When I went back to Croatia this summer to visit family and friends, little did I think I would find myself standing in the hospital where I trained as an intern. At 1:00 _AM I took my father to the ER for an acute episode of nausea, vomiting, dizziness, chest tightness, and dyspnea. Earlier that day, he had been watching the World Cup, not moving from his chair for several hours. The ER saw him promptly and transferred him to the main hospital in town.

Hours later, I was alone in the middle of a wide, marble corridor. Memories flowed back to when I was a young nursing student and later an intern, full of life, energy, and dreams. Now the walls were yellow and darker than I remembered. They were barren, almost sad: no pictures, no art, no life. On my left, patients were taken to a room for procedures such as thoracentesis and lumbar puncture. The next door led to a balcony where cigarettes glowed like orange fireflies. Dark shapes murmured to one another as they nursed their habit. At least smoking wasn't allowed in the patient rooms.

On my right were alternating male and female patient rooms: up to 7 beds per room. They would add an eighth and potentially squeeze in a ninth bed when needed. There were no private rooms, even if you had money or status. There were no dividers or curtains between patients. With no privacy and nothing else to do, patients entertained each other. Some were young, others older. Some had fought in the last war; others were tourists who were visiting. They shared their stories. They overheard each other's plans of care during morning rounds conducted by physicians and nurses.

Each hospital bed had a little nightstand, but that was about it. If you were lucky, you got pajamas. My dad got warm flannel pajamas in the middle of the summer, but at least he got something. We left the house in a hurry and didn't bring anything. No towels? You had to bring your own. No toothpaste or a toothbrush? There was running water but no cup to drink it in. There was not even toilet paper. You had to bring your own.

Everything was nice and clean but something was missing in this former military hospital, as if the life had been drained out of it. It was once a premier facility. Maybe it was getting older or worn out by the war, or lack of maintenance. The best equipment (including new ventilators) were reportedly stolen and sent to another city.

There was no army of people serving you. No medical assistants, physicians assistants, nurse‐practitioners, or technicians. No physical therapists or occupational therapists or even a front desk where people were greeted. No case managers. The hospital population was so much younger than in the United States. There was only 1 patient on the ward who was 90 years old, as opposed to the usual 10 patients on my service in their 80s and 90s. Most patients were discharged home with their families; very few were sent to nursing homes. There was no length of stay to worry about. There were no insurance hassles, preapproval for a test or for an additional day of hospitalization.

There were no daily blood draws. They are not watching him closely enough, I worried. The ER physician apparently ruled out cardiac causes before admitting my father to the neurology service for presumed vertebrobasilar insufficiency. Was the ER physician's history, cardiac bedside exam, 2 normal EKGs an hour apart, and CXR enough to assure him there was no need for a CPK or a troponin? I was told the CPK was normal but never saw the result. They used to do troponin but had stopped because it was too expensive. I cannot imagine admitting a patient in the United States with chest tightness without ordering cardiac enzymes. Are we scared we'll miss something or afraid of litigation? There was no such fear that I could detect in Croatia.

The inpatient workup was otherwise thorough, and everyone was courteous. Nonetheless, the money was tight. If a patient needed over the‐counter medications, a family member would be asked to buy it, sometimes at significant cost. Almost every patient had a peripheral IV but there were no unnecessary IV infusions, unlike the occasional TKO IVs we see here to justify hospitalization for a little old lady who didn't have a place to go or whose insurance would otherwise refuse to pay.

My father seemed dehydrated.

Could you put some normal saline in? I asked.

He already got some, the charge nurse replied.

What did he get?

Metoclopramide infusion in 500 cc of normal saline. He is not vomiting any longer, he can eat and drink, and he doesn't need any more IVs. It is expensive. Go buy some water and juices for him, the charge nurse said.

The meals were served 3 times a day. No snacks in‐between unless friends and family brought something.

Visiting hours were 2‐4 _PM daily. Information time for families took place on Tuesday and Friday afternoons. I arrived 30 minutes early to speak with the neurologist. In less than 20 minutes the room was filled. Everyone patiently waited their turn. The time spent with the doctor was brief but was better than nothing. As hospitalists, we spend a significant amount of time on the telephone tracking down family members, talking to them, or arranging a meeting to accommodate their schedule. On the other hand, there are family members who become frustrated because they have difficulty catching the doctor. I wonder if it would be helpful for us to have a dedicated information time. It could prevent frustration, unnecessary phone calls and pages, and perhaps save us time. Given our shorter length of stay, information time only twice a week probably wouldn't be enough.

What are you doing here? Dr. T., a friend of mine, exclaimed. Come on, a doctor from America waiting for the information! Come here, you don't need to wait! Your father is already better. We did a head CT, and we'll do a cervical spine x‐ray and carotid ultrasound tomorrow. Although I was hesitant, my brother, a medical student, tried to question the current treatment.

Why are you giving him diazepam and diclofenac intramuscularly? he asked.

What do you mean why? Because this is how we do it, Dr. T. said.

You already have an IV access. Couldn't you give it to him IV? my brother persisted. Dr. T. looked at him like he had fallen off the apple cart.

I had never seen it done this way in Austria or Germany, my brother continued. Why cause unnecessary pain and complications?

What complications? said Dr. T., now impatient. We use it intramuscularly. This is how it is done. It is only 10 injections. That's nothing.

Ten injections? You can injure a nerve! my brother exclaimed.

What nerve? Not if you do it right. We've been doing it this way forever. Your dad had dizziness and vomiting, and now he is better.

My father was better. Something had worked. Was it the medications or that he had slept and was rested?

The night had sneaked up on us again. The ward was quiet. No call lights. No patient telephones. No TVs. No IV machines and their beeping. No vital signs were taken in the middle of the night. No early‐morning blood draws. No pagers. The hospital was a place to get some rest.

The following day I spoke to the on‐call physician. The head CT and labs were normal. After 4 days in the hospital, I needed to know what the weekend plans would be.

How much longer will he need to be in the hospital? I asked.

Oh, about 10 to 14 days.

Ten to 14 days? I couldn't hide my surprise. What for? I might have as well asked if pigs were falling from the sky. This is how it was done.

Documentation was scanty. No worries of audits to justify the work done. How much time was saved this way? No wonder each physician saw 20 to 30 patients or more. There were 2 forms at discharge typed into a computer by the physician: a short one containing discharge medications and follow‐up plans and a long one to be completed later. We got the short one immediately and made follow‐up appointments. But many weeks later, we are still waiting for the long one. Apparently not all the lab tests are back.

Looking back, I see that when I tried to push for more information, I was viewed as pushy. So I stopped pushing. When I asked some logical questions, I felt like I was showing off. So I stopped asking too many questions. When I asked dad to tell me what happened during the day, he did not know. He did not remember the name of the consultants or what they said. When I asked him to try harder, he refused. When I asked him to write things down, he hesitated. It would mark him as a troublemaker. He was concerned that he would be labeled as an outsider, despite having lived in Croatia his whole life. Years after the war, a person's last name could still conjure up barely concealed hatred or suspicion. My father wanted to be seen as a good and compliant patient. He felt too vulnerable to be pushing for answers. Somehow, against my better judgment, I fell into the same mode.

Coming back to my hometown curiously hampered me. I still don't understand why. Was it sadness in my heart and nostalgia? Or emotional remnants of the recent war lingering in the air? Or a more patriarchal mentality and the unwritten rules of thinking and behaving that I had forgotten about? I was both a daughter and a visitor. I grew up in Croatia, but I left 2 weeks before the fighting broke out, and my prewar memories were still pristine. I was both a native and an American physician with all the expectations of stateside care. When I was a student there, physicians were authoritative and almost never questioned.

In the end, my father received care that was professional and thorough. The hospital lacked some basic necessities. They were on a strict budget for medicines including IV solutions. On the other hand, they kept my father in for 9 days, consulted an internist, an ENT. and a urologist. They also did numerous studies, including a head CT, cervical spine x‐ray, carotid ultrasound, hearing test and vestibulogram, CXR, and abdominal ultrasound. He had only 2 blood draws: CBC and Chem 7 (one time, one stick) and thyroid tests and PSA (one time, second stick). If he had been my patient, I would have probably tried to discharge him within 2 days and have him complete the evaluation as an outpatient. They gave him 9 days of diclofenac and diazepam intramuscularly and 7 days of 500 cc of normal saline and metoclopramide IV. My father was released from the hospital several days early at his insistence and mine. He had no more nausea or vomiting, no chest pain or shortness of breath. He was calm and relaxed. He was well rested. He felt better. And he is fine today.

When I went back to Croatia this summer to visit family and friends, little did I think I would find myself standing in the hospital where I trained as an intern. At 1:00 _AM I took my father to the ER for an acute episode of nausea, vomiting, dizziness, chest tightness, and dyspnea. Earlier that day, he had been watching the World Cup, not moving from his chair for several hours. The ER saw him promptly and transferred him to the main hospital in town.

Hours later, I was alone in the middle of a wide, marble corridor. Memories flowed back to when I was a young nursing student and later an intern, full of life, energy, and dreams. Now the walls were yellow and darker than I remembered. They were barren, almost sad: no pictures, no art, no life. On my left, patients were taken to a room for procedures such as thoracentesis and lumbar puncture. The next door led to a balcony where cigarettes glowed like orange fireflies. Dark shapes murmured to one another as they nursed their habit. At least smoking wasn't allowed in the patient rooms.

On my right were alternating male and female patient rooms: up to 7 beds per room. They would add an eighth and potentially squeeze in a ninth bed when needed. There were no private rooms, even if you had money or status. There were no dividers or curtains between patients. With no privacy and nothing else to do, patients entertained each other. Some were young, others older. Some had fought in the last war; others were tourists who were visiting. They shared their stories. They overheard each other's plans of care during morning rounds conducted by physicians and nurses.

Each hospital bed had a little nightstand, but that was about it. If you were lucky, you got pajamas. My dad got warm flannel pajamas in the middle of the summer, but at least he got something. We left the house in a hurry and didn't bring anything. No towels? You had to bring your own. No toothpaste or a toothbrush? There was running water but no cup to drink it in. There was not even toilet paper. You had to bring your own.

Everything was nice and clean but something was missing in this former military hospital, as if the life had been drained out of it. It was once a premier facility. Maybe it was getting older or worn out by the war, or lack of maintenance. The best equipment (including new ventilators) were reportedly stolen and sent to another city.

There was no army of people serving you. No medical assistants, physicians assistants, nurse‐practitioners, or technicians. No physical therapists or occupational therapists or even a front desk where people were greeted. No case managers. The hospital population was so much younger than in the United States. There was only 1 patient on the ward who was 90 years old, as opposed to the usual 10 patients on my service in their 80s and 90s. Most patients were discharged home with their families; very few were sent to nursing homes. There was no length of stay to worry about. There were no insurance hassles, preapproval for a test or for an additional day of hospitalization.

There were no daily blood draws. They are not watching him closely enough, I worried. The ER physician apparently ruled out cardiac causes before admitting my father to the neurology service for presumed vertebrobasilar insufficiency. Was the ER physician's history, cardiac bedside exam, 2 normal EKGs an hour apart, and CXR enough to assure him there was no need for a CPK or a troponin? I was told the CPK was normal but never saw the result. They used to do troponin but had stopped because it was too expensive. I cannot imagine admitting a patient in the United States with chest tightness without ordering cardiac enzymes. Are we scared we'll miss something or afraid of litigation? There was no such fear that I could detect in Croatia.

The inpatient workup was otherwise thorough, and everyone was courteous. Nonetheless, the money was tight. If a patient needed over the‐counter medications, a family member would be asked to buy it, sometimes at significant cost. Almost every patient had a peripheral IV but there were no unnecessary IV infusions, unlike the occasional TKO IVs we see here to justify hospitalization for a little old lady who didn't have a place to go or whose insurance would otherwise refuse to pay.

My father seemed dehydrated.

Could you put some normal saline in? I asked.

He already got some, the charge nurse replied.

What did he get?

Metoclopramide infusion in 500 cc of normal saline. He is not vomiting any longer, he can eat and drink, and he doesn't need any more IVs. It is expensive. Go buy some water and juices for him, the charge nurse said.

The meals were served 3 times a day. No snacks in‐between unless friends and family brought something.

Visiting hours were 2‐4 _PM daily. Information time for families took place on Tuesday and Friday afternoons. I arrived 30 minutes early to speak with the neurologist. In less than 20 minutes the room was filled. Everyone patiently waited their turn. The time spent with the doctor was brief but was better than nothing. As hospitalists, we spend a significant amount of time on the telephone tracking down family members, talking to them, or arranging a meeting to accommodate their schedule. On the other hand, there are family members who become frustrated because they have difficulty catching the doctor. I wonder if it would be helpful for us to have a dedicated information time. It could prevent frustration, unnecessary phone calls and pages, and perhaps save us time. Given our shorter length of stay, information time only twice a week probably wouldn't be enough.

What are you doing here? Dr. T., a friend of mine, exclaimed. Come on, a doctor from America waiting for the information! Come here, you don't need to wait! Your father is already better. We did a head CT, and we'll do a cervical spine x‐ray and carotid ultrasound tomorrow. Although I was hesitant, my brother, a medical student, tried to question the current treatment.

Why are you giving him diazepam and diclofenac intramuscularly? he asked.

What do you mean why? Because this is how we do it, Dr. T. said.

You already have an IV access. Couldn't you give it to him IV? my brother persisted. Dr. T. looked at him like he had fallen off the apple cart.

I had never seen it done this way in Austria or Germany, my brother continued. Why cause unnecessary pain and complications?

What complications? said Dr. T., now impatient. We use it intramuscularly. This is how it is done. It is only 10 injections. That's nothing.

Ten injections? You can injure a nerve! my brother exclaimed.

What nerve? Not if you do it right. We've been doing it this way forever. Your dad had dizziness and vomiting, and now he is better.

My father was better. Something had worked. Was it the medications or that he had slept and was rested?

The night had sneaked up on us again. The ward was quiet. No call lights. No patient telephones. No TVs. No IV machines and their beeping. No vital signs were taken in the middle of the night. No early‐morning blood draws. No pagers. The hospital was a place to get some rest.

The following day I spoke to the on‐call physician. The head CT and labs were normal. After 4 days in the hospital, I needed to know what the weekend plans would be.

How much longer will he need to be in the hospital? I asked.

Oh, about 10 to 14 days.

Ten to 14 days? I couldn't hide my surprise. What for? I might have as well asked if pigs were falling from the sky. This is how it was done.

Documentation was scanty. No worries of audits to justify the work done. How much time was saved this way? No wonder each physician saw 20 to 30 patients or more. There were 2 forms at discharge typed into a computer by the physician: a short one containing discharge medications and follow‐up plans and a long one to be completed later. We got the short one immediately and made follow‐up appointments. But many weeks later, we are still waiting for the long one. Apparently not all the lab tests are back.

Looking back, I see that when I tried to push for more information, I was viewed as pushy. So I stopped pushing. When I asked some logical questions, I felt like I was showing off. So I stopped asking too many questions. When I asked dad to tell me what happened during the day, he did not know. He did not remember the name of the consultants or what they said. When I asked him to try harder, he refused. When I asked him to write things down, he hesitated. It would mark him as a troublemaker. He was concerned that he would be labeled as an outsider, despite having lived in Croatia his whole life. Years after the war, a person's last name could still conjure up barely concealed hatred or suspicion. My father wanted to be seen as a good and compliant patient. He felt too vulnerable to be pushing for answers. Somehow, against my better judgment, I fell into the same mode.

Coming back to my hometown curiously hampered me. I still don't understand why. Was it sadness in my heart and nostalgia? Or emotional remnants of the recent war lingering in the air? Or a more patriarchal mentality and the unwritten rules of thinking and behaving that I had forgotten about? I was both a daughter and a visitor. I grew up in Croatia, but I left 2 weeks before the fighting broke out, and my prewar memories were still pristine. I was both a native and an American physician with all the expectations of stateside care. When I was a student there, physicians were authoritative and almost never questioned.

In the end, my father received care that was professional and thorough. The hospital lacked some basic necessities. They were on a strict budget for medicines including IV solutions. On the other hand, they kept my father in for 9 days, consulted an internist, an ENT. and a urologist. They also did numerous studies, including a head CT, cervical spine x‐ray, carotid ultrasound, hearing test and vestibulogram, CXR, and abdominal ultrasound. He had only 2 blood draws: CBC and Chem 7 (one time, one stick) and thyroid tests and PSA (one time, second stick). If he had been my patient, I would have probably tried to discharge him within 2 days and have him complete the evaluation as an outpatient. They gave him 9 days of diclofenac and diazepam intramuscularly and 7 days of 500 cc of normal saline and metoclopramide IV. My father was released from the hospital several days early at his insistence and mine. He had no more nausea or vomiting, no chest pain or shortness of breath. He was calm and relaxed. He was well rested. He felt better. And he is fine today.

When I went back to Croatia this summer to visit family and friends, little did I think I would find myself standing in the hospital where I trained as an intern. At 1:00 _AM I took my father to the ER for an acute episode of nausea, vomiting, dizziness, chest tightness, and dyspnea. Earlier that day, he had been watching the World Cup, not moving from his chair for several hours. The ER saw him promptly and transferred him to the main hospital in town.

Hours later, I was alone in the middle of a wide, marble corridor. Memories flowed back to when I was a young nursing student and later an intern, full of life, energy, and dreams. Now the walls were yellow and darker than I remembered. They were barren, almost sad: no pictures, no art, no life. On my left, patients were taken to a room for procedures such as thoracentesis and lumbar puncture. The next door led to a balcony where cigarettes glowed like orange fireflies. Dark shapes murmured to one another as they nursed their habit. At least smoking wasn't allowed in the patient rooms.

On my right were alternating male and female patient rooms: up to 7 beds per room. They would add an eighth and potentially squeeze in a ninth bed when needed. There were no private rooms, even if you had money or status. There were no dividers or curtains between patients. With no privacy and nothing else to do, patients entertained each other. Some were young, others older. Some had fought in the last war; others were tourists who were visiting. They shared their stories. They overheard each other's plans of care during morning rounds conducted by physicians and nurses.

