however, calcium citrate is equally well absorbed in the fasting or fed state and so can be taken without regard for achlorhydria or timing of meals.⁴⁴

Another potential advantage of calcium citrate is that it has never been shown to increase the risk of kidney stones the way calcium carbonate has.¹² Further, potassium citrate is a treatment for certain types of kidney stones,⁴⁵ and it is possible that when calcium is given as citrate there is less danger of kidney stones.⁴⁶ For these reasons, we generally recommend calcium citrate over other forms of calcium.

The brand of calcium citrate most readily available is Citracal, but any version of calcium citrate is acceptable.

SOURCES OF CONFUSION

Labels that describe calcium content of supplements are often misleading, and this lack of clarity can interfere with the patient’s ability to correctly identify how much calcium is in each pill.

Serving size. Whereas 1 serving of Caltrate is 1 pill, 1 serving of Tums or Citracal is 2 pills; for other brands a serving may be 3 or 4 pills.

Calcium salt vs elemental calcium. The amount of elemental calcium contained in different calcium salts varies according to the molecular weight of the salt: 1,000 mg of calcium carbonate has 400 mg of elemental calcium, while 1,000 mg of calcium citrate has 200 mg of elemental calcium.

When we recommend 1,000 to 1,200 mg of calcium daily, we mean the amount of elemental calcium. The label on calcium supplements usually indicates the amount of elemental calcium, but some have confusing information about the amount of calcium salt they contain. For instance, Tums lists the amount of calcium carbonate per pill on the top of the label, but elsewhere lists the amount of elemental calcium.

Same brand, different preparation. Some brands of calcium have more than 1 formulation, each with a different amount of calcium. For instance, Citracal has a maximum-strength 315-mg tablet and a “petite” 200-mg tablet. Careful reading of the label is required to make sure that the patient is getting the amount of calcium she thinks she is getting.

OPTIONS FOR THOSE WITH DIFFICULTY SWALLOWING LARGE PILLS

Many calcium pills are large and difficult to swallow. Patients often ask if calcium pills can be crushed, and the answer is that they certainly can, but this approach is cumbersome and usually results in patients eventually stopping calcium in frustration.

CALCIUM SUPPLEMENTS AND CONSTIPATION

Constipation is a common side effect of calcium supplementation.⁴⁷ Many patients report that they cannot take a calcium supplement because of constipation, or ask if there are calcium preparations that are less constipating than others.

There are ways of overcoming the constipating effects of calcium. Osmotic laxatives and stool softeners such as polyethylene glycol, magnesium citrate, and docusate sodium are safe and effective, although patients are often reluctant to take a medicine to combat the side effects from another medicine.

In such circumstances patients are often amenable to taking a combination product such as calcium with magnesium, since the cathartic effects of magnesium nicely counteract the constipating effects of calcium. This idea is exploited in antacids such as Rolaids, which are combinations of calcium carbonate and magnesium oxide that usually have no net effect on stool consistency.⁴⁷

Many patients believe that calcium must be combined with magnesium to be absorbed. Although there are no data to support this idea, a patient already harboring this misconception may be more amenable to calcium-magnesium combinations for the purpose of avoiding constipation.

If a patient cannot find a calcium preparation that she can take at the full recommended doses, we often suggest starting with a very small dose for 2 weeks, and then adjusting the dose upward every 2 weeks until reaching the maximum dose that the patient can tolerate. Even if the dose is well below recommended doses, most of the benefit of calcium is obtained by bringing total intake to more than 500 mg daily,³⁷ so continued use should be encouraged even when optimal targets cannot be sustained.

For patients who cannot tolerate enough calcium, we recommend being especially sure to optimize the vitamin D levels, since there are studies that suggest that secondary hyperparathyroidism mostly occurs in states of low calcium intake if vitamin D levels are insufficient.⁴⁸

If the patient has secondary hyperpara­thyroidism despite best attempts at supplementation with calcium and vitamin D, consider prescribing calcitriol (activated vitamin D), which stimulates gut absorption of whatever calcium is taken.⁴⁹ If calcitriol is given, the patient must undergo cumbersome monitoring for hypercalcemia and hypercalciuria. Fortunately, it is unusual to require calcitriol unless the patient has significant structural gastrointestinal abnormalities such as gastric bypass or Crohn disease.

With so much emphasis on clinical trials, evidence-based joint decision-making, and comparative-benefit studies when choosing treatment, the growth of the supplement market is a strong comment on the perceived and often real failings of traditional therapies. It also reflects our apparent failure as a profession to educate ourselves and the public about the difference between anecdote-based belief and clinical trial-based confidence, the difference between evidence and innuendo, and, equally important, the limitations of applying population-based clinical trial data to an individual patient.