Each hospital bed had a little nightstand, but that was about it. If you were lucky, you got pajamas. My dad got warm flannel pajamas in the middle of the summer, but at least he got something. We left the house in a hurry and didn't bring anything. No towels? You had to bring your own. No toothpaste or a toothbrush? There was running water but no cup to drink it in. There was not even toilet paper. You had to bring your own.

Everything was nice and clean but something was missing in this former military hospital, as if the life had been drained out of it. It was once a premier facility. Maybe it was getting older or worn out by the war, or lack of maintenance. The best equipment (including new ventilators) were reportedly stolen and sent to another city.

There was no army of people serving you. No medical assistants, physicians assistants, nurse‐practitioners, or technicians. No physical therapists or occupational therapists or even a front desk where people were greeted. No case managers. The hospital population was so much younger than in the United States. There was only 1 patient on the ward who was 90 years old, as opposed to the usual 10 patients on my service in their 80s and 90s. Most patients were discharged home with their families; very few were sent to nursing homes. There was no length of stay to worry about. There were no insurance hassles, preapproval for a test or for an additional day of hospitalization.

There were no daily blood draws. They are not watching him closely enough, I worried. The ER physician apparently ruled out cardiac causes before admitting my father to the neurology service for presumed vertebrobasilar insufficiency. Was the ER physician's history, cardiac bedside exam, 2 normal EKGs an hour apart, and CXR enough to assure him there was no need for a CPK or a troponin? I was told the CPK was normal but never saw the result. They used to do troponin but had stopped because it was too expensive. I cannot imagine admitting a patient in the United States with chest tightness without ordering cardiac enzymes. Are we scared we'll miss something or afraid of litigation? There was no such fear that I could detect in Croatia.

The inpatient workup was otherwise thorough, and everyone was courteous. Nonetheless, the money was tight. If a patient needed over the‐counter medications, a family member would be asked to buy it, sometimes at significant cost. Almost every patient had a peripheral IV but there were no unnecessary IV infusions, unlike the occasional TKO IVs we see here to justify hospitalization for a little old lady who didn't have a place to go or whose insurance would otherwise refuse to pay.

My father seemed dehydrated.

Could you put some normal saline in? I asked.

He already got some, the charge nurse replied.

What did he get?

Metoclopramide infusion in 500 cc of normal saline. He is not vomiting any longer, he can eat and drink, and he doesn't need any more IVs. It is expensive. Go buy some water and juices for him, the charge nurse said.

The meals were served 3 times a day. No snacks in‐between unless friends and family brought something.

Visiting hours were 2‐4 _PM daily. Information time for families took place on Tuesday and Friday afternoons. I arrived 30 minutes early to speak with the neurologist. In less than 20 minutes the room was filled. Everyone patiently waited their turn. The time spent with the doctor was brief but was better than nothing. As hospitalists, we spend a significant amount of time on the telephone tracking down family members, talking to them, or arranging a meeting to accommodate their schedule. On the other hand, there are family members who become frustrated because they have difficulty catching the doctor. I wonder if it would be helpful for us to have a dedicated information time. It could prevent frustration, unnecessary phone calls and pages, and perhaps save us time. Given our shorter length of stay, information time only twice a week probably wouldn't be enough.

What are you doing here? Dr. T., a friend of mine, exclaimed. Come on, a doctor from America waiting for the information! Come here, you don't need to wait! Your father is already better. We did a head CT, and we'll do a cervical spine x‐ray and carotid ultrasound tomorrow. Although I was hesitant, my brother, a medical student, tried to question the current treatment.

Why are you giving him diazepam and diclofenac intramuscularly? he asked.

What do you mean why? Because this is how we do it, Dr. T. said.

You already have an IV access. Couldn't you give it to him IV? my brother persisted. Dr. T. looked at him like he had fallen off the apple cart.

I had never seen it done this way in Austria or Germany, my brother continued. Why cause unnecessary pain and complications?

What complications? said Dr. T., now impatient. We use it intramuscularly. This is how it is done. It is only 10 injections. That's nothing.

Ten injections? You can injure a nerve! my brother exclaimed.

What nerve? Not if you do it right. We've been doing it this way forever. Your dad had dizziness and vomiting, and now he is better.

My father was better. Something had worked. Was it the medications or that he had slept and was rested?

The night had sneaked up on us again. The ward was quiet. No call lights. No patient telephones. No TVs. No IV machines and their beeping. No vital signs were taken in the middle of the night. No early‐morning blood draws. No pagers. The hospital was a place to get some rest.

The following day I spoke to the on‐call physician. The head CT and labs were normal. After 4 days in the hospital, I needed to know what the weekend plans would be.

How much longer will he need to be in the hospital? I asked.

Oh, about 10 to 14 days.

Ten to 14 days? I couldn't hide my surprise. What for? I might have as well asked if pigs were falling from the sky. This is how it was done.

Documentation was scanty. No worries of audits to justify the work done. How much time was saved this way? No wonder each physician saw 20 to 30 patients or more. There were 2 forms at discharge typed into a computer by the physician: a short one containing discharge medications and follow‐up plans and a long one to be completed later. We got the short one immediately and made follow‐up appointments. But many weeks later, we are still waiting for the long one. Apparently not all the lab tests are back.

Looking back, I see that when I tried to push for more information, I was viewed as pushy. So I stopped pushing. When I asked some logical questions, I felt like I was showing off. So I stopped asking too many questions. When I asked dad to tell me what happened during the day, he did not know. He did not remember the name of the consultants or what they said. When I asked him to try harder, he refused. When I asked him to write things down, he hesitated. It would mark him as a troublemaker. He was concerned that he would be labeled as an outsider, despite having lived in Croatia his whole life. Years after the war, a person's last name could still conjure up barely concealed hatred or suspicion. My father wanted to be seen as a good and compliant patient. He felt too vulnerable to be pushing for answers. Somehow, against my better judgment, I fell into the same mode.

Coming back to my hometown curiously hampered me. I still don't understand why. Was it sadness in my heart and nostalgia? Or emotional remnants of the recent war lingering in the air? Or a more patriarchal mentality and the unwritten rules of thinking and behaving that I had forgotten about? I was both a daughter and a visitor. I grew up in Croatia, but I left 2 weeks before the fighting broke out, and my prewar memories were still pristine. I was both a native and an American physician with all the expectations of stateside care. When I was a student there, physicians were authoritative and almost never questioned.

In the end, my father received care that was professional and thorough. The hospital lacked some basic necessities. They were on a strict budget for medicines including IV solutions. On the other hand, they kept my father in for 9 days, consulted an internist, an ENT. and a urologist. They also did numerous studies, including a head CT, cervical spine x‐ray, carotid ultrasound, hearing test and vestibulogram, CXR, and abdominal ultrasound. He had only 2 blood draws: CBC and Chem 7 (one time, one stick) and thyroid tests and PSA (one time, second stick). If he had been my patient, I would have probably tried to discharge him within 2 days and have him complete the evaluation as an outpatient. They gave him 9 days of diclofenac and diazepam intramuscularly and 7 days of 500 cc of normal saline and metoclopramide IV. My father was released from the hospital several days early at his insistence and mine. He had no more nausea or vomiting, no chest pain or shortness of breath. He was calm and relaxed. He was well rested. He felt better. And he is fine today.

A 56‐year‐old woman from Colombia presented to the emergency department after 24 hours of abdominal pain. One week before, she had experienced similar pain that lasted for 4 hours and spontaneously resolved. She was nauseated but had no vomiting. She reported an unintentional 14‐pound weight loss over the preceding 3 weeks. She denied fever, chills, night sweats, diarrhea, constipation, dysuria, or jaundice.

In a middle‐aged woman with abdominal pain and nausea, diagnostic considerations include gallbladder disease, diseases of the bowel (such as a partial small‐bowel obstruction or inflammatory conditions), hepatic or pancreatic conditions, and nongastrointestinal ailments such as cardiac ischemia. Knowing the specific location of pain, its quality, precipitating factors, and accompanying systemic symptoms may help to narrow the diagnosis. The unintentional weight loss preceding the onset of pain may be an important clue because it suggests a systemic condition, and in a South American immigrantparticularly if she has traveled recentlyit is important to consider parasitic illnesses. The absence of fever makes some infections such as tuberculosis and malaria less likely. At this point, in addition to a thorough history and physical, laboratory tests should include a complete blood count (with quantification of eosinophils) and a metabolic panel with liver enzymes and albumin.

The patient described pain in the midline, just inferior to the umbilicus. The pain was constant, developed without any particular provocation, and was not related to meals or exertion. There were no constitutional symptoms aside from weight loss. She had a history of bipolar disorder, hypothyroidism, osteoarthritis, and chronic sinusitis and had previously undergone cholecystectomy and abdominal hysterectomy. She was taking levothyroxine, montelukast, bupropion, oxcarbazepine, fexofenadine, meloxicam, zolpidem, and, as needed, acetaminophen. She had recently completed a 10‐day course of levofloxacin for acute sinusitis. She had immigrated to the United States 10 years earlier and lived with her husband and daughter. She denied the use of tobacco, alcohol or illicit drugs. She had visited Colombia 6 months earlier but had no other recent travel history.

The history of cholecystectomy makes a biliary tract process unlikely. Its location reduces the likelihood of a hepatic or pancreatic process, but I would like to see the liver enzymes, especially given her recent acetaminophen use. The comorbid illnessesparticularly her bipolar disordermay be relevant because psychiatric illness might be associated with medication overuse or undisclosed toxic ingestions. For example, excess thyroxine might lead to weight loss while overuse of nonsteroidal anti‐inflammatory drugs such as meloxicam can cause intestinal ulceration, not only in the upper tract, but also in the colon. Undisclosed ingestions may also be associated with abdominal symptoms. Her surgical history makes adhesions with a secondary partial bowel obstruction possible. With no travel outside this country in the last 6 months, exotic infections are less likely. Finally, the recent course of levofloxacin may be relevant because many antibiotics are associated with nonspecific abdominal symptoms, and Clostridium difficile colitis occasionally presents without diarrhea.

The patient reported taking her medications as prescribed and denied ingesting other medications. On physical examination, she had a temperature of 98.9F, a pulse of 81 beats per minute, a blood pressure of 110/80 mm Hg, and a respiratory rate of 16 respirations per minute. She had a normal oxygen saturation while breathing ambient air. Her weight was 58 kg. There was no scleral icterus or jugular venous distension. She had a small painless ulcer involving the hard palate. Her lungs were clear to auscultation, and cardiac examination was normal. The abdomen was soft, bowel sounds were present, and there was moderate tenderness to palpation inferior to the umbilicus. There was no rebound or guarding, hepatosplenomegaly or other masses. There was no peripheral edema and no lymphadenopathy. Neurological examination was normal.

The oral ulcer may or may not be related to the clinical presentation because oral ulcers, whether painful or painless, are ubiquitous and may be isolated or may be associated with a wide range of infectious and noninfectious systemic diseases. Although some systemic causes of mucocutaneous ulcers are associated with weight loss (including Crohn's disease, Behcet's disease, celiac sprue, human immunodeficiency virus [HIV], herpesviruses, syphilis, and systemic lupus erythematosus [SLE], among others), the lack of specificity of this finding limits its diagnostic utility. However, it is reasonable to ask whether the patient has noted frequent ulceration in the mouth or genitalia, as recurrent or severe ulcerations may narrow the diagnostic considerations. On the other hand, the focal nature of the pain inferior to the umbilicus suggests a discrete process in the abdomen or pelvis, such as an abscess, mass, or localized area of bowel inflammation. A plain abdominal film is likely to be low yield in this situation, so pursuing computed tomography is appropriate. Not all patients with focal abdominal pain require abdominal imaging, but in the context of weight loss and persistent symptoms for more than a week, imaging is prudent in this case.

The patient denied genital ulceration but did report painless oral ulcers over the preceding months. Laboratory evaluation revealed a white‐cell count of 1000/mm³, of which 6% were neutrophils, 5% were band forms, 36% were lymphocytes, and 47% were monocytes. The absolute neutrophil count was 110/mm³. Hemoglobin level was 10.2 g/dL with a mean corpuscular volume of 90 m³, and the platelet count was 151,000/mm³. Other results of laboratory studies were: sodium, 140 mmol/L; potassium, 3.8 mmol/L; chloride, 96 mmol/L; bicarbonate, 23 mmol/L; blood urea nitrogen, 13 mg/dL; creatinine, 0.4 mg/dL; lipase, 32 U/L (normal range, 13‐60); amylase, 73 U/L (normal range, 30‐110); albumin, 4.0 g/dL; aspartate aminotransferase, 779 U/L (normal range, 13‐35); alanine aminotransferase, 330 U/L (normal range, 7‐35); alkaline phosphatase, 510 U/L (normal range, 35‐104); and total bilirubin, 0.9 mg/dL (normal range, 0.1‐1.2). The lactate dehydrogenase level was 200 U/L (normal range, 135‐214). The corrected reticulocyte count was 1.6% (normal range, 0.3‐2.3), and haptoglobin was 190 mg/dL (normal range, 43‐212). A direct Coomb's test was positive. The erythrocyte sedimentation rate was 113 mm/hour (normal range, 1‐25). Urinalysis was normal without evidence of protein or blood.

Laboratory abnormalities include elevated transaminases and alkaline phosphatase, a markedly elevated erythrocyte sedimentation rate, and profound leukopenia with neutropenia. The patient is anemic, which may elevate the sedimentation rate but not typically to this degree. The patient is not febrile, but if she were to develop a fever, empiric antibiotics would be prudent. The normal albumin and bilirubin suggest that hepatic synthetic and excretory functions remain intact. Although the direct Coombs test is positive, the reticulocyte and lactate dehydrogenase levels argue against brisk hemolysis; this abnormality may simply be a marker of nonspecific immune activation. A variety of infections can cause neutropenia and liver enzyme abnormalities including parasites (malaria or leishmaniasis), viruses (cytomegalovirus or Epstein‐Barr virus [EBV]), tick‐borne bacterial infections (ehrlichiosis or rickettsial infection), and granulomatous infections (tuberculosis). Malignant infiltration of the reticuloendothelial system can also lead to cytopenias and liver enzyme abnormalities. Autoimmunity remains a consideration, as SLE may lead to cytopenias, oral ulcers, and nonspecific immune phenomena. Rather than ordering a large number of blood tests, I favor a targeted approach with abdominal computed tomography followed by biopsy of either the liver or bone marrow.

Chest radiography revealed no abnormalities. Computed tomography of the chest, abdomen, and pelvis with intravenous and oral contrast demonstrated concentric wall thickening of the transverse colon, but no evidence of obstruction or free air. The patient was treated with intravenous fluids, morphine, and cefepime. Bone marrow biopsy was performed, which demonstrated a hypercellular marrow with increased myeloid precursors and a left shift and megakaryocytic hyperplasia. Flow cytometry revealed no abnormally restricted clonal populations. A concerted search for an infectious etiology of the patient's neutropenia was unrevealing, including tests for HIV, cytomegalovirus, hepatitis A, hepatitis B, hepatitis C, Mycoplasma pneumoniae, EBV, and parvovirus B19.

I hope blood cultures were drawn prior to the initiation of antibiotics. Hypercellularity of the bone marrow in the context of leukopenia raises concern that white blood cells are being destroyed peripherally. Autoimmunity against neutrophils can be transiently induced by viruses such as HIV, hepatitis B, and EBV, but these infections have been excluded. Testing for antinuclear antibodies is reasonable. A normal‐sized spleen on the abdominal CT excludes hypersplenism. Colonic thickening can be associated with infection, ischemia, inflammatory bowel disease, and malignancy. The question is whether the colonic thickening is part of the same disease process causing the leukopenia and liver enzyme elevation or whether it represents a secondary infectious process in the setting of neutropenia (such as Clostridium difficile infection or typhlitis). Testing for stool pathogens (including ova and parasites) is certainly appropriate, and consideration of a colonoscopy with biopsy is reasonable, provided that appropriate antimicrobial coverage remains in place.

Blood cultures obtained prior to starting antibiotics were negative. The patient's abdominal pain improved, and she was discharged home to have close follow‐up with a hematologist. The results of her liver function tests improved, and her absolute neutrophil count was 230/mm³ at the time of discharge. Her neutropenia was believed to be secondary to peripheral destruction from a viral, drug‐mediated, or autoimmune process. Oxcarbazepine (Trileptal) was discontinued, as it was believed to be the medication most likely to be responsible. She returned to the hospital 3 days later with recurrence of her abdominal pain and diarrhea. She remained afebrile. Additional history revealed arthralgias over the previous 2 months, mild alopecia, and prior symptoms suggestive of Raynaud's phenomenon. Stool studies failed to establish an infectious etiology for the diarrhea, and her continued neutropenia responded appropriately to treatment with subcutaneous filgrastim. Colonoscopy could be performed only to the hepatic flexure and revealed no abnormalities. A serologic test for antinuclear antibodies was positive at a titer of 1:640 in a homogenous pattern, and a test for antineutrophil cytoplasmic antibodies was negative. Complement levels were normal, and tests for cryoglobulins, rapid plasma reagin, anticardiolipin antibody, lupus anticoagulant, rheumatoid factor, and antibodies to extractable nuclear antigens were all negative.

Raynaud's phenomenon is consistent with lupus. Double‐stranded DNA antibodies should be sent, although the urine did not demonstrate protein or an active sediment. Systemic sclerosis and the CREST syndrome is strongly associated with Raynaud's phenomenon and high‐titer ANA, but the patient does not have sclerodactyly, which is generally the earliest skin involvement. Autoimmune hepatitis is often associated with high‐titer ANA but does not fit this clinical picture. Given that the patient's presentation included segmental bowel wall thickening and a transient but marked liver enzyme elevation with AST predominance, I am concerned about vasculitis of the abdominal vasculature and would strongly consider a mesenteric angiogram.