Which brings me to the discussion of calcium and vitamin D supplementation by Drs. Kilim and Rosen in this issue of the Journal. We know a lot about calcium homeostasis and the role vitamin D plays in regulating circulating calcium levels. Only a small fraction of the calcium in the body circulates (most is in our skeleton), and likely only about 1% is truly exchangeable. But the circulating free calcium level is tightly controlled, as the function of our neuromuscular system, brain, and heart depend on keeping intra- and extracellular calcium levels within precise limits. If necessary, our bodies maintain stable levels of circulating free calcium at the expense of leaching calcium from our bones, placing us at risk of potentially fatal fractures. Thus was born the concept of guaranteeing adequate calcium stores through calcium supplementation.

Control of the free calcium level is not simple. There are several interrelated sensing and modulatory pathways, eg:

• Gut absorption, which is affected by the total gut load of calcium, intestinal integrity, and the specific ingested foodstuffs, and likely by our microbiome
• The parathyroid hormone (PTH) level, which directly or indirectly affects calcium absorption, the calcium-phosphate ratio, and thus, extraskeletal calcium localization and bone calcium content
• Vitamin D, with its many effects after interorgan multistep activation.

Despite this knowledge of calcium metabolism and the intricate cross-talk between the different pathways, I do not believe we truly understand how to determine the amount of dietary and supplemental calcium or vitamin D that is ideal for a given patient. I also do not believe we know with certainty what is the “normal” or ideal 25-hydroxyvitamin D level in that same patient: note the different ranges of normal proposed by different expert working groups.

How do we know when there is insufficient calcium in our diet? The total or free circulating calcium level is far too insensitive and, as noted above, complex homeostatic mechanisms are always trying to maintain an appropriate physiologic calcium level, whatever the intake. Urinary calcium excretion does not necessarily equal the ingested calcium load; there are too many factors influencing renal calcium excretion. Gastrointestinal excretion is also variable and complex. We know when the vitamin D level is functionally much too low, as the PTH level begins to rise; but the “normal” PTH range is wide, and the slope of the relationship between vitamin D and PTH is affected by many factors.

Additionally, accumulating information suggests that vitamin D metabolites significantly affect immune regulation and the onset and expression of a number of organ-specific and systemic autoimmune disorders. Further, the ideal 25-hydroxyvitamin D level for a healthy immune system is not known. Does the body have to compromise something in reconciling the target for a healthy skeleton and the target for a healthy immune system, which may conceivably be different? But importantly, this new knowledge does not imply that vitamin D supplementation will reduce the pain and symptoms from inflammatory arthritis or noninflammatory fibromyalgia.

Despite these many areas of uncertainty, Kilim and Rosen focus on bone health, summarize the wealth of accumulated data, and provide practical management advice we can use in the clinic. But if we struggle so much to know the correct way to manage calcium and vitamin D supplementation in our patients, it is little surprise that most of us struggle even more when asked about using supplements for which the biology is far less understood. As a medical community, we need to uniformly address this lack of understanding wherever it exists. Believing in a supplement or a treatment is not the same as understanding it or having strong evidence about its efficacy and safety.

With so much emphasis on clinical trials, evidence-based joint decision-making, and comparative-benefit studies when choosing treatment, the growth of the supplement market is a strong comment on the perceived and often real failings of traditional therapies. It also reflects our apparent failure as a profession to educate ourselves and the public about the difference between anecdote-based belief and clinical trial-based confidence, the difference between evidence and innuendo, and, equally important, the limitations of applying population-based clinical trial data to an individual patient.

Which brings me to the discussion of calcium and vitamin D supplementation by Drs. Kilim and Rosen in this issue of the Journal. We know a lot about calcium homeostasis and the role vitamin D plays in regulating circulating calcium levels. Only a small fraction of the calcium in the body circulates (most is in our skeleton), and likely only about 1% is truly exchangeable. But the circulating free calcium level is tightly controlled, as the function of our neuromuscular system, brain, and heart depend on keeping intra- and extracellular calcium levels within precise limits. If necessary, our bodies maintain stable levels of circulating free calcium at the expense of leaching calcium from our bones, placing us at risk of potentially fatal fractures. Thus was born the concept of guaranteeing adequate calcium stores through calcium supplementation.

Control of the free calcium level is not simple. There are several interrelated sensing and modulatory pathways, eg:

• Gut absorption, which is affected by the total gut load of calcium, intestinal integrity, and the specific ingested foodstuffs, and likely by our microbiome
• The parathyroid hormone (PTH) level, which directly or indirectly affects calcium absorption, the calcium-phosphate ratio, and thus, extraskeletal calcium localization and bone calcium content
• Vitamin D, with its many effects after interorgan multistep activation.

Despite this knowledge of calcium metabolism and the intricate cross-talk between the different pathways, I do not believe we truly understand how to determine the amount of dietary and supplemental calcium or vitamin D that is ideal for a given patient. I also do not believe we know with certainty what is the “normal” or ideal 25-hydroxyvitamin D level in that same patient: note the different ranges of normal proposed by different expert working groups.

How do we know when there is insufficient calcium in our diet? The total or free circulating calcium level is far too insensitive and, as noted above, complex homeostatic mechanisms are always trying to maintain an appropriate physiologic calcium level, whatever the intake. Urinary calcium excretion does not necessarily equal the ingested calcium load; there are too many factors influencing renal calcium excretion. Gastrointestinal excretion is also variable and complex. We know when the vitamin D level is functionally much too low, as the PTH level begins to rise; but the “normal” PTH range is wide, and the slope of the relationship between vitamin D and PTH is affected by many factors.

Additionally, accumulating information suggests that vitamin D metabolites significantly affect immune regulation and the onset and expression of a number of organ-specific and systemic autoimmune disorders. Further, the ideal 25-hydroxyvitamin D level for a healthy immune system is not known. Does the body have to compromise something in reconciling the target for a healthy skeleton and the target for a healthy immune system, which may conceivably be different? But importantly, this new knowledge does not imply that vitamin D supplementation will reduce the pain and symptoms from inflammatory arthritis or noninflammatory fibromyalgia.

Despite these many areas of uncertainty, Kilim and Rosen focus on bone health, summarize the wealth of accumulated data, and provide practical management advice we can use in the clinic. But if we struggle so much to know the correct way to manage calcium and vitamin D supplementation in our patients, it is little surprise that most of us struggle even more when asked about using supplements for which the biology is far less understood. As a medical community, we need to uniformly address this lack of understanding wherever it exists. Believing in a supplement or a treatment is not the same as understanding it or having strong evidence about its efficacy and safety.

With so much emphasis on clinical trials, evidence-based joint decision-making, and comparative-benefit studies when choosing treatment, the growth of the supplement market is a strong comment on the perceived and often real failings of traditional therapies. It also reflects our apparent failure as a profession to educate ourselves and the public about the difference between anecdote-based belief and clinical trial-based confidence, the difference between evidence and innuendo, and, equally important, the limitations of applying population-based clinical trial data to an individual patient.

Which brings me to the discussion of calcium and vitamin D supplementation by Drs. Kilim and Rosen in this issue of the Journal. We know a lot about calcium homeostasis and the role vitamin D plays in regulating circulating calcium levels. Only a small fraction of the calcium in the body circulates (most is in our skeleton), and likely only about 1% is truly exchangeable. But the circulating free calcium level is tightly controlled, as the function of our neuromuscular system, brain, and heart depend on keeping intra- and extracellular calcium levels within precise limits. If necessary, our bodies maintain stable levels of circulating free calcium at the expense of leaching calcium from our bones, placing us at risk of potentially fatal fractures. Thus was born the concept of guaranteeing adequate calcium stores through calcium supplementation.

Control of the free calcium level is not simple. There are several interrelated sensing and modulatory pathways, eg:

• Gut absorption, which is affected by the total gut load of calcium, intestinal integrity, and the specific ingested foodstuffs, and likely by our microbiome
• The parathyroid hormone (PTH) level, which directly or indirectly affects calcium absorption, the calcium-phosphate ratio, and thus, extraskeletal calcium localization and bone calcium content
• Vitamin D, with its many effects after interorgan multistep activation.

Despite this knowledge of calcium metabolism and the intricate cross-talk between the different pathways, I do not believe we truly understand how to determine the amount of dietary and supplemental calcium or vitamin D that is ideal for a given patient. I also do not believe we know with certainty what is the “normal” or ideal 25-hydroxyvitamin D level in that same patient: note the different ranges of normal proposed by different expert working groups.

How do we know when there is insufficient calcium in our diet? The total or free circulating calcium level is far too insensitive and, as noted above, complex homeostatic mechanisms are always trying to maintain an appropriate physiologic calcium level, whatever the intake. Urinary calcium excretion does not necessarily equal the ingested calcium load; there are too many factors influencing renal calcium excretion. Gastrointestinal excretion is also variable and complex. We know when the vitamin D level is functionally much too low, as the PTH level begins to rise; but the “normal” PTH range is wide, and the slope of the relationship between vitamin D and PTH is affected by many factors.

Additionally, accumulating information suggests that vitamin D metabolites significantly affect immune regulation and the onset and expression of a number of organ-specific and systemic autoimmune disorders. Further, the ideal 25-hydroxyvitamin D level for a healthy immune system is not known. Does the body have to compromise something in reconciling the target for a healthy skeleton and the target for a healthy immune system, which may conceivably be different? But importantly, this new knowledge does not imply that vitamin D supplementation will reduce the pain and symptoms from inflammatory arthritis or noninflammatory fibromyalgia.

Despite these many areas of uncertainty, Kilim and Rosen focus on bone health, summarize the wealth of accumulated data, and provide practical management advice we can use in the clinic. But if we struggle so much to know the correct way to manage calcium and vitamin D supplementation in our patients, it is little surprise that most of us struggle even more when asked about using supplements for which the biology is far less understood. As a medical community, we need to uniformly address this lack of understanding wherever it exists. Believing in a supplement or a treatment is not the same as understanding it or having strong evidence about its efficacy and safety.