To exclude mesenteric vasculitis, the patient underwent magnetic resonance angiography of the abdomen, the results of which were normal. A repeat test for antinuclear antibodies was positive at a titer of 1:2560 in a uniform pattern. A test for anti‐double‐stranded DNA was positive at 1370 U/mL. The patient was diagnosed with systemic lupus and probable lupus enteritis, and therapy with oral prednisone (10 mg daily) and hydroxychloroquine was initiated. She had prompt improvement in her abdominal pain, and was discharged home. Five months later she developed proteinuria and underwent a renal biopsy, which showed minor, nonspecific glomerular abnormalities, suggesting possible mild lupus nephritis. Eight months after her initial presentation, she remains free of abdominal pain and has regained the weight she had initially lost. Her oral ulcers have resolved, and her blood counts have normalized. Her serum creatinine has remained normal. She is now maintained on prednisone (15 mg daily), hydroxychloroquine, and mycophenolate mofetil.

COMMENTARY

A diagnosis of systemic lupus erythematosus (SLE) provided a unifying explanation for the patient's findings. Indeed, she manifested 4 of the 11 American College of Rheumatology criteria for systemic lupus (oral ulcers, leukopenia, positive anti‐DNA, and positive ANA), meeting criteria for a definite diagnosis of SLE. She additionally had multiple other features suggestive of lupus including Raynaud's phenomenon, arthralgias, alopecia, mild thrombocytopenia, and a positive Coombs' test (although the normal reticulocyte count, lactate dehydrogenase, and haptoglobin were most consistent with anemia of a chronic disease).

The protean manifestations of SLE can present significant diagnostic challenges. In this case, physicians were immediately drawn to the patient's acute abdominal pain and severe neutropenia and failed to recognize more subtle disease manifestations that may have aided in establishing a unifying diagnosis sooner. The initial history and review of systems did not disclose arthralgias, alopecia, or Raynaud's phenomenon. In an era of increasing use of hospitalists, which creates potential discontinuity between inpatient and outpatient physicians, a thorough history and review of systems may be particularly important in diagnosing acute manifestations of chronic systemic disease. Inpatient physicians may be overly focused on the small subset of acute complaints leading to hospitalization, without considering the larger constellation of symptoms that may facilitate accurate diagnosis. Our discussant quickly recognized the multisystem nature of the patient's illness and appropriately focused on infectious, neoplastic, and autoimmune categories of disease as being most likely. When infectious and neoplastic conditions were excluded with reasonable certainty, a directed serologic investigation for autoimmune disease was requested, culminating in a diagnosis of SLE.

Involvement of the skin as well as hematologic, renal, and musculoskeletal systems in SLE is commonly recognized, whereas gastrointestinal involvement is perceived to occur much less frequently. However, abdominal pain occurs in up to 40% of patients with lupus.14 Abdominal pain in lupus patients can arise from non‐lupus‐related conditions as well as lupus‐related entities, including serositis, mesenteric vasculitis with or without infarction, mesenteric thrombosis, pancreatitis, inflammatory bowel disease, and adverse medication effects including peptic ulcer disease. Abnormal liver chemistries, as seen in our patient, occur in 20%‐50% of patients with lupus and may be due to lupus hepatitis, concomitant autoimmune hepatitis, or medications including NSAIDs.5, 6 Oral ulcers and leukopenia are likewise common in SLE, with each seen in up to half of patients.4, 7, 8 Leukopenia in SLE may a result of neutropenia, lymphocytopenia, or both. However, severe neutropenia (ie, absolute count less than 500/L), as seen in our case, is more often a result of myelotoxicity from immunosuppressive therapy, rather than SLE itself.9

Lupus enteritis represents bowel microischemia from small‐vessel arteritis or venulitis that often is not evident on conventional mesenteric angiography.4, 10, 11 The reported prevalence of intestinal vasculitis in patients with SLE varies widely, depending on the characteristics of lupus patients sampled in individual studies. Intestinal vasculitis affects 0.2%‐0.5% of SLE patients in general,4, 12 whereas among SLE patients with active disease and an acute abdomen, vasculitis has been reported in up to 53% of patients.10 Antiphospholipid antibodies, antibodies to extractable nuclear antigens, the SLE Disease Activity Index, complement levels, erythrocyte sedimentation rate, C‐reactive protein, and anti‐double‐stranded DNA do not reliably differentiate lupus enteritis from acute abdominal pain due to other etiologies in patients with SLE.11 However, a concomitant drop in the white blood cell count at the onset of symptoms may be useful in distinguishing lupus enteritis from other causes of acute abdominal pain among lupus patients.11 Computed tomography findings consistent with lupus enteritis are nonspecific and include bowel‐wall thickening, submucosal edema (eg, target sign), dilatation of intestinal segments, engorgement of mesenteric vessels, and increased attenuation of mesenteric fat.13 Colonoscopy may reveal areas of ischemia and ulceration, and biopsy can confirm intestinal vasculitis. However, intestinal involvement may be segmental, and pathologic confirmation may be difficult. Contrast enema, gallium scanning, and indium‐labeled white cell scanning may be useful, but lack specificity. No controlled trials to date have evaluated the optimal therapy for lupus enteritis, but pulsed methylprednisolone is often recommended.4 Cyclophosphamide, azathioprine, methotrexate, and cyclosporine have also been used as adjunctive agents. Patients may progress to intestinal infarction and perforation, which augurs a poor prognosis, and early surgical exploration should be considered in severely ill patients.10 Death may occur in more than two‐thirds of patients whose disease progresses to intestinal perforation.1

In summary, a multisystem disease such as SLE requires a comprehensive history, physical exam, and review of systems to establish a correct diagnosis. In our case, an extensive evaluation was necessary to exclude other etiologies of abdominal pain and systemic illness, particularly as infectious and neoplastic conditions occur far more often than lupus enteritis in the general population. However, profound laboratory abnormalities may have preoccupied the attention of treating physicians, leading them to overlook less obvious but important historical and physical findings suggestive of SLE. The cohesively abnormal forest may thus have been obscured by erratically abnormal individual trees. Gastrointestinal symptoms may be underrecognized in SLE. When these result for lupus enteritis, timely recognition may be lifesaving.

A 56‐year‐old woman from Colombia presented to the emergency department after 24 hours of abdominal pain. One week before, she had experienced similar pain that lasted for 4 hours and spontaneously resolved. She was nauseated but had no vomiting. She reported an unintentional 14‐pound weight loss over the preceding 3 weeks. She denied fever, chills, night sweats, diarrhea, constipation, dysuria, or jaundice.

In a middle‐aged woman with abdominal pain and nausea, diagnostic considerations include gallbladder disease, diseases of the bowel (such as a partial small‐bowel obstruction or inflammatory conditions), hepatic or pancreatic conditions, and nongastrointestinal ailments such as cardiac ischemia. Knowing the specific location of pain, its quality, precipitating factors, and accompanying systemic symptoms may help to narrow the diagnosis. The unintentional weight loss preceding the onset of pain may be an important clue because it suggests a systemic condition, and in a South American immigrantparticularly if she has traveled recentlyit is important to consider parasitic illnesses. The absence of fever makes some infections such as tuberculosis and malaria less likely. At this point, in addition to a thorough history and physical, laboratory tests should include a complete blood count (with quantification of eosinophils) and a metabolic panel with liver enzymes and albumin.

The patient described pain in the midline, just inferior to the umbilicus. The pain was constant, developed without any particular provocation, and was not related to meals or exertion. There were no constitutional symptoms aside from weight loss. She had a history of bipolar disorder, hypothyroidism, osteoarthritis, and chronic sinusitis and had previously undergone cholecystectomy and abdominal hysterectomy. She was taking levothyroxine, montelukast, bupropion, oxcarbazepine, fexofenadine, meloxicam, zolpidem, and, as needed, acetaminophen. She had recently completed a 10‐day course of levofloxacin for acute sinusitis. She had immigrated to the United States 10 years earlier and lived with her husband and daughter. She denied the use of tobacco, alcohol or illicit drugs. She had visited Colombia 6 months earlier but had no other recent travel history.

The history of cholecystectomy makes a biliary tract process unlikely. Its location reduces the likelihood of a hepatic or pancreatic process, but I would like to see the liver enzymes, especially given her recent acetaminophen use. The comorbid illnessesparticularly her bipolar disordermay be relevant because psychiatric illness might be associated with medication overuse or undisclosed toxic ingestions. For example, excess thyroxine might lead to weight loss while overuse of nonsteroidal anti‐inflammatory drugs such as meloxicam can cause intestinal ulceration, not only in the upper tract, but also in the colon. Undisclosed ingestions may also be associated with abdominal symptoms. Her surgical history makes adhesions with a secondary partial bowel obstruction possible. With no travel outside this country in the last 6 months, exotic infections are less likely. Finally, the recent course of levofloxacin may be relevant because many antibiotics are associated with nonspecific abdominal symptoms, and Clostridium difficile colitis occasionally presents without diarrhea.

The patient reported taking her medications as prescribed and denied ingesting other medications. On physical examination, she had a temperature of 98.9F, a pulse of 81 beats per minute, a blood pressure of 110/80 mm Hg, and a respiratory rate of 16 respirations per minute. She had a normal oxygen saturation while breathing ambient air. Her weight was 58 kg. There was no scleral icterus or jugular venous distension. She had a small painless ulcer involving the hard palate. Her lungs were clear to auscultation, and cardiac examination was normal. The abdomen was soft, bowel sounds were present, and there was moderate tenderness to palpation inferior to the umbilicus. There was no rebound or guarding, hepatosplenomegaly or other masses. There was no peripheral edema and no lymphadenopathy. Neurological examination was normal.

The oral ulcer may or may not be related to the clinical presentation because oral ulcers, whether painful or painless, are ubiquitous and may be isolated or may be associated with a wide range of infectious and noninfectious systemic diseases. Although some systemic causes of mucocutaneous ulcers are associated with weight loss (including Crohn's disease, Behcet's disease, celiac sprue, human immunodeficiency virus [HIV], herpesviruses, syphilis, and systemic lupus erythematosus [SLE], among others), the lack of specificity of this finding limits its diagnostic utility. However, it is reasonable to ask whether the patient has noted frequent ulceration in the mouth or genitalia, as recurrent or severe ulcerations may narrow the diagnostic considerations. On the other hand, the focal nature of the pain inferior to the umbilicus suggests a discrete process in the abdomen or pelvis, such as an abscess, mass, or localized area of bowel inflammation. A plain abdominal film is likely to be low yield in this situation, so pursuing computed tomography is appropriate. Not all patients with focal abdominal pain require abdominal imaging, but in the context of weight loss and persistent symptoms for more than a week, imaging is prudent in this case.

The patient denied genital ulceration but did report painless oral ulcers over the preceding months. Laboratory evaluation revealed a white‐cell count of 1000/mm³, of which 6% were neutrophils, 5% were band forms, 36% were lymphocytes, and 47% were monocytes. The absolute neutrophil count was 110/mm³. Hemoglobin level was 10.2 g/dL with a mean corpuscular volume of 90 m³, and the platelet count was 151,000/mm³. Other results of laboratory studies were: sodium, 140 mmol/L; potassium, 3.8 mmol/L; chloride, 96 mmol/L; bicarbonate, 23 mmol/L; blood urea nitrogen, 13 mg/dL; creatinine, 0.4 mg/dL; lipase, 32 U/L (normal range, 13‐60); amylase, 73 U/L (normal range, 30‐110); albumin, 4.0 g/dL; aspartate aminotransferase, 779 U/L (normal range, 13‐35); alanine aminotransferase, 330 U/L (normal range, 7‐35); alkaline phosphatase, 510 U/L (normal range, 35‐104); and total bilirubin, 0.9 mg/dL (normal range, 0.1‐1.2). The lactate dehydrogenase level was 200 U/L (normal range, 135‐214). The corrected reticulocyte count was 1.6% (normal range, 0.3‐2.3), and haptoglobin was 190 mg/dL (normal range, 43‐212). A direct Coomb's test was positive. The erythrocyte sedimentation rate was 113 mm/hour (normal range, 1‐25). Urinalysis was normal without evidence of protein or blood.

Laboratory abnormalities include elevated transaminases and alkaline phosphatase, a markedly elevated erythrocyte sedimentation rate, and profound leukopenia with neutropenia. The patient is anemic, which may elevate the sedimentation rate but not typically to this degree. The patient is not febrile, but if she were to develop a fever, empiric antibiotics would be prudent. The normal albumin and bilirubin suggest that hepatic synthetic and excretory functions remain intact. Although the direct Coombs test is positive, the reticulocyte and lactate dehydrogenase levels argue against brisk hemolysis; this abnormality may simply be a marker of nonspecific immune activation. A variety of infections can cause neutropenia and liver enzyme abnormalities including parasites (malaria or leishmaniasis), viruses (cytomegalovirus or Epstein‐Barr virus [EBV]), tick‐borne bacterial infections (ehrlichiosis or rickettsial infection), and granulomatous infections (tuberculosis). Malignant infiltration of the reticuloendothelial system can also lead to cytopenias and liver enzyme abnormalities. Autoimmunity remains a consideration, as SLE may lead to cytopenias, oral ulcers, and nonspecific immune phenomena. Rather than ordering a large number of blood tests, I favor a targeted approach with abdominal computed tomography followed by biopsy of either the liver or bone marrow.

Chest radiography revealed no abnormalities. Computed tomography of the chest, abdomen, and pelvis with intravenous and oral contrast demonstrated concentric wall thickening of the transverse colon, but no evidence of obstruction or free air. The patient was treated with intravenous fluids, morphine, and cefepime. Bone marrow biopsy was performed, which demonstrated a hypercellular marrow with increased myeloid precursors and a left shift and megakaryocytic hyperplasia. Flow cytometry revealed no abnormally restricted clonal populations. A concerted search for an infectious etiology of the patient's neutropenia was unrevealing, including tests for HIV, cytomegalovirus, hepatitis A, hepatitis B, hepatitis C, Mycoplasma pneumoniae, EBV, and parvovirus B19.

I hope blood cultures were drawn prior to the initiation of antibiotics. Hypercellularity of the bone marrow in the context of leukopenia raises concern that white blood cells are being destroyed peripherally. Autoimmunity against neutrophils can be transiently induced by viruses such as HIV, hepatitis B, and EBV, but these infections have been excluded. Testing for antinuclear antibodies is reasonable. A normal‐sized spleen on the abdominal CT excludes hypersplenism. Colonic thickening can be associated with infection, ischemia, inflammatory bowel disease, and malignancy. The question is whether the colonic thickening is part of the same disease process causing the leukopenia and liver enzyme elevation or whether it represents a secondary infectious process in the setting of neutropenia (such as Clostridium difficile infection or typhlitis). Testing for stool pathogens (including ova and parasites) is certainly appropriate, and consideration of a colonoscopy with biopsy is reasonable, provided that appropriate antimicrobial coverage remains in place.

Blood cultures obtained prior to starting antibiotics were negative. The patient's abdominal pain improved, and she was discharged home to have close follow‐up with a hematologist. The results of her liver function tests improved, and her absolute neutrophil count was 230/mm³ at the time of discharge. Her neutropenia was believed to be secondary to peripheral destruction from a viral, drug‐mediated, or autoimmune process. Oxcarbazepine (Trileptal) was discontinued, as it was believed to be the medication most likely to be responsible. She returned to the hospital 3 days later with recurrence of her abdominal pain and diarrhea. She remained afebrile. Additional history revealed arthralgias over the previous 2 months, mild alopecia, and prior symptoms suggestive of Raynaud's phenomenon. Stool studies failed to establish an infectious etiology for the diarrhea, and her continued neutropenia responded appropriately to treatment with subcutaneous filgrastim. Colonoscopy could be performed only to the hepatic flexure and revealed no abnormalities. A serologic test for antinuclear antibodies was positive at a titer of 1:640 in a homogenous pattern, and a test for antineutrophil cytoplasmic antibodies was negative. Complement levels were normal, and tests for cryoglobulins, rapid plasma reagin, anticardiolipin antibody, lupus anticoagulant, rheumatoid factor, and antibodies to extractable nuclear antigens were all negative.

Raynaud's phenomenon is consistent with lupus. Double‐stranded DNA antibodies should be sent, although the urine did not demonstrate protein or an active sediment. Systemic sclerosis and the CREST syndrome is strongly associated with Raynaud's phenomenon and high‐titer ANA, but the patient does not have sclerodactyly, which is generally the earliest skin involvement. Autoimmune hepatitis is often associated with high‐titer ANA but does not fit this clinical picture. Given that the patient's presentation included segmental bowel wall thickening and a transient but marked liver enzyme elevation with AST predominance, I am concerned about vasculitis of the abdominal vasculature and would strongly consider a mesenteric angiogram.

To exclude mesenteric vasculitis, the patient underwent magnetic resonance angiography of the abdomen, the results of which were normal. A repeat test for antinuclear antibodies was positive at a titer of 1:2560 in a uniform pattern. A test for anti‐double‐stranded DNA was positive at 1370 U/mL. The patient was diagnosed with systemic lupus and probable lupus enteritis, and therapy with oral prednisone (10 mg daily) and hydroxychloroquine was initiated. She had prompt improvement in her abdominal pain, and was discharged home. Five months later she developed proteinuria and underwent a renal biopsy, which showed minor, nonspecific glomerular abnormalities, suggesting possible mild lupus nephritis. Eight months after her initial presentation, she remains free of abdominal pain and has regained the weight she had initially lost. Her oral ulcers have resolved, and her blood counts have normalized. Her serum creatinine has remained normal. She is now maintained on prednisone (15 mg daily), hydroxychloroquine, and mycophenolate mofetil.

COMMENTARY

A diagnosis of systemic lupus erythematosus (SLE) provided a unifying explanation for the patient's findings. Indeed, she manifested 4 of the 11 American College of Rheumatology criteria for systemic lupus (oral ulcers, leukopenia, positive anti‐DNA, and positive ANA), meeting criteria for a definite diagnosis of SLE. She additionally had multiple other features suggestive of lupus including Raynaud's phenomenon, arthralgias, alopecia, mild thrombocytopenia, and a positive Coombs' test (although the normal reticulocyte count, lactate dehydrogenase, and haptoglobin were most consistent with anemia of a chronic disease).

The protean manifestations of SLE can present significant diagnostic challenges. In this case, physicians were immediately drawn to the patient's acute abdominal pain and severe neutropenia and failed to recognize more subtle disease manifestations that may have aided in establishing a unifying diagnosis sooner. The initial history and review of systems did not disclose arthralgias, alopecia, or Raynaud's phenomenon. In an era of increasing use of hospitalists, which creates potential discontinuity between inpatient and outpatient physicians, a thorough history and review of systems may be particularly important in diagnosing acute manifestations of chronic systemic disease. Inpatient physicians may be overly focused on the small subset of acute complaints leading to hospitalization, without considering the larger constellation of symptoms that may facilitate accurate diagnosis. Our discussant quickly recognized the multisystem nature of the patient's illness and appropriately focused on infectious, neoplastic, and autoimmune categories of disease as being most likely. When infectious and neoplastic conditions were excluded with reasonable certainty, a directed serologic investigation for autoimmune disease was requested, culminating in a diagnosis of SLE.

Involvement of the skin as well as hematologic, renal, and musculoskeletal systems in SLE is commonly recognized, whereas gastrointestinal involvement is perceived to occur much less frequently. However, abdominal pain occurs in up to 40% of patients with lupus.14 Abdominal pain in lupus patients can arise from non‐lupus‐related conditions as well as lupus‐related entities, including serositis, mesenteric vasculitis with or without infarction, mesenteric thrombosis, pancreatitis, inflammatory bowel disease, and adverse medication effects including peptic ulcer disease. Abnormal liver chemistries, as seen in our patient, occur in 20%‐50% of patients with lupus and may be due to lupus hepatitis, concomitant autoimmune hepatitis, or medications including NSAIDs.5, 6 Oral ulcers and leukopenia are likewise common in SLE, with each seen in up to half of patients.4, 7, 8 Leukopenia in SLE may a result of neutropenia, lymphocytopenia, or both. However, severe neutropenia (ie, absolute count less than 500/L), as seen in our case, is more often a result of myelotoxicity from immunosuppressive therapy, rather than SLE itself.9

Lupus enteritis represents bowel microischemia from small‐vessel arteritis or venulitis that often is not evident on conventional mesenteric angiography.4, 10, 11 The reported prevalence of intestinal vasculitis in patients with SLE varies widely, depending on the characteristics of lupus patients sampled in individual studies. Intestinal vasculitis affects 0.2%‐0.5% of SLE patients in general,4, 12 whereas among SLE patients with active disease and an acute abdomen, vasculitis has been reported in up to 53% of patients.10 Antiphospholipid antibodies, antibodies to extractable nuclear antigens, the SLE Disease Activity Index, complement levels, erythrocyte sedimentation rate, C‐reactive protein, and anti‐double‐stranded DNA do not reliably differentiate lupus enteritis from acute abdominal pain due to other etiologies in patients with SLE.11 However, a concomitant drop in the white blood cell count at the onset of symptoms may be useful in distinguishing lupus enteritis from other causes of acute abdominal pain among lupus patients.11 Computed tomography findings consistent with lupus enteritis are nonspecific and include bowel‐wall thickening, submucosal edema (eg, target sign), dilatation of intestinal segments, engorgement of mesenteric vessels, and increased attenuation of mesenteric fat.13 Colonoscopy may reveal areas of ischemia and ulceration, and biopsy can confirm intestinal vasculitis. However, intestinal involvement may be segmental, and pathologic confirmation may be difficult. Contrast enema, gallium scanning, and indium‐labeled white cell scanning may be useful, but lack specificity. No controlled trials to date have evaluated the optimal therapy for lupus enteritis, but pulsed methylprednisolone is often recommended.4 Cyclophosphamide, azathioprine, methotrexate, and cyclosporine have also been used as adjunctive agents. Patients may progress to intestinal infarction and perforation, which augurs a poor prognosis, and early surgical exploration should be considered in severely ill patients.10 Death may occur in more than two‐thirds of patients whose disease progresses to intestinal perforation.1

In summary, a multisystem disease such as SLE requires a comprehensive history, physical exam, and review of systems to establish a correct diagnosis. In our case, an extensive evaluation was necessary to exclude other etiologies of abdominal pain and systemic illness, particularly as infectious and neoplastic conditions occur far more often than lupus enteritis in the general population. However, profound laboratory abnormalities may have preoccupied the attention of treating physicians, leading them to overlook less obvious but important historical and physical findings suggestive of SLE. The cohesively abnormal forest may thus have been obscured by erratically abnormal individual trees. Gastrointestinal symptoms may be underrecognized in SLE. When these result for lupus enteritis, timely recognition may be lifesaving.

A 56‐year‐old woman from Colombia presented to the emergency department after 24 hours of abdominal pain. One week before, she had experienced similar pain that lasted for 4 hours and spontaneously resolved. She was nauseated but had no vomiting. She reported an unintentional 14‐pound weight loss over the preceding 3 weeks. She denied fever, chills, night sweats, diarrhea, constipation, dysuria, or jaundice.

In a middle‐aged woman with abdominal pain and nausea, diagnostic considerations include gallbladder disease, diseases of the bowel (such as a partial small‐bowel obstruction or inflammatory conditions), hepatic or pancreatic conditions, and nongastrointestinal ailments such as cardiac ischemia. Knowing the specific location of pain, its quality, precipitating factors, and accompanying systemic symptoms may help to narrow the diagnosis. The unintentional weight loss preceding the onset of pain may be an important clue because it suggests a systemic condition, and in a South American immigrantparticularly if she has traveled recentlyit is important to consider parasitic illnesses. The absence of fever makes some infections such as tuberculosis and malaria less likely. At this point, in addition to a thorough history and physical, laboratory tests should include a complete blood count (with quantification of eosinophils) and a metabolic panel with liver enzymes and albumin.

The patient described pain in the midline, just inferior to the umbilicus. The pain was constant, developed without any particular provocation, and was not related to meals or exertion. There were no constitutional symptoms aside from weight loss. She had a history of bipolar disorder, hypothyroidism, osteoarthritis, and chronic sinusitis and had previously undergone cholecystectomy and abdominal hysterectomy. She was taking levothyroxine, montelukast, bupropion, oxcarbazepine, fexofenadine, meloxicam, zolpidem, and, as needed, acetaminophen. She had recently completed a 10‐day course of levofloxacin for acute sinusitis. She had immigrated to the United States 10 years earlier and lived with her husband and daughter. She denied the use of tobacco, alcohol or illicit drugs. She had visited Colombia 6 months earlier but had no other recent travel history.

The history of cholecystectomy makes a biliary tract process unlikely. Its location reduces the likelihood of a hepatic or pancreatic process, but I would like to see the liver enzymes, especially given her recent acetaminophen use. The comorbid illnessesparticularly her bipolar disordermay be relevant because psychiatric illness might be associated with medication overuse or undisclosed toxic ingestions. For example, excess thyroxine might lead to weight loss while overuse of nonsteroidal anti‐inflammatory drugs such as meloxicam can cause intestinal ulceration, not only in the upper tract, but also in the colon. Undisclosed ingestions may also be associated with abdominal symptoms. Her surgical history makes adhesions with a secondary partial bowel obstruction possible. With no travel outside this country in the last 6 months, exotic infections are less likely. Finally, the recent course of levofloxacin may be relevant because many antibiotics are associated with nonspecific abdominal symptoms, and Clostridium difficile colitis occasionally presents without diarrhea.

The patient reported taking her medications as prescribed and denied ingesting other medications. On physical examination, she had a temperature of 98.9F, a pulse of 81 beats per minute, a blood pressure of 110/80 mm Hg, and a respiratory rate of 16 respirations per minute. She had a normal oxygen saturation while breathing ambient air. Her weight was 58 kg. There was no scleral icterus or jugular venous distension. She had a small painless ulcer involving the hard palate. Her lungs were clear to auscultation, and cardiac examination was normal. The abdomen was soft, bowel sounds were present, and there was moderate tenderness to palpation inferior to the umbilicus. There was no rebound or guarding, hepatosplenomegaly or other masses. There was no peripheral edema and no lymphadenopathy. Neurological examination was normal.

The oral ulcer may or may not be related to the clinical presentation because oral ulcers, whether painful or painless, are ubiquitous and may be isolated or may be associated with a wide range of infectious and noninfectious systemic diseases. Although some systemic causes of mucocutaneous ulcers are associated with weight loss (including Crohn's disease, Behcet's disease, celiac sprue, human immunodeficiency virus [HIV], herpesviruses, syphilis, and systemic lupus erythematosus [SLE], among others), the lack of specificity of this finding limits its diagnostic utility. However, it is reasonable to ask whether the patient has noted frequent ulceration in the mouth or genitalia, as recurrent or severe ulcerations may narrow the diagnostic considerations. On the other hand, the focal nature of the pain inferior to the umbilicus suggests a discrete process in the abdomen or pelvis, such as an abscess, mass, or localized area of bowel inflammation. A plain abdominal film is likely to be low yield in this situation, so pursuing computed tomography is appropriate. Not all patients with focal abdominal pain require abdominal imaging, but in the context of weight loss and persistent symptoms for more than a week, imaging is prudent in this case.

The patient denied genital ulceration but did report painless oral ulcers over the preceding months. Laboratory evaluation revealed a white‐cell count of 1000/mm³, of which 6% were neutrophils, 5% were band forms, 36% were lymphocytes, and 47% were monocytes. The absolute neutrophil count was 110/mm³. Hemoglobin level was 10.2 g/dL with a mean corpuscular volume of 90 m³, and the platelet count was 151,000/mm³. Other results of laboratory studies were: sodium, 140 mmol/L; potassium, 3.8 mmol/L; chloride, 96 mmol/L; bicarbonate, 23 mmol/L; blood urea nitrogen, 13 mg/dL; creatinine, 0.4 mg/dL; lipase, 32 U/L (normal range, 13‐60); amylase, 73 U/L (normal range, 30‐110); albumin, 4.0 g/dL; aspartate aminotransferase, 779 U/L (normal range, 13‐35); alanine aminotransferase, 330 U/L (normal range, 7‐35); alkaline phosphatase, 510 U/L (normal range, 35‐104); and total bilirubin, 0.9 mg/dL (normal range, 0.1‐1.2). The lactate dehydrogenase level was 200 U/L (normal range, 135‐214). The corrected reticulocyte count was 1.6% (normal range, 0.3‐2.3), and haptoglobin was 190 mg/dL (normal range, 43‐212). A direct Coomb's test was positive. The erythrocyte sedimentation rate was 113 mm/hour (normal range, 1‐25). Urinalysis was normal without evidence of protein or blood.

Laboratory abnormalities include elevated transaminases and alkaline phosphatase, a markedly elevated erythrocyte sedimentation rate, and profound leukopenia with neutropenia. The patient is anemic, which may elevate the sedimentation rate but not typically to this degree. The patient is not febrile, but if she were to develop a fever, empiric antibiotics would be prudent. The normal albumin and bilirubin suggest that hepatic synthetic and excretory functions remain intact. Although the direct Coombs test is positive, the reticulocyte and lactate dehydrogenase levels argue against brisk hemolysis; this abnormality may simply be a marker of nonspecific immune activation. A variety of infections can cause neutropenia and liver enzyme abnormalities including parasites (malaria or leishmaniasis), viruses (cytomegalovirus or Epstein‐Barr virus [EBV]), tick‐borne bacterial infections (ehrlichiosis or rickettsial infection), and granulomatous infections (tuberculosis). Malignant infiltration of the reticuloendothelial system can also lead to cytopenias and liver enzyme abnormalities. Autoimmunity remains a consideration, as SLE may lead to cytopenias, oral ulcers, and nonspecific immune phenomena. Rather than ordering a large number of blood tests, I favor a targeted approach with abdominal computed tomography followed by biopsy of either the liver or bone marrow.

Chest radiography revealed no abnormalities. Computed tomography of the chest, abdomen, and pelvis with intravenous and oral contrast demonstrated concentric wall thickening of the transverse colon, but no evidence of obstruction or free air. The patient was treated with intravenous fluids, morphine, and cefepime. Bone marrow biopsy was performed, which demonstrated a hypercellular marrow with increased myeloid precursors and a left shift and megakaryocytic hyperplasia. Flow cytometry revealed no abnormally restricted clonal populations. A concerted search for an infectious etiology of the patient's neutropenia was unrevealing, including tests for HIV, cytomegalovirus, hepatitis A, hepatitis B, hepatitis C, Mycoplasma pneumoniae, EBV, and parvovirus B19.

I hope blood cultures were drawn prior to the initiation of antibiotics. Hypercellularity of the bone marrow in the context of leukopenia raises concern that white blood cells are being destroyed peripherally. Autoimmunity against neutrophils can be transiently induced by viruses such as HIV, hepatitis B, and EBV, but these infections have been excluded. Testing for antinuclear antibodies is reasonable. A normal‐sized spleen on the abdominal CT excludes hypersplenism. Colonic thickening can be associated with infection, ischemia, inflammatory bowel disease, and malignancy. The question is whether the colonic thickening is part of the same disease process causing the leukopenia and liver enzyme elevation or whether it represents a secondary infectious process in the setting of neutropenia (such as Clostridium difficile infection or typhlitis). Testing for stool pathogens (including ova and parasites) is certainly appropriate, and consideration of a colonoscopy with biopsy is reasonable, provided that appropriate antimicrobial coverage remains in place.

Blood cultures obtained prior to starting antibiotics were negative. The patient's abdominal pain improved, and she was discharged home to have close follow‐up with a hematologist. The results of her liver function tests improved, and her absolute neutrophil count was 230/mm³ at the time of discharge. Her neutropenia was believed to be secondary to peripheral destruction from a viral, drug‐mediated, or autoimmune process. Oxcarbazepine (Trileptal) was discontinued, as it was believed to be the medication most likely to be responsible. She returned to the hospital 3 days later with recurrence of her abdominal pain and diarrhea. She remained afebrile. Additional history revealed arthralgias over the previous 2 months, mild alopecia, and prior symptoms suggestive of Raynaud's phenomenon. Stool studies failed to establish an infectious etiology for the diarrhea, and her continued neutropenia responded appropriately to treatment with subcutaneous filgrastim. Colonoscopy could be performed only to the hepatic flexure and revealed no abnormalities. A serologic test for antinuclear antibodies was positive at a titer of 1:640 in a homogenous pattern, and a test for antineutrophil cytoplasmic antibodies was negative. Complement levels were normal, and tests for cryoglobulins, rapid plasma reagin, anticardiolipin antibody, lupus anticoagulant, rheumatoid factor, and antibodies to extractable nuclear antigens were all negative.

Raynaud's phenomenon is consistent with lupus. Double‐stranded DNA antibodies should be sent, although the urine did not demonstrate protein or an active sediment. Systemic sclerosis and the CREST syndrome is strongly associated with Raynaud's phenomenon and high‐titer ANA, but the patient does not have sclerodactyly, which is generally the earliest skin involvement. Autoimmune hepatitis is often associated with high‐titer ANA but does not fit this clinical picture. Given that the patient's presentation included segmental bowel wall thickening and a transient but marked liver enzyme elevation with AST predominance, I am concerned about vasculitis of the abdominal vasculature and would strongly consider a mesenteric angiogram.

To exclude mesenteric vasculitis, the patient underwent magnetic resonance angiography of the abdomen, the results of which were normal. A repeat test for antinuclear antibodies was positive at a titer of 1:2560 in a uniform pattern. A test for anti‐double‐stranded DNA was positive at 1370 U/mL. The patient was diagnosed with systemic lupus and probable lupus enteritis, and therapy with oral prednisone (10 mg daily) and hydroxychloroquine was initiated. She had prompt improvement in her abdominal pain, and was discharged home. Five months later she developed proteinuria and underwent a renal biopsy, which showed minor, nonspecific glomerular abnormalities, suggesting possible mild lupus nephritis. Eight months after her initial presentation, she remains free of abdominal pain and has regained the weight she had initially lost. Her oral ulcers have resolved, and her blood counts have normalized. Her serum creatinine has remained normal. She is now maintained on prednisone (15 mg daily), hydroxychloroquine, and mycophenolate mofetil.

COMMENTARY

A diagnosis of systemic lupus erythematosus (SLE) provided a unifying explanation for the patient's findings. Indeed, she manifested 4 of the 11 American College of Rheumatology criteria for systemic lupus (oral ulcers, leukopenia, positive anti‐DNA, and positive ANA), meeting criteria for a definite diagnosis of SLE. She additionally had multiple other features suggestive of lupus including Raynaud's phenomenon, arthralgias, alopecia, mild thrombocytopenia, and a positive Coombs' test (although the normal reticulocyte count, lactate dehydrogenase, and haptoglobin were most consistent with anemia of a chronic disease).

The protean manifestations of SLE can present significant diagnostic challenges. In this case, physicians were immediately drawn to the patient's acute abdominal pain and severe neutropenia and failed to recognize more subtle disease manifestations that may have aided in establishing a unifying diagnosis sooner. The initial history and review of systems did not disclose arthralgias, alopecia, or Raynaud's phenomenon. In an era of increasing use of hospitalists, which creates potential discontinuity between inpatient and outpatient physicians, a thorough history and review of systems may be particularly important in diagnosing acute manifestations of chronic systemic disease. Inpatient physicians may be overly focused on the small subset of acute complaints leading to hospitalization, without considering the larger constellation of symptoms that may facilitate accurate diagnosis. Our discussant quickly recognized the multisystem nature of the patient's illness and appropriately focused on infectious, neoplastic, and autoimmune categories of disease as being most likely. When infectious and neoplastic conditions were excluded with reasonable certainty, a directed serologic investigation for autoimmune disease was requested, culminating in a diagnosis of SLE.

Involvement of the skin as well as hematologic, renal, and musculoskeletal systems in SLE is commonly recognized, whereas gastrointestinal involvement is perceived to occur much less frequently. However, abdominal pain occurs in up to 40% of patients with lupus.14 Abdominal pain in lupus patients can arise from non‐lupus‐related conditions as well as lupus‐related entities, including serositis, mesenteric vasculitis with or without infarction, mesenteric thrombosis, pancreatitis, inflammatory bowel disease, and adverse medication effects including peptic ulcer disease. Abnormal liver chemistries, as seen in our patient, occur in 20%‐50% of patients with lupus and may be due to lupus hepatitis, concomitant autoimmune hepatitis, or medications including NSAIDs.5, 6 Oral ulcers and leukopenia are likewise common in SLE, with each seen in up to half of patients.4, 7, 8 Leukopenia in SLE may a result of neutropenia, lymphocytopenia, or both. However, severe neutropenia (ie, absolute count less than 500/L), as seen in our case, is more often a result of myelotoxicity from immunosuppressive therapy, rather than SLE itself.9

Lupus enteritis represents bowel microischemia from small‐vessel arteritis or venulitis that often is not evident on conventional mesenteric angiography.4, 10, 11 The reported prevalence of intestinal vasculitis in patients with SLE varies widely, depending on the characteristics of lupus patients sampled in individual studies. Intestinal vasculitis affects 0.2%‐0.5% of SLE patients in general,4, 12 whereas among SLE patients with active disease and an acute abdomen, vasculitis has been reported in up to 53% of patients.10 Antiphospholipid antibodies, antibodies to extractable nuclear antigens, the SLE Disease Activity Index, complement levels, erythrocyte sedimentation rate, C‐reactive protein, and anti‐double‐stranded DNA do not reliably differentiate lupus enteritis from acute abdominal pain due to other etiologies in patients with SLE.11 However, a concomitant drop in the white blood cell count at the onset of symptoms may be useful in distinguishing lupus enteritis from other causes of acute abdominal pain among lupus patients.11 Computed tomography findings consistent with lupus enteritis are nonspecific and include bowel‐wall thickening, submucosal edema (eg, target sign), dilatation of intestinal segments, engorgement of mesenteric vessels, and increased attenuation of mesenteric fat.13 Colonoscopy may reveal areas of ischemia and ulceration, and biopsy can confirm intestinal vasculitis. However, intestinal involvement may be segmental, and pathologic confirmation may be difficult. Contrast enema, gallium scanning, and indium‐labeled white cell scanning may be useful, but lack specificity. No controlled trials to date have evaluated the optimal therapy for lupus enteritis, but pulsed methylprednisolone is often recommended.4 Cyclophosphamide, azathioprine, methotrexate, and cyclosporine have also been used as adjunctive agents. Patients may progress to intestinal infarction and perforation, which augurs a poor prognosis, and early surgical exploration should be considered in severely ill patients.10 Death may occur in more than two‐thirds of patients whose disease progresses to intestinal perforation.1

In summary, a multisystem disease such as SLE requires a comprehensive history, physical exam, and review of systems to establish a correct diagnosis. In our case, an extensive evaluation was necessary to exclude other etiologies of abdominal pain and systemic illness, particularly as infectious and neoplastic conditions occur far more often than lupus enteritis in the general population. However, profound laboratory abnormalities may have preoccupied the attention of treating physicians, leading them to overlook less obvious but important historical and physical findings suggestive of SLE. The cohesively abnormal forest may thus have been obscured by erratically abnormal individual trees. Gastrointestinal symptoms may be underrecognized in SLE. When these result for lupus enteritis, timely recognition may be lifesaving.

A60‐year‐old man presented with agitation and a forehead mass (Figs. 1 and 2). His wife had noticed its rapid growth over several weeks and said he had recently become extremely confused and hostile. He had a history of smoking and exposures to silica and Agent Orange. His vitals and oxygen saturation were normal. He was cachectic but in no distress, and although he was uncooperative, his examination did not demonstrate an obvious neurological deficit. Routine electrolytes were within normal limits.

Figure 1

Figure 2

Noncontrast computed tomography of the skull revealed a 5.5 5.4 7.7cm frontal soft‐tissue density eroding his frontal bone and extending intracranially, with extensive displacement of both frontal lobes and invasion into his superior sagittal sinus (Fig. 3) and possible involvement of the brain parenchyma. A subsequent CT scan of the chest demonstrated a 7.8 7.9cm right mass in the lower lobe of the lung encasing the right pulmonary artery and 2 left renal masses.

Figure 3

Biopsy of the forehead mass demonstrated a necrotic, poorly differentiated carcinoma with focal clear‐cell features. Immunohistochemical staining was consistent with squamous cell carcinoma.

The forehead mass was painless, and the lung mass unresectable. His behavioral changes persisted and were attributed to the tumor compressing and possibly invading both frontal lobes. At his wife's request, he was discharged on dexamethasone with home hospice and died 2 weeks later.

Although there is little literature on the epidemiology of skull metastases, the most common malignancies to metastasize to the skull are breast and lung carcinomas. Others include prostate, thyroid, myeloma, and melanoma. Symptomatic metastases, including neurological findings, are unusual, except for tumors that metastasize to the skull base and cause cranial nerve deficits. Skeletal metastasis as the first manifestation of lung cancer occurs in about 2% of lung cancer patients and is a marker of poor prognosis. Received 2 November 2006; revision received 15 December 2006; accepted 16 January 2007.

A60‐year‐old man presented with agitation and a forehead mass (Figs. 1 and 2). His wife had noticed its rapid growth over several weeks and said he had recently become extremely confused and hostile. He had a history of smoking and exposures to silica and Agent Orange. His vitals and oxygen saturation were normal. He was cachectic but in no distress, and although he was uncooperative, his examination did not demonstrate an obvious neurological deficit. Routine electrolytes were within normal limits.

Figure 1

Figure 2

Noncontrast computed tomography of the skull revealed a 5.5 5.4 7.7cm frontal soft‐tissue density eroding his frontal bone and extending intracranially, with extensive displacement of both frontal lobes and invasion into his superior sagittal sinus (Fig. 3) and possible involvement of the brain parenchyma. A subsequent CT scan of the chest demonstrated a 7.8 7.9cm right mass in the lower lobe of the lung encasing the right pulmonary artery and 2 left renal masses.

Figure 3

Biopsy of the forehead mass demonstrated a necrotic, poorly differentiated carcinoma with focal clear‐cell features. Immunohistochemical staining was consistent with squamous cell carcinoma.

The forehead mass was painless, and the lung mass unresectable. His behavioral changes persisted and were attributed to the tumor compressing and possibly invading both frontal lobes. At his wife's request, he was discharged on dexamethasone with home hospice and died 2 weeks later.

Although there is little literature on the epidemiology of skull metastases, the most common malignancies to metastasize to the skull are breast and lung carcinomas. Others include prostate, thyroid, myeloma, and melanoma. Symptomatic metastases, including neurological findings, are unusual, except for tumors that metastasize to the skull base and cause cranial nerve deficits. Skeletal metastasis as the first manifestation of lung cancer occurs in about 2% of lung cancer patients and is a marker of poor prognosis. Received 2 November 2006; revision received 15 December 2006; accepted 16 January 2007.

A60‐year‐old man presented with agitation and a forehead mass (Figs. 1 and 2). His wife had noticed its rapid growth over several weeks and said he had recently become extremely confused and hostile. He had a history of smoking and exposures to silica and Agent Orange. His vitals and oxygen saturation were normal. He was cachectic but in no distress, and although he was uncooperative, his examination did not demonstrate an obvious neurological deficit. Routine electrolytes were within normal limits.

Figure 1

Figure 2

Noncontrast computed tomography of the skull revealed a 5.5 5.4 7.7cm frontal soft‐tissue density eroding his frontal bone and extending intracranially, with extensive displacement of both frontal lobes and invasion into his superior sagittal sinus (Fig. 3) and possible involvement of the brain parenchyma. A subsequent CT scan of the chest demonstrated a 7.8 7.9cm right mass in the lower lobe of the lung encasing the right pulmonary artery and 2 left renal masses.

Figure 3

Biopsy of the forehead mass demonstrated a necrotic, poorly differentiated carcinoma with focal clear‐cell features. Immunohistochemical staining was consistent with squamous cell carcinoma.

The forehead mass was painless, and the lung mass unresectable. His behavioral changes persisted and were attributed to the tumor compressing and possibly invading both frontal lobes. At his wife's request, he was discharged on dexamethasone with home hospice and died 2 weeks later.

Although there is little literature on the epidemiology of skull metastases, the most common malignancies to metastasize to the skull are breast and lung carcinomas. Others include prostate, thyroid, myeloma, and melanoma. Symptomatic metastases, including neurological findings, are unusual, except for tumors that metastasize to the skull base and cause cranial nerve deficits. Skeletal metastasis as the first manifestation of lung cancer occurs in about 2% of lung cancer patients and is a marker of poor prognosis. Received 2 November 2006; revision received 15 December 2006; accepted 16 January 2007.

Bronchiolitis was the most common primary diagnosis of infants hospitalized in the United States from 2000 to 2001.1 Consequently, much research has focused on the effectiveness of management24 and variation in care, especially the use of unproven diagnostic tests such as chest x‐rays.5 Such variation may have substantial financial and medical impact and has been shown to correlate significantly with hospital costs and length of stay.6

Because bronchiolitis is primarily a clinical diagnosis,7 there is no strong evidence to support the role of diagnostic testing, particularly that of complete blood counts (CBCs).8 Moreover, given the limited diagnostic utility of a single CBC, the benefit of obtaining a second CBC, especially with its associated physical discomfort and additional financial costs, is questionable. Yet despite the lack of evidence and rationale to support initial and repeated ordering of CBCs, we suspect that this practice may be more widespread and variable than currently appreciated.

Using a national database of children's hospitals, we sought to determine the frequency with which CBCs are ordered and repeated during hospitalizations for bronchiolitis, the extent to which these practices vary across institutions, and the relationship of these practices to average charges for a hospital stay.

METHODS

RESULTS

A total of 17,397 children met the inclusion criteria. Children under 3 months were more likely to be covered by Medicaid, be admitted to the ICU, have a longer length of stay, and have at least 1 CBC (Table 1). Of all children hospitalized, 48.2% had at least 1 CBC, and 7.8% had more than 1 CBC performed during their hospital stay. Notably, the proportion of all admissions with at least 1 CBC varied from 23.2% to 79.2% (Fig. 1), and those with repeat CBCs varied from 0% to 18.6% across hospitals (Fig. 2). This variation was significant when stratified by age and adjusted for covariates, which included length of stay and severity of illness (P < .001). In additional post hoc analyses we found differences in ordering pattern by disease severity that should be noted. The proportion of admissions with repeat CBCs varied significantly across severity groups (mild 3.9%, moderate 10.3%, and severe 21.3%, P < .001) and ICU admission status (ICU admission 5.5%, no ICU admission 23%, P <.001). Stratified analyses indicated an interaction between ICU utilization and disease severity, but neither covariate showed significant interactions with other variables in the model (data not shown).

Figure 1

Figure 2

With respect to repeat CBCs, for children at least 3 months old, the strongest predictor was ICU admission (odds ratio [OR] 2.53, 95% CI: 1.69‐3.77), followed by a severe or extreme APR‐DRG severity score (OR 1.75, 95% CI: 1.23‐2.49) and LOS (OR 1.22, 95% CI: 1.15‐1.28). For children less than 3 months old, some of these associations strengthened ICU admission (OR 2.58, 95% CI: 1.84‐3.61), followed by a severe or extreme APR‐DRG severity score (OR 2.31, 95% CI: 1.64‐3.24) and LOS (OR 1.24, 95% CI: 1.16‐1.32). Additional predictors for this age group were a moderate severity score (OR 1.67, 95% CI: 1.29‐2.16) and Medicaid status (OR 1.20, 95% CI: 1.0‐1.43) (Table 2).

Compared with hospitals that had the lowest proportion of admissions in which CBCs were ordered, hospitals with higher proportions of CBCs ordered had significantly higher mean charges per hospital stay (Table 3).

DISCUSSION

We found that in a nationwide sample of children hospitalized with bronchiolitis, 48% had at least 1 CBC and nearly 8% had a repeat CBC ordered during their hospital stay. Moreover, even after adjusting for covariates, the proportion of children with initial and repeat CBCs during a single admission varied widely and significantly across a nationwide sample of children's hospitals.

We can only speculate on the reasons for institutional variation. Although it is not unusual for some cases of illness to vary from a standard course and so trigger initial or repeat evaluations with a CBC, we do not have any a priori reason to expect the proportion of unusual cases to vary by institution in a national cohort of children's hospitals. One compelling explanation for this variation is differing institutional patterns of practice. For example, it may be that some institutions have protocols that require the ordering of a CBC on admission. This practice could prompt a costly and unnecessary testing cascade14 generated by an initially abnormal CBC and so could trigger additional testing and/or procedures, such as x‐rays and parental antibiotics. Such a cascade of testing and intervention could conceivably lead to additional, and dependent, costs not captured by a simple tally of the costs of individual CBCs. Indeed, in our analysis we found that those hospitals with higher proportion of admissions in which CBCs were ordered also had significantly higher admission charges that exceeded the cost of a CBC. Previous studies support the finding that institutional variation in care for viral respiratory illness is significantly correlated with hospital costs.6

Limitations of this study should be noted. First, the PHIS database does not provide indications for, results of, or hospital location of tests, so we cannot determine whether clinical condition or results prompted initial and/or repeat testing. However, because children with complicated courses or atypical disease presentations likely have longer hospital stays, severe disease, or additional diagnoses, we attempted to control for these factors in our analysis. Second, although we selected cases based on a discharge diagnosis of bronchiolitis, it is possible that admitting physicians obtained an initial CBC to rule out alternative diagnoses, such as bacteremia, which can occur but is rare in this population.12, 13 It is plausible that bacteremia is most likely in children with other comorbidities or higher disease severity. In additional stratified analyses we did find that the proportion of repeat CBCs increased with higher disease severity and that there was an interaction between severe disease status and ICU admission. However, all participating institutions are children's hospitals and so are likely to treat children with a range of severity of illness and comorbidities. Finally, as with other analyses of the PHIS database, we used charges to identify diagnostic tests.5

Given that more than 120,000 U.S. infants are hospitalized annually with bronchiolitis,15 the cost and discomfort associated with unnecessary testing warrants attention. The issue of cost is particularly relevant in light of recent research findings of increased costs for admissions at freestanding children's hospitals.16 We found that mean charges per hospital stay were significantly higher for hospitals that had a higher proportion of admissions during which multiple CBCs were ordered. Although we cannot exclude illness severity and age as explanations for the higher charges, we have no reason to believe that one freestanding children's hospital would have a sicker and younger population than another. An alternative and compelling explanation is that a variation in the standard of care exists across these hospitals.

The institutional variation in and the limited evidence for the utility of the ordering of CBCs in the evaluation of bronchiolitis call into question the necessity of this testing strategy. Exploration of the reasons for this institutional variation will help to create quality initiatives and directed interventions to improve and standardize care in bronchiolitis.

Bronchiolitis was the most common primary diagnosis of infants hospitalized in the United States from 2000 to 2001.1 Consequently, much research has focused on the effectiveness of management24 and variation in care, especially the use of unproven diagnostic tests such as chest x‐rays.5 Such variation may have substantial financial and medical impact and has been shown to correlate significantly with hospital costs and length of stay.6

Because bronchiolitis is primarily a clinical diagnosis,7 there is no strong evidence to support the role of diagnostic testing, particularly that of complete blood counts (CBCs).8 Moreover, given the limited diagnostic utility of a single CBC, the benefit of obtaining a second CBC, especially with its associated physical discomfort and additional financial costs, is questionable. Yet despite the lack of evidence and rationale to support initial and repeated ordering of CBCs, we suspect that this practice may be more widespread and variable than currently appreciated.

Using a national database of children's hospitals, we sought to determine the frequency with which CBCs are ordered and repeated during hospitalizations for bronchiolitis, the extent to which these practices vary across institutions, and the relationship of these practices to average charges for a hospital stay.

METHODS

RESULTS

A total of 17,397 children met the inclusion criteria. Children under 3 months were more likely to be covered by Medicaid, be admitted to the ICU, have a longer length of stay, and have at least 1 CBC (Table 1). Of all children hospitalized, 48.2% had at least 1 CBC, and 7.8% had more than 1 CBC performed during their hospital stay. Notably, the proportion of all admissions with at least 1 CBC varied from 23.2% to 79.2% (Fig. 1), and those with repeat CBCs varied from 0% to 18.6% across hospitals (Fig. 2). This variation was significant when stratified by age and adjusted for covariates, which included length of stay and severity of illness (P < .001). In additional post hoc analyses we found differences in ordering pattern by disease severity that should be noted. The proportion of admissions with repeat CBCs varied significantly across severity groups (mild 3.9%, moderate 10.3%, and severe 21.3%, P < .001) and ICU admission status (ICU admission 5.5%, no ICU admission 23%, P <.001). Stratified analyses indicated an interaction between ICU utilization and disease severity, but neither covariate showed significant interactions with other variables in the model (data not shown).

Figure 1

Figure 2

With respect to repeat CBCs, for children at least 3 months old, the strongest predictor was ICU admission (odds ratio [OR] 2.53, 95% CI: 1.69‐3.77), followed by a severe or extreme APR‐DRG severity score (OR 1.75, 95% CI: 1.23‐2.49) and LOS (OR 1.22, 95% CI: 1.15‐1.28). For children less than 3 months old, some of these associations strengthened ICU admission (OR 2.58, 95% CI: 1.84‐3.61), followed by a severe or extreme APR‐DRG severity score (OR 2.31, 95% CI: 1.64‐3.24) and LOS (OR 1.24, 95% CI: 1.16‐1.32). Additional predictors for this age group were a moderate severity score (OR 1.67, 95% CI: 1.29‐2.16) and Medicaid status (OR 1.20, 95% CI: 1.0‐1.43) (Table 2).

Compared with hospitals that had the lowest proportion of admissions in which CBCs were ordered, hospitals with higher proportions of CBCs ordered had significantly higher mean charges per hospital stay (Table 3).

DISCUSSION

We found that in a nationwide sample of children hospitalized with bronchiolitis, 48% had at least 1 CBC and nearly 8% had a repeat CBC ordered during their hospital stay. Moreover, even after adjusting for covariates, the proportion of children with initial and repeat CBCs during a single admission varied widely and significantly across a nationwide sample of children's hospitals.

We can only speculate on the reasons for institutional variation. Although it is not unusual for some cases of illness to vary from a standard course and so trigger initial or repeat evaluations with a CBC, we do not have any a priori reason to expect the proportion of unusual cases to vary by institution in a national cohort of children's hospitals. One compelling explanation for this variation is differing institutional patterns of practice. For example, it may be that some institutions have protocols that require the ordering of a CBC on admission. This practice could prompt a costly and unnecessary testing cascade14 generated by an initially abnormal CBC and so could trigger additional testing and/or procedures, such as x‐rays and parental antibiotics. Such a cascade of testing and intervention could conceivably lead to additional, and dependent, costs not captured by a simple tally of the costs of individual CBCs. Indeed, in our analysis we found that those hospitals with higher proportion of admissions in which CBCs were ordered also had significantly higher admission charges that exceeded the cost of a CBC. Previous studies support the finding that institutional variation in care for viral respiratory illness is significantly correlated with hospital costs.6

Limitations of this study should be noted. First, the PHIS database does not provide indications for, results of, or hospital location of tests, so we cannot determine whether clinical condition or results prompted initial and/or repeat testing. However, because children with complicated courses or atypical disease presentations likely have longer hospital stays, severe disease, or additional diagnoses, we attempted to control for these factors in our analysis. Second, although we selected cases based on a discharge diagnosis of bronchiolitis, it is possible that admitting physicians obtained an initial CBC to rule out alternative diagnoses, such as bacteremia, which can occur but is rare in this population.12, 13 It is plausible that bacteremia is most likely in children with other comorbidities or higher disease severity. In additional stratified analyses we did find that the proportion of repeat CBCs increased with higher disease severity and that there was an interaction between severe disease status and ICU admission. However, all participating institutions are children's hospitals and so are likely to treat children with a range of severity of illness and comorbidities. Finally, as with other analyses of the PHIS database, we used charges to identify diagnostic tests.5

Given that more than 120,000 U.S. infants are hospitalized annually with bronchiolitis,15 the cost and discomfort associated with unnecessary testing warrants attention. The issue of cost is particularly relevant in light of recent research findings of increased costs for admissions at freestanding children's hospitals.16 We found that mean charges per hospital stay were significantly higher for hospitals that had a higher proportion of admissions during which multiple CBCs were ordered. Although we cannot exclude illness severity and age as explanations for the higher charges, we have no reason to believe that one freestanding children's hospital would have a sicker and younger population than another. An alternative and compelling explanation is that a variation in the standard of care exists across these hospitals.

The institutional variation in and the limited evidence for the utility of the ordering of CBCs in the evaluation of bronchiolitis call into question the necessity of this testing strategy. Exploration of the reasons for this institutional variation will help to create quality initiatives and directed interventions to improve and standardize care in bronchiolitis.

Bronchiolitis was the most common primary diagnosis of infants hospitalized in the United States from 2000 to 2001.1 Consequently, much research has focused on the effectiveness of management24 and variation in care, especially the use of unproven diagnostic tests such as chest x‐rays.5 Such variation may have substantial financial and medical impact and has been shown to correlate significantly with hospital costs and length of stay.6

Because bronchiolitis is primarily a clinical diagnosis,7 there is no strong evidence to support the role of diagnostic testing, particularly that of complete blood counts (CBCs).8 Moreover, given the limited diagnostic utility of a single CBC, the benefit of obtaining a second CBC, especially with its associated physical discomfort and additional financial costs, is questionable. Yet despite the lack of evidence and rationale to support initial and repeated ordering of CBCs, we suspect that this practice may be more widespread and variable than currently appreciated.

Using a national database of children's hospitals, we sought to determine the frequency with which CBCs are ordered and repeated during hospitalizations for bronchiolitis, the extent to which these practices vary across institutions, and the relationship of these practices to average charges for a hospital stay.

METHODS

RESULTS

A total of 17,397 children met the inclusion criteria. Children under 3 months were more likely to be covered by Medicaid, be admitted to the ICU, have a longer length of stay, and have at least 1 CBC (Table 1). Of all children hospitalized, 48.2% had at least 1 CBC, and 7.8% had more than 1 CBC performed during their hospital stay. Notably, the proportion of all admissions with at least 1 CBC varied from 23.2% to 79.2% (Fig. 1), and those with repeat CBCs varied from 0% to 18.6% across hospitals (Fig. 2). This variation was significant when stratified by age and adjusted for covariates, which included length of stay and severity of illness (P < .001). In additional post hoc analyses we found differences in ordering pattern by disease severity that should be noted. The proportion of admissions with repeat CBCs varied significantly across severity groups (mild 3.9%, moderate 10.3%, and severe 21.3%, P < .001) and ICU admission status (ICU admission 5.5%, no ICU admission 23%, P <.001). Stratified analyses indicated an interaction between ICU utilization and disease severity, but neither covariate showed significant interactions with other variables in the model (data not shown).

Figure 1

Figure 2

With respect to repeat CBCs, for children at least 3 months old, the strongest predictor was ICU admission (odds ratio [OR] 2.53, 95% CI: 1.69‐3.77), followed by a severe or extreme APR‐DRG severity score (OR 1.75, 95% CI: 1.23‐2.49) and LOS (OR 1.22, 95% CI: 1.15‐1.28). For children less than 3 months old, some of these associations strengthened ICU admission (OR 2.58, 95% CI: 1.84‐3.61), followed by a severe or extreme APR‐DRG severity score (OR 2.31, 95% CI: 1.64‐3.24) and LOS (OR 1.24, 95% CI: 1.16‐1.32). Additional predictors for this age group were a moderate severity score (OR 1.67, 95% CI: 1.29‐2.16) and Medicaid status (OR 1.20, 95% CI: 1.0‐1.43) (Table 2).

Compared with hospitals that had the lowest proportion of admissions in which CBCs were ordered, hospitals with higher proportions of CBCs ordered had significantly higher mean charges per hospital stay (Table 3).

DISCUSSION

We found that in a nationwide sample of children hospitalized with bronchiolitis, 48% had at least 1 CBC and nearly 8% had a repeat CBC ordered during their hospital stay. Moreover, even after adjusting for covariates, the proportion of children with initial and repeat CBCs during a single admission varied widely and significantly across a nationwide sample of children's hospitals.

We can only speculate on the reasons for institutional variation. Although it is not unusual for some cases of illness to vary from a standard course and so trigger initial or repeat evaluations with a CBC, we do not have any a priori reason to expect the proportion of unusual cases to vary by institution in a national cohort of children's hospitals. One compelling explanation for this variation is differing institutional patterns of practice. For example, it may be that some institutions have protocols that require the ordering of a CBC on admission. This practice could prompt a costly and unnecessary testing cascade14 generated by an initially abnormal CBC and so could trigger additional testing and/or procedures, such as x‐rays and parental antibiotics. Such a cascade of testing and intervention could conceivably lead to additional, and dependent, costs not captured by a simple tally of the costs of individual CBCs. Indeed, in our analysis we found that those hospitals with higher proportion of admissions in which CBCs were ordered also had significantly higher admission charges that exceeded the cost of a CBC. Previous studies support the finding that institutional variation in care for viral respiratory illness is significantly correlated with hospital costs.6

Limitations of this study should be noted. First, the PHIS database does not provide indications for, results of, or hospital location of tests, so we cannot determine whether clinical condition or results prompted initial and/or repeat testing. However, because children with complicated courses or atypical disease presentations likely have longer hospital stays, severe disease, or additional diagnoses, we attempted to control for these factors in our analysis. Second, although we selected cases based on a discharge diagnosis of bronchiolitis, it is possible that admitting physicians obtained an initial CBC to rule out alternative diagnoses, such as bacteremia, which can occur but is rare in this population.12, 13 It is plausible that bacteremia is most likely in children with other comorbidities or higher disease severity. In additional stratified analyses we did find that the proportion of repeat CBCs increased with higher disease severity and that there was an interaction between severe disease status and ICU admission. However, all participating institutions are children's hospitals and so are likely to treat children with a range of severity of illness and comorbidities. Finally, as with other analyses of the PHIS database, we used charges to identify diagnostic tests.5

Given that more than 120,000 U.S. infants are hospitalized annually with bronchiolitis,15 the cost and discomfort associated with unnecessary testing warrants attention. The issue of cost is particularly relevant in light of recent research findings of increased costs for admissions at freestanding children's hospitals.16 We found that mean charges per hospital stay were significantly higher for hospitals that had a higher proportion of admissions during which multiple CBCs were ordered. Although we cannot exclude illness severity and age as explanations for the higher charges, we have no reason to believe that one freestanding children's hospital would have a sicker and younger population than another. An alternative and compelling explanation is that a variation in the standard of care exists across these hospitals.

The institutional variation in and the limited evidence for the utility of the ordering of CBCs in the evaluation of bronchiolitis call into question the necessity of this testing strategy. Exploration of the reasons for this institutional variation will help to create quality initiatives and directed interventions to improve and standardize care in bronchiolitis.

Venous thromboembolism prophylaxis (VTE PX) has been identified as an area of primary importance to improve patient safety in research and clinical practice.13 Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common, often preventable life‐threatening condition for hospitalized patients.4 Up to half of patients admitted to the hospital are admitted from the emergency department (ED). Most of these patients are acutely ill with multiple risk factors for VTE. To reduce the incidence of VTE, these patients require routine evaluation to determine if thromboprophylaxis is needed, and when indicated, therapy should be started promptly on admission. The Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy outlines recommendations for VTE PX that reduce the development of DVT and PE.3 Despite there being effective VTE PX and the current focus on increasing its utilization to improve patient safety, VTE PX is underutilized. In particular, the subgroup of patients admitted from the ED, a group at high risk for VTE, has been neglected in the literature.

Our hypothesis was that VTE PX is underutilized in patients admitted through the ED. The specific objective of this study was to measure the rate at which hospitalized patients admitted though the ED received VTE PX.

METHODS

The study was conducted with the approval of and in accordance with the ethical standards of the Institutional Review Board of Baylor College of Medicine and Affiliated Hospitals. Prior to initiating chart review, passive consent was sought from physicians who were identified through the hospital medical records system as having admitted patients to this hospital through the ED in the preceding 6 months. Physicians were contacted twice in writing in a 1‐month period prior to study inception. Those who objected to their charts being reviewed were to notify the investigators. Otherwise, they were assumed to have consented to chart review. Fifteen percent of physicians declined chart review. Physicians were not informed of the particulars of the study, only that medication use in the ED was being evaluated.

This study was conducted at a private 900‐bed urban teaching hospital. The ED evaluates approximately 31,000 patients per year, predominantly a medical population. During the previous year, the ED had admitted roughly 30 patients per day, or 36% of all patients examined. Approximately 29% of admissions to this hospital (800/month) are admitted through the ED.

A convenience sample of every other hospital admission through the ED during 1 month was prospectively identified for inclusion in the study and chart review. Data were abstracted by a single reviewer on admission and at the time of discharge. The following data were collected: demographic characteristics, anticoagulant use or existing IVC filter, diagnoses, indications for full‐dose anticoagulation, indications for VTE PX (ie, immobilization, respiratory failure, congestive heart failure, limb trauma, surgery, or stroke), whether therapeutic anticoagulation or VTE PX was given, and date of initiation of this regimen, contraindications to anticoagulation, primary physician, and use of a standard order set. Patients were excluded if the attending physician declined chart review via the passive consent process. Other exclusion criteria were: receiving full‐dose anticoagulants before presentation to the ED, presence of an inferior vena cava (IVC) filter, indication for full‐dose anticoagulation (presented with DVT, PE, acute coronary syndrome), renal failure requiring hemodialysis (controversial risk for VTE59), length of stay (LOS) less than 2 days, and admission for psychiatric evaluation or treatment.

A modified Caprini's Risk Assessment Model for Surgical and Nonsurgical Patients was used to classify VTE risk.10 This tool assigns points to VTE risk factors so that risk and the need for VTE PX can be determined. For example, major surgery, central venous access, age older than 60 years, and bed rest for more than 72 hours are each assigned 2 points; higher‐risk factors such as hip or leg fractures or stroke are each assigned 5 points. This tool is generally in accord with the ACCP guidelines. Modifications made to this tool were to assign 3 points to patients in respiratory failure on ventilators and 5 points to patients who were critically ill on vasopressor medication. Decreased venous return associated with mechanical ventilation and peripheral vasoconstriction associated with the use of vasopressor medication justified the addition of these risk factors.11, 12 Patients were assigned to one of these risk categories: no risk (0 points), low risk (1 point), moderate risk (2 points), high risk (3‐4 points), or very high risk (5 or more points). As indicated by this risk assessment tool, those with moderate, high, or very high risk were considered in need of VTE PX.

Appropriate VTE PX was defined as any currently accepted medical (unfractionated heparin, low‐molecular‐weight heparin, or warfarin for orthopedic patients) or mechanical methods of VTE PX (sequential compression devices, and graduated compression stockings) for those in need and no VTE PX if none indicated. Aspirin, clopidogrel, or a combination of the 2 was not considered sufficient VTE PX.3 In addition, we established whether VTE PX as determined by the modified Caprini score was in line with ACCP guidelines, taking into account contraindications to anticoagulation. Preprinted order sets were divided into those that included VTE PX and those that did not. Order sets that included options for VTE PX were defined as standard order sets.

The primary objective of this study was to determine how frequently VTE PX was implemented in ED admissions. Secondary objectives were determining factors associated with correct VTE PX decision making and the proximity of orders for VTE PX to the time of admission.

RESULTS

Four hundred and fourteen charts of patient admissions were reviewed, of which 254 met the inclusion criteria. One‐hundred and sixty patients were excluded because they received full‐dose anticoagulation or had an existing IVC filter prior to admission (49 patients), received treatment with full‐dose anticoagulation in the ED (42 patients), had a LOS of less than 2 days (39 patients), or had end‐stage renal disease requiring hemodialysis (30 patients; Fig. 1).

Figure 1

Eighty percent of patients were admitted for medical problems, and 20% were admitted for surgery (Table 1). The most frequent admitting diagnoses were abdominal pain, congestive heart failure, chronic obstructive pulmonary disease, altered mental status, cerebral vascular accident, and pneumonia. The average patient had 5 comorbid conditions, the most frequently noted were hypertension, diabetes mellitus, anemia, urinary tract infections, and coronary artery disease. The principal admitting services were general medicine, pulmonary, cardiology, hematology‐oncology, neurology, surgery, and gastroenterology. Six patients died (2.4%), and 2 patients were diagnosed with pulmonary emboli (0.8%). The study group's average length of stay was 6.7 days (range 2‐52 days), 48.8% were male, and average age was 61 19.7 years. Overall, the correct VTE PX decision making occurred in 44.9% of patients admitted, including the 49 of 254 patients who did not require and did not receive VTE PX. Of the 254 patients, 201 (79%) had indications for VTE PX, 65 of whom (32.3%) received it (Table 2). For those receiving VTE PX, 78% of orders were written within the first day of hospitalization.

When the data were reanalyzed per ACCP guidelines using the modified Caprini's risk assessment tool, the results were consistent with the initial findings. Overall, 46% of all patients (116 of 254) received prophylaxis in compliance with ACCP guidelines. In this group, 52 of 116 patients (44.8%) did not require and did not receive VTE PX. Sixty‐four patients (32% of those with indications for prophylaxis) had indications for VTE PX, were in compliance with ACCP guidelines, and received the indicated prophylaxis (30 patients received mechanical prophylaxis, 19 patients received medical prophylaxis, and 15 patients received both medical and mechanical prophylaxis). The difference between the assessments was explained by high‐risk patients with no contraindications to medical prophylaxis who received only mechanical prophylaxis but required medical prophylaxis through ACCP guidelines. Note, the Caprini tool recommended medical prophylaxis for these high‐risk patients; however, our original application was simply to assess if prophylaxis was employed. In addition, several patients with a prolonged INR suggestive of bleeding risk or autoprophylaxis were reclassified as compliant and not needing prophylaxis.

Fifty‐five patients with indications for VTE prophylaxis had contraindications to medical prophylaxis: 44 had bleeding risk, 8 had spine injury or surgery, and 3 had brain metastases and thrombocytopenia. Twenty of the 55 patients (36%) received mechanical prophylaxis; they were considered in compliance with ACCP guidelines and were included in the appropriate decisions regarding VTE PX count. Prophylaxed patients at moderate to high risk were more likely to receive mechanical prophylaxis, whereas two‐thirds of those prophylaxed patients who were at very high risk received medical prophylaxis or a combination of medical and mechanical prophylaxis.

Standard order sets increased the likelihood of appropriate VTE PX. Increasing age and a primary cardiovascular diagnosis (chest pain, congestive heart failure, syncope/near‐syncope, chronic ischemic heart disease, sinus tachycardia) decreased the likelihood of VTE PX (Table 3). VTE PX was not significantly related to bed rest (OR = 1.46, P = .14). In 26 of the 254 patient admissions, standard order sets that included VTE PX were utilized. Of these 26 patients, 69.2% (18; P = .01) received appropriate VTE PX compared with the overall rate of 44.9% receiving appropriate VTE PX. The use of VTE PX was significantly associated with level of risk: from 0% in patients at no or low risk of VTE to 47% in patients at very high risk (P = .0001). This significance persisted when controlling for age greater than 60 years (Table 4).

Aspirin and other antiplatelet medications (clopidogrel, dipyridamole, and cilostazol) were ordered for 22 and 5 patients, respectively, of the 39 patients with primary cardiovascular diagnosis who had indications for VTE PX but did not receive it. Forty‐seven percent (17 of 36 with activity orders) of those in our cardiovascular at‐risk but not prophylaxed group had activity orders of ambulatory ad lib or had physical therapy ordered.

DISCUSSION

An estimated 200,000‐300,000 cases of VTE with 60,000‐200,000 fatal pulmonary emboli occur annually.1316 The inpatient fatality rate due to PE is estimated to be 12%.13 The frequency of VTE varies with risk that relates to the population studied and the diagnosis. VTE rates range from 3%‐55% for medical patients to 80% for patients who receive total hip replacement or have multiple trauma, though the higher numbers cited are based on studies using fibrinogen uptake scanning or venography, with the true rates probably between the extremes noted.3, 4, 17, 18 Many of these acutely ill patients are admitted through the ED. Though VTE is common in patients admitted through the ED, with respect to VTE PX, this population is understudied.

In this study, the first to our knowledge to focus on VTE PX in an unselected cohort of ED admissions, the most significant findings were: 79% of ED admissions had indications for VTE PX, yet only 32% of those received it, and 78% of these orders were written within the first day of hospitalization. We also noted a direct association of the use of VTE PX with the level of risk, which increased from 9% in the moderate‐risk group to 23% for high‐risk patients and 47% for very‐high‐risk patients (P < .0001; Table 4.). Thus, most of our patients, including those at highest risk for VTE never received prophylaxis at any time during their hospitalization. Also explored in this study was the relationship of risk factors for VTE with the use of prophylaxis. These risk factors were age, cardiovascular diagnosis, and use of standard order sets. Increasing age and having a primary cardiovascular diagnosis (ie, congestive heart failure, atrial fibrillation) were the risk factors that increased the likelihood of receiving VTE. Therefore, it was expected that the rate of VTE PX would be higher for patients who were older or had these diagnoses. However, in the current study, increasing age alone did not influence the likelihood of physicians ordering VTE PX. In addition, we found markedly decreased rates of VTE PX in cardiac patients.

Other investigators have reported similar findings in selected groups of hospitalized patients.1922 A retrospective chart review of internal medicine discharges from 2 Italian hospitals determined that VTE PX was prescribed in 46.4% and 58.3% of at‐risk patients in nonteaching and teaching hospitals, respectively.20 In a retrospective study of surgical patients in 20 hospitals, 38% of patients received VTE PX.21 Similar results were found in a registry of hospitalized patients who developed VTE, in which only 42% of patients who developed VTE received VTE PX within 30 days prior to diagnosis.23

Bosson et al. reported no increased use of VTE PX in patients with myocardial infarction, similar to that in the current study, though they did find VTE PX administered more frequently to patients with congestive heart failure.22 Antiplatelet medications and activity orders are commonly prescribed for cardiac patients. According to reports that indicated a degree of protection from antiplatelet agents,24, 25 frequent use of activity orders, and the belief that ambulation eliminates the risk of VTE, it is possible physicians believed patients were sufficiently prophylaxed. However, although early ambulation and antiplatelet medications decrease risk of VTE, neither is sufficient to prevent it.3 The administration of aspirin and other antiplatelet medications implies that in our study group bleeding risk was not the primary deterrent to ordering VTE PX. Furthermore, bleeding risk would not be a deterrent to mechanical VTE PX.

In the current study, use of standard order sets was associated with correct decision making and increased use of VTE PX. Risk of VTE might be decreased through the use of standard order sets that result in increased utilization of VTE PX. However, despite evidence that standard order sets can successfully modify prescribing patterns,2629 Cook et al. found that only 5 of 29 Canadian ICU directors surveyed for their approach to VTE prevention and diagnosis in critically ill patients used preprinted orders.30

The present study had several limitations. First, determination of VTE was not an end point. As a single‐center study of prospectively selected subjects, this would have required too large a sample to be feasible. Our data may be biased by not including patients admitted by physicians who declined to allow their charts to be reviewed. However, although physicians were informed that we were examining drug use of patients admitted through the ED, they were not aware that the study focused on VTE PX. Our results are consistent with results of inpatient studies citing inadequate VTE PX.19, 21, 31, 32 Using the modified Caprini Scoring System, we found that only 32% of patients with indications for VTE PX received it. This result was unchanged when stratifying using ACCP guidelines. Finally, we found that prophylaxed patients who were at moderate to high risk were more likely to receive mechanical prophylaxis, whereas two‐thirds of patients who received prophylaxis who were at very high risk received medical prophylaxis or a combination of medical and mechanical prophylaxis.

CONCLUSIONS

Most patients needing VTE PX did not receive it, and those who did receive VTE PX usually had it prescribed in the first 24 hours. As risk factors increased, patients were more often prophylaxed, though fewer than 50% of those in the very‐high‐risk group received VTE PX. This study suggests that in hospital systems similar to ours with 30% or more of hospital admissions coming from the ED implementing a standard order set for patients admitted through the ED may increase VTE PX, which, in turn, could have a major impact on their course. Future studies need to determine the best way to implement these changes.

Venous thromboembolism prophylaxis (VTE PX) has been identified as an area of primary importance to improve patient safety in research and clinical practice.13 Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common, often preventable life‐threatening condition for hospitalized patients.4 Up to half of patients admitted to the hospital are admitted from the emergency department (ED). Most of these patients are acutely ill with multiple risk factors for VTE. To reduce the incidence of VTE, these patients require routine evaluation to determine if thromboprophylaxis is needed, and when indicated, therapy should be started promptly on admission. The Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy outlines recommendations for VTE PX that reduce the development of DVT and PE.3 Despite there being effective VTE PX and the current focus on increasing its utilization to improve patient safety, VTE PX is underutilized. In particular, the subgroup of patients admitted from the ED, a group at high risk for VTE, has been neglected in the literature.

Our hypothesis was that VTE PX is underutilized in patients admitted through the ED. The specific objective of this study was to measure the rate at which hospitalized patients admitted though the ED received VTE PX.

METHODS

The study was conducted with the approval of and in accordance with the ethical standards of the Institutional Review Board of Baylor College of Medicine and Affiliated Hospitals. Prior to initiating chart review, passive consent was sought from physicians who were identified through the hospital medical records system as having admitted patients to this hospital through the ED in the preceding 6 months. Physicians were contacted twice in writing in a 1‐month period prior to study inception. Those who objected to their charts being reviewed were to notify the investigators. Otherwise, they were assumed to have consented to chart review. Fifteen percent of physicians declined chart review. Physicians were not informed of the particulars of the study, only that medication use in the ED was being evaluated.

This study was conducted at a private 900‐bed urban teaching hospital. The ED evaluates approximately 31,000 patients per year, predominantly a medical population. During the previous year, the ED had admitted roughly 30 patients per day, or 36% of all patients examined. Approximately 29% of admissions to this hospital (800/month) are admitted through the ED.

A convenience sample of every other hospital admission through the ED during 1 month was prospectively identified for inclusion in the study and chart review. Data were abstracted by a single reviewer on admission and at the time of discharge. The following data were collected: demographic characteristics, anticoagulant use or existing IVC filter, diagnoses, indications for full‐dose anticoagulation, indications for VTE PX (ie, immobilization, respiratory failure, congestive heart failure, limb trauma, surgery, or stroke), whether therapeutic anticoagulation or VTE PX was given, and date of initiation of this regimen, contraindications to anticoagulation, primary physician, and use of a standard order set. Patients were excluded if the attending physician declined chart review via the passive consent process. Other exclusion criteria were: receiving full‐dose anticoagulants before presentation to the ED, presence of an inferior vena cava (IVC) filter, indication for full‐dose anticoagulation (presented with DVT, PE, acute coronary syndrome), renal failure requiring hemodialysis (controversial risk for VTE59), length of stay (LOS) less than 2 days, and admission for psychiatric evaluation or treatment.

A modified Caprini's Risk Assessment Model for Surgical and Nonsurgical Patients was used to classify VTE risk.10 This tool assigns points to VTE risk factors so that risk and the need for VTE PX can be determined. For example, major surgery, central venous access, age older than 60 years, and bed rest for more than 72 hours are each assigned 2 points; higher‐risk factors such as hip or leg fractures or stroke are each assigned 5 points. This tool is generally in accord with the ACCP guidelines. Modifications made to this tool were to assign 3 points to patients in respiratory failure on ventilators and 5 points to patients who were critically ill on vasopressor medication. Decreased venous return associated with mechanical ventilation and peripheral vasoconstriction associated with the use of vasopressor medication justified the addition of these risk factors.11, 12 Patients were assigned to one of these risk categories: no risk (0 points), low risk (1 point), moderate risk (2 points), high risk (3‐4 points), or very high risk (5 or more points). As indicated by this risk assessment tool, those with moderate, high, or very high risk were considered in need of VTE PX.

Appropriate VTE PX was defined as any currently accepted medical (unfractionated heparin, low‐molecular‐weight heparin, or warfarin for orthopedic patients) or mechanical methods of VTE PX (sequential compression devices, and graduated compression stockings) for those in need and no VTE PX if none indicated. Aspirin, clopidogrel, or a combination of the 2 was not considered sufficient VTE PX.3 In addition, we established whether VTE PX as determined by the modified Caprini score was in line with ACCP guidelines, taking into account contraindications to anticoagulation. Preprinted order sets were divided into those that included VTE PX and those that did not. Order sets that included options for VTE PX were defined as standard order sets.

The primary objective of this study was to determine how frequently VTE PX was implemented in ED admissions. Secondary objectives were determining factors associated with correct VTE PX decision making and the proximity of orders for VTE PX to the time of admission.

RESULTS

Four hundred and fourteen charts of patient admissions were reviewed, of which 254 met the inclusion criteria. One‐hundred and sixty patients were excluded because they received full‐dose anticoagulation or had an existing IVC filter prior to admission (49 patients), received treatment with full‐dose anticoagulation in the ED (42 patients), had a LOS of less than 2 days (39 patients), or had end‐stage renal disease requiring hemodialysis (30 patients; Fig. 1).

Figure 1

Eighty percent of patients were admitted for medical problems, and 20% were admitted for surgery (Table 1). The most frequent admitting diagnoses were abdominal pain, congestive heart failure, chronic obstructive pulmonary disease, altered mental status, cerebral vascular accident, and pneumonia. The average patient had 5 comorbid conditions, the most frequently noted were hypertension, diabetes mellitus, anemia, urinary tract infections, and coronary artery disease. The principal admitting services were general medicine, pulmonary, cardiology, hematology‐oncology, neurology, surgery, and gastroenterology. Six patients died (2.4%), and 2 patients were diagnosed with pulmonary emboli (0.8%). The study group's average length of stay was 6.7 days (range 2‐52 days), 48.8% were male, and average age was 61 19.7 years. Overall, the correct VTE PX decision making occurred in 44.9% of patients admitted, including the 49 of 254 patients who did not require and did not receive VTE PX. Of the 254 patients, 201 (79%) had indications for VTE PX, 65 of whom (32.3%) received it (Table 2). For those receiving VTE PX, 78% of orders were written within the first day of hospitalization.

When the data were reanalyzed per ACCP guidelines using the modified Caprini's risk assessment tool, the results were consistent with the initial findings. Overall, 46% of all patients (116 of 254) received prophylaxis in compliance with ACCP guidelines. In this group, 52 of 116 patients (44.8%) did not require and did not receive VTE PX. Sixty‐four patients (32% of those with indications for prophylaxis) had indications for VTE PX, were in compliance with ACCP guidelines, and received the indicated prophylaxis (30 patients received mechanical prophylaxis, 19 patients received medical prophylaxis, and 15 patients received both medical and mechanical prophylaxis). The difference between the assessments was explained by high‐risk patients with no contraindications to medical prophylaxis who received only mechanical prophylaxis but required medical prophylaxis through ACCP guidelines. Note, the Caprini tool recommended medical prophylaxis for these high‐risk patients; however, our original application was simply to assess if prophylaxis was employed. In addition, several patients with a prolonged INR suggestive of bleeding risk or autoprophylaxis were reclassified as compliant and not needing prophylaxis.

Fifty‐five patients with indications for VTE prophylaxis had contraindications to medical prophylaxis: 44 had bleeding risk, 8 had spine injury or surgery, and 3 had brain metastases and thrombocytopenia. Twenty of the 55 patients (36%) received mechanical prophylaxis; they were considered in compliance with ACCP guidelines and were included in the appropriate decisions regarding VTE PX count. Prophylaxed patients at moderate to high risk were more likely to receive mechanical prophylaxis, whereas two‐thirds of those prophylaxed patients who were at very high risk received medical prophylaxis or a combination of medical and mechanical prophylaxis.

Standard order sets increased the likelihood of appropriate VTE PX. Increasing age and a primary cardiovascular diagnosis (chest pain, congestive heart failure, syncope/near‐syncope, chronic ischemic heart disease, sinus tachycardia) decreased the likelihood of VTE PX (Table 3). VTE PX was not significantly related to bed rest (OR = 1.46, P = .14). In 26 of the 254 patient admissions, standard order sets that included VTE PX were utilized. Of these 26 patients, 69.2% (18; P = .01) received appropriate VTE PX compared with the overall rate of 44.9% receiving appropriate VTE PX. The use of VTE PX was significantly associated with level of risk: from 0% in patients at no or low risk of VTE to 47% in patients at very high risk (P = .0001). This significance persisted when controlling for age greater than 60 years (Table 4).

Aspirin and other antiplatelet medications (clopidogrel, dipyridamole, and cilostazol) were ordered for 22 and 5 patients, respectively, of the 39 patients with primary cardiovascular diagnosis who had indications for VTE PX but did not receive it. Forty‐seven percent (17 of 36 with activity orders) of those in our cardiovascular at‐risk but not prophylaxed group had activity orders of ambulatory ad lib or had physical therapy ordered.

DISCUSSION

An estimated 200,000‐300,000 cases of VTE with 60,000‐200,000 fatal pulmonary emboli occur annually.1316 The inpatient fatality rate due to PE is estimated to be 12%.13 The frequency of VTE varies with risk that relates to the population studied and the diagnosis. VTE rates range from 3%‐55% for medical patients to 80% for patients who receive total hip replacement or have multiple trauma, though the higher numbers cited are based on studies using fibrinogen uptake scanning or venography, with the true rates probably between the extremes noted.3, 4, 17, 18 Many of these acutely ill patients are admitted through the ED. Though VTE is common in patients admitted through the ED, with respect to VTE PX, this population is understudied.

In this study, the first to our knowledge to focus on VTE PX in an unselected cohort of ED admissions, the most significant findings were: 79% of ED admissions had indications for VTE PX, yet only 32% of those received it, and 78% of these orders were written within the first day of hospitalization. We also noted a direct association of the use of VTE PX with the level of risk, which increased from 9% in the moderate‐risk group to 23% for high‐risk patients and 47% for very‐high‐risk patients (P < .0001; Table 4.). Thus, most of our patients, including those at highest risk for VTE never received prophylaxis at any time during their hospitalization. Also explored in this study was the relationship of risk factors for VTE with the use of prophylaxis. These risk factors were age, cardiovascular diagnosis, and use of standard order sets. Increasing age and having a primary cardiovascular diagnosis (ie, congestive heart failure, atrial fibrillation) were the risk factors that increased the likelihood of receiving VTE. Therefore, it was expected that the rate of VTE PX would be higher for patients who were older or had these diagnoses. However, in the current study, increasing age alone did not influence the likelihood of physicians ordering VTE PX. In addition, we found markedly decreased rates of VTE PX in cardiac patients.

Other investigators have reported similar findings in selected groups of hospitalized patients.1922 A retrospective chart review of internal medicine discharges from 2 Italian hospitals determined that VTE PX was prescribed in 46.4% and 58.3% of at‐risk patients in nonteaching and teaching hospitals, respectively.20 In a retrospective study of surgical patients in 20 hospitals, 38% of patients received VTE PX.21 Similar results were found in a registry of hospitalized patients who developed VTE, in which only 42% of patients who developed VTE received VTE PX within 30 days prior to diagnosis.23

Bosson et al. reported no increased use of VTE PX in patients with myocardial infarction, similar to that in the current study, though they did find VTE PX administered more frequently to patients with congestive heart failure.22 Antiplatelet medications and activity orders are commonly prescribed for cardiac patients. According to reports that indicated a degree of protection from antiplatelet agents,24, 25 frequent use of activity orders, and the belief that ambulation eliminates the risk of VTE, it is possible physicians believed patients were sufficiently prophylaxed. However, although early ambulation and antiplatelet medications decrease risk of VTE, neither is sufficient to prevent it.3 The administration of aspirin and other antiplatelet medications implies that in our study group bleeding risk was not the primary deterrent to ordering VTE PX. Furthermore, bleeding risk would not be a deterrent to mechanical VTE PX.

In the current study, use of standard order sets was associated with correct decision making and increased use of VTE PX. Risk of VTE might be decreased through the use of standard order sets that result in increased utilization of VTE PX. However, despite evidence that standard order sets can successfully modify prescribing patterns,2629 Cook et al. found that only 5 of 29 Canadian ICU directors surveyed for their approach to VTE prevention and diagnosis in critically ill patients used preprinted orders.30

The present study had several limitations. First, determination of VTE was not an end point. As a single‐center study of prospectively selected subjects, this would have required too large a sample to be feasible. Our data may be biased by not including patients admitted by physicians who declined to allow their charts to be reviewed. However, although physicians were informed that we were examining drug use of patients admitted through the ED, they were not aware that the study focused on VTE PX. Our results are consistent with results of inpatient studies citing inadequate VTE PX.19, 21, 31, 32 Using the modified Caprini Scoring System, we found that only 32% of patients with indications for VTE PX received it. This result was unchanged when stratifying using ACCP guidelines. Finally, we found that prophylaxed patients who were at moderate to high risk were more likely to receive mechanical prophylaxis, whereas two‐thirds of patients who received prophylaxis who were at very high risk received medical prophylaxis or a combination of medical and mechanical prophylaxis.

CONCLUSIONS

Most patients needing VTE PX did not receive it, and those who did receive VTE PX usually had it prescribed in the first 24 hours. As risk factors increased, patients were more often prophylaxed, though fewer than 50% of those in the very‐high‐risk group received VTE PX. This study suggests that in hospital systems similar to ours with 30% or more of hospital admissions coming from the ED implementing a standard order set for patients admitted through the ED may increase VTE PX, which, in turn, could have a major impact on their course. Future studies need to determine the best way to implement these changes.

Venous thromboembolism prophylaxis (VTE PX) has been identified as an area of primary importance to improve patient safety in research and clinical practice.13 Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common, often preventable life‐threatening condition for hospitalized patients.4 Up to half of patients admitted to the hospital are admitted from the emergency department (ED). Most of these patients are acutely ill with multiple risk factors for VTE. To reduce the incidence of VTE, these patients require routine evaluation to determine if thromboprophylaxis is needed, and when indicated, therapy should be started promptly on admission. The Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy outlines recommendations for VTE PX that reduce the development of DVT and PE.3 Despite there being effective VTE PX and the current focus on increasing its utilization to improve patient safety, VTE PX is underutilized. In particular, the subgroup of patients admitted from the ED, a group at high risk for VTE, has been neglected in the literature.

Our hypothesis was that VTE PX is underutilized in patients admitted through the ED. The specific objective of this study was to measure the rate at which hospitalized patients admitted though the ED received VTE PX.

METHODS

The study was conducted with the approval of and in accordance with the ethical standards of the Institutional Review Board of Baylor College of Medicine and Affiliated Hospitals. Prior to initiating chart review, passive consent was sought from physicians who were identified through the hospital medical records system as having admitted patients to this hospital through the ED in the preceding 6 months. Physicians were contacted twice in writing in a 1‐month period prior to study inception. Those who objected to their charts being reviewed were to notify the investigators. Otherwise, they were assumed to have consented to chart review. Fifteen percent of physicians declined chart review. Physicians were not informed of the particulars of the study, only that medication use in the ED was being evaluated.

This study was conducted at a private 900‐bed urban teaching hospital. The ED evaluates approximately 31,000 patients per year, predominantly a medical population. During the previous year, the ED had admitted roughly 30 patients per day, or 36% of all patients examined. Approximately 29% of admissions to this hospital (800/month) are admitted through the ED.

A convenience sample of every other hospital admission through the ED during 1 month was prospectively identified for inclusion in the study and chart review. Data were abstracted by a single reviewer on admission and at the time of discharge. The following data were collected: demographic characteristics, anticoagulant use or existing IVC filter, diagnoses, indications for full‐dose anticoagulation, indications for VTE PX (ie, immobilization, respiratory failure, congestive heart failure, limb trauma, surgery, or stroke), whether therapeutic anticoagulation or VTE PX was given, and date of initiation of this regimen, contraindications to anticoagulation, primary physician, and use of a standard order set. Patients were excluded if the attending physician declined chart review via the passive consent process. Other exclusion criteria were: receiving full‐dose anticoagulants before presentation to the ED, presence of an inferior vena cava (IVC) filter, indication for full‐dose anticoagulation (presented with DVT, PE, acute coronary syndrome), renal failure requiring hemodialysis (controversial risk for VTE59), length of stay (LOS) less than 2 days, and admission for psychiatric evaluation or treatment.

A modified Caprini's Risk Assessment Model for Surgical and Nonsurgical Patients was used to classify VTE risk.10 This tool assigns points to VTE risk factors so that risk and the need for VTE PX can be determined. For example, major surgery, central venous access, age older than 60 years, and bed rest for more than 72 hours are each assigned 2 points; higher‐risk factors such as hip or leg fractures or stroke are each assigned 5 points. This tool is generally in accord with the ACCP guidelines. Modifications made to this tool were to assign 3 points to patients in respiratory failure on ventilators and 5 points to patients who were critically ill on vasopressor medication. Decreased venous return associated with mechanical ventilation and peripheral vasoconstriction associated with the use of vasopressor medication justified the addition of these risk factors.11, 12 Patients were assigned to one of these risk categories: no risk (0 points), low risk (1 point), moderate risk (2 points), high risk (3‐4 points), or very high risk (5 or more points). As indicated by this risk assessment tool, those with moderate, high, or very high risk were considered in need of VTE PX.

Appropriate VTE PX was defined as any currently accepted medical (unfractionated heparin, low‐molecular‐weight heparin, or warfarin for orthopedic patients) or mechanical methods of VTE PX (sequential compression devices, and graduated compression stockings) for those in need and no VTE PX if none indicated. Aspirin, clopidogrel, or a combination of the 2 was not considered sufficient VTE PX.3 In addition, we established whether VTE PX as determined by the modified Caprini score was in line with ACCP guidelines, taking into account contraindications to anticoagulation. Preprinted order sets were divided into those that included VTE PX and those that did not. Order sets that included options for VTE PX were defined as standard order sets.

The primary objective of this study was to determine how frequently VTE PX was implemented in ED admissions. Secondary objectives were determining factors associated with correct VTE PX decision making and the proximity of orders for VTE PX to the time of admission.

RESULTS

Four hundred and fourteen charts of patient admissions were reviewed, of which 254 met the inclusion criteria. One‐hundred and sixty patients were excluded because they received full‐dose anticoagulation or had an existing IVC filter prior to admission (49 patients), received treatment with full‐dose anticoagulation in the ED (42 patients), had a LOS of less than 2 days (39 patients), or had end‐stage renal disease requiring hemodialysis (30 patients; Fig. 1).

Figure 1

Eighty percent of patients were admitted for medical problems, and 20% were admitted for surgery (Table 1). The most frequent admitting diagnoses were abdominal pain, congestive heart failure, chronic obstructive pulmonary disease, altered mental status, cerebral vascular accident, and pneumonia. The average patient had 5 comorbid conditions, the most frequently noted were hypertension, diabetes mellitus, anemia, urinary tract infections, and coronary artery disease. The principal admitting services were general medicine, pulmonary, cardiology, hematology‐oncology, neurology, surgery, and gastroenterology. Six patients died (2.4%), and 2 patients were diagnosed with pulmonary emboli (0.8%). The study group's average length of stay was 6.7 days (range 2‐52 days), 48.8% were male, and average age was 61 19.7 years. Overall, the correct VTE PX decision making occurred in 44.9% of patients admitted, including the 49 of 254 patients who did not require and did not receive VTE PX. Of the 254 patients, 201 (79%) had indications for VTE PX, 65 of whom (32.3%) received it (Table 2). For those receiving VTE PX, 78% of orders were written within the first day of hospitalization.

When the data were reanalyzed per ACCP guidelines using the modified Caprini's risk assessment tool, the results were consistent with the initial findings. Overall, 46% of all patients (116 of 254) received prophylaxis in compliance with ACCP guidelines. In this group, 52 of 116 patients (44.8%) did not require and did not receive VTE PX. Sixty‐four patients (32% of those with indications for prophylaxis) had indications for VTE PX, were in compliance with ACCP guidelines, and received the indicated prophylaxis (30 patients received mechanical prophylaxis, 19 patients received medical prophylaxis, and 15 patients received both medical and mechanical prophylaxis). The difference between the assessments was explained by high‐risk patients with no contraindications to medical prophylaxis who received only mechanical prophylaxis but required medical prophylaxis through ACCP guidelines. Note, the Caprini tool recommended medical prophylaxis for these high‐risk patients; however, our original application was simply to assess if prophylaxis was employed. In addition, several patients with a prolonged INR suggestive of bleeding risk or autoprophylaxis were reclassified as compliant and not needing prophylaxis.

Fifty‐five patients with indications for VTE prophylaxis had contraindications to medical prophylaxis: 44 had bleeding risk, 8 had spine injury or surgery, and 3 had brain metastases and thrombocytopenia. Twenty of the 55 patients (36%) received mechanical prophylaxis; they were considered in compliance with ACCP guidelines and were included in the appropriate decisions regarding VTE PX count. Prophylaxed patients at moderate to high risk were more likely to receive mechanical prophylaxis, whereas two‐thirds of those prophylaxed patients who were at very high risk received medical prophylaxis or a combination of medical and mechanical prophylaxis.

Standard order sets increased the likelihood of appropriate VTE PX. Increasing age and a primary cardiovascular diagnosis (chest pain, congestive heart failure, syncope/near‐syncope, chronic ischemic heart disease, sinus tachycardia) decreased the likelihood of VTE PX (Table 3). VTE PX was not significantly related to bed rest (OR = 1.46, P = .14). In 26 of the 254 patient admissions, standard order sets that included VTE PX were utilized. Of these 26 patients, 69.2% (18; P = .01) received appropriate VTE PX compared with the overall rate of 44.9% receiving appropriate VTE PX. The use of VTE PX was significantly associated with level of risk: from 0% in patients at no or low risk of VTE to 47% in patients at very high risk (P = .0001). This significance persisted when controlling for age greater than 60 years (Table 4).

Aspirin and other antiplatelet medications (clopidogrel, dipyridamole, and cilostazol) were ordered for 22 and 5 patients, respectively, of the 39 patients with primary cardiovascular diagnosis who had indications for VTE PX but did not receive it. Forty‐seven percent (17 of 36 with activity orders) of those in our cardiovascular at‐risk but not prophylaxed group had activity orders of ambulatory ad lib or had physical therapy ordered.

DISCUSSION

An estimated 200,000‐300,000 cases of VTE with 60,000‐200,000 fatal pulmonary emboli occur annually.1316 The inpatient fatality rate due to PE is estimated to be 12%.13 The frequency of VTE varies with risk that relates to the population studied and the diagnosis. VTE rates range from 3%‐55% for medical patients to 80% for patients who receive total hip replacement or have multiple trauma, though the higher numbers cited are based on studies using fibrinogen uptake scanning or venography, with the true rates probably between the extremes noted.3, 4, 17, 18 Many of these acutely ill patients are admitted through the ED. Though VTE is common in patients admitted through the ED, with respect to VTE PX, this population is understudied.

In this study, the first to our knowledge to focus on VTE PX in an unselected cohort of ED admissions, the most significant findings were: 79% of ED admissions had indications for VTE PX, yet only 32% of those received it, and 78% of these orders were written within the first day of hospitalization. We also noted a direct association of the use of VTE PX with the level of risk, which increased from 9% in the moderate‐risk group to 23% for high‐risk patients and 47% for very‐high‐risk patients (P < .0001; Table 4.). Thus, most of our patients, including those at highest risk for VTE never received prophylaxis at any time during their hospitalization. Also explored in this study was the relationship of risk factors for VTE with the use of prophylaxis. These risk factors were age, cardiovascular diagnosis, and use of standard order sets. Increasing age and having a primary cardiovascular diagnosis (ie, congestive heart failure, atrial fibrillation) were the risk factors that increased the likelihood of receiving VTE. Therefore, it was expected that the rate of VTE PX would be higher for patients who were older or had these diagnoses. However, in the current study, increasing age alone did not influence the likelihood of physicians ordering VTE PX. In addition, we found markedly decreased rates of VTE PX in cardiac patients.

Other investigators have reported similar findings in selected groups of hospitalized patients.1922 A retrospective chart review of internal medicine discharges from 2 Italian hospitals determined that VTE PX was prescribed in 46.4% and 58.3% of at‐risk patients in nonteaching and teaching hospitals, respectively.20 In a retrospective study of surgical patients in 20 hospitals, 38% of patients received VTE PX.21 Similar results were found in a registry of hospitalized patients who developed VTE, in which only 42% of patients who developed VTE received VTE PX within 30 days prior to diagnosis.23

Bosson et al. reported no increased use of VTE PX in patients with myocardial infarction, similar to that in the current study, though they did find VTE PX administered more frequently to patients with congestive heart failure.22 Antiplatelet medications and activity orders are commonly prescribed for cardiac patients. According to reports that indicated a degree of protection from antiplatelet agents,24, 25 frequent use of activity orders, and the belief that ambulation eliminates the risk of VTE, it is possible physicians believed patients were sufficiently prophylaxed. However, although early ambulation and antiplatelet medications decrease risk of VTE, neither is sufficient to prevent it.3 The administration of aspirin and other antiplatelet medications implies that in our study group bleeding risk was not the primary deterrent to ordering VTE PX. Furthermore, bleeding risk would not be a deterrent to mechanical VTE PX.

In the current study, use of standard order sets was associated with correct decision making and increased use of VTE PX. Risk of VTE might be decreased through the use of standard order sets that result in increased utilization of VTE PX. However, despite evidence that standard order sets can successfully modify prescribing patterns,2629 Cook et al. found that only 5 of 29 Canadian ICU directors surveyed for their approach to VTE prevention and diagnosis in critically ill patients used preprinted orders.30

The present study had several limitations. First, determination of VTE was not an end point. As a single‐center study of prospectively selected subjects, this would have required too large a sample to be feasible. Our data may be biased by not including patients admitted by physicians who declined to allow their charts to be reviewed. However, although physicians were informed that we were examining drug use of patients admitted through the ED, they were not aware that the study focused on VTE PX. Our results are consistent with results of inpatient studies citing inadequate VTE PX.19, 21, 31, 32 Using the modified Caprini Scoring System, we found that only 32% of patients with indications for VTE PX received it. This result was unchanged when stratifying using ACCP guidelines. Finally, we found that prophylaxed patients who were at moderate to high risk were more likely to receive mechanical prophylaxis, whereas two‐thirds of patients who received prophylaxis who were at very high risk received medical prophylaxis or a combination of medical and mechanical prophylaxis.

CONCLUSIONS

Most patients needing VTE PX did not receive it, and those who did receive VTE PX usually had it prescribed in the first 24 hours. As risk factors increased, patients were more often prophylaxed, though fewer than 50% of those in the very‐high‐risk group received VTE PX. This study suggests that in hospital systems similar to ours with 30% or more of hospital admissions coming from the ED implementing a standard order set for patients admitted through the ED may increase VTE PX, which, in turn, could have a major impact on their course. Future studies need to determine the best way to implement these changes.

Patients suffering from a critical life‐threatening illness have long been known to have an increased risk of spontaneous upper gastrointestinal bleeding, even in the absence of previously known gastrointestinal pathology. This phenomenon is generally known as the stress‐ulcer syndrome or stress‐related mucosal disease. Although the incidence in critically ill patients has declined in recent years to less than 10%, the mortality rate in patients experiencing bleeding is often considered to be nearly 50%.1, 2 Various pathophysiological processes including respiratory failure, sepsis, coagulopathy, burns, and severe trauma have been implicated in the development of stress ulcers in critically ill patients.1, 3 The administration of acid‐suppressing medications such as histamine‐2 receptor antagonists, proton‐pump inhibitors, and sucralfate has been shown to decrease the risk of stress‐related gastrointestinal bleeding in these patients.46 As a result, it is standard practice in many intensive care units to use such medications, commonly referred to as stress‐ulcer prophylaxis, to reduce the production of gastric acid and raise intragastric pH. Many intensivists prescribe stress‐ulcer prophylaxis to all ICU patients, including those without risk factors.7

Patients admitted to general medical wards also experience gastrointestinal bleeding. There appears to be an association between stress‐ulcer bleeding in general medical patients and overall severity of illness, similar to that in critically ill patients. Risk factors may include ischemic heart disease, chronic renal failure, and a prior intensive care unit stay or mechanical ventilation.8, 9 Studies in limited populations found that 3% of patients admitted with acute stroke and 13% of patients admitted with renal failure have experienced bleeding. However, only about half these episodes were clinically significant.10, 11 A more recent review that included a much larger and medically diverse population found a rate of less than 1%. In this study mortality did not differ between patients with and without bleeding.12 An older report found that mortality in a set of 125 hospitalized patients with secondary gastrointestinal bleeding was 28%, but only a small fraction of the deaths was directly attributable to the bleeding episode.13

Widespread use of acid‐suppressive therapy for stress‐ulcer prophylaxis in general medical settings has been recognized, especially among patients cared for by medical residents. However, this practice has been significantly less well characterized than the use of stress‐ulcer prophylaxis in critical care settings.1416 This article reports a systematic review of the literature to answer 2 questions: (1) What is the frequency of prescription of acid‐suppressive therapy for stress‐ulcer prophylaxis among adult general medical inpatients? (2) What evidence exists to support this practice?

METHODS

RESULTS

The search criteria identified 3979 citations from the electronic databases and 106 references from the included studies. After eliminating non‐English‐language articles and articles that did not have human subjects, 2912 articles were examined. Of these, only 5 citations met the inclusion criteria (Fig. 1).

Figure 1

DISCUSSION

To our knowledge, this is the first systematic review of the literature that examined the use of acid‐suppressing medications as stress‐ulcer bleeding prophylaxis among general medical patients. Results indicate that there is widespread use of these medications among general medical patients, but little evidence demonstrating a reduction in clinically important gastrointestinal bleeding.

Nardino et al., Parente et al., and Gullota et al. indicated that acid‐suppressive therapies are prescribed to 29%‐54% of hospitalized inpatients. The most common indication for such therapy is stress‐ulcer prophylaxis in patients believed to be at low or no risk, which was true for 20%‐25% of all such patients. Interestingly, both Nardino et al. and Parente et al. assumed there were risk factors that place some general medical patients in a higher‐risk category. In their assessment, these patients warrant prophylaxis. This is somewhat problematic though, as such risk factors have yet to be firmly established. All studies were localized, and results should be confirmed in a larger series that spans multiple institutions. Widespread use of stress‐ulcer prophylaxis may be driven by fear of the previously reported high mortality rates associated with stress‐ulcer bleeding. This fear may be largely unjustified, as overall rates of bleeding episodes appear low.12 Furthermore, patients who die with stress‐ulcer‐related bleeding likely die from their underlying severe illness rather than the bleed itself.

We identified only 2 studies that tested the effectiveness of stress‐ulcer prophylaxis in general medical populations. Both indicated a relatively low risk of gastrointestinal bleeding in patients receiving prophylaxis. Most notably, the work by Estruch et al. comparing an antacid regimen (magaldrate) to placebo showed a significant reduction in bleeding in the active treatment group. However, these trials possess characteristics that limit their applicability to a broad medical population. In particular, these trials were designed to represent only patients with severe illness, many of whom possessed presumed risk factors for stress‐ulcer bleeding. Although all the patients in these 2 series were managed on a general medical ward, many (eg, heart failure patients requiring inotropic support) would likely qualify for intensive care at some institutions. The rate of minor gastrointestinal hemorrhages in the placebo group of the magaldrate trial was significantly higher than in previous observational trials, further suggesting that this population had greater severity of illness than a typical medical population. In addition, although the studies contributed some useful information about severely ill patients, both controlled trials had design limitations. Neither study described why the respective populations were chosen or how the sample sizes were derived. More important, neither was double‐blinded. In sum, given the small number of trials, the limited generalizability to more severely ill patients, and design limitations, the existing literature provides minimal guidance about stress‐ulcer prophylaxis in a diverse inpatient service.

There were no major drug‐related adverse effects reported in these trials, and all the acid‐suppressive drugs currently available are considered relatively safe. However, widespread prophylaxis could result in adverse outcomes on balance. For example, in intensive care populations, there is evidence of an increased risk of nosocomial pneumonia associated with universal acid suppression.27 Many of these patients, however, have other risk factors for pneumonia such as mechanical ventilation.28, 29 Similarly, there has been an association between proton‐pump inhibitor use and increased risk for Clostridium difficileassociated diarrhea.30, 31 Also, H2 receptor antagonists have been implicated in thrombocytopenia, but this is still somewhat controversial.32 Whether these or any other adverse events occur commonly in general medical patients is unclear. Finally, every medication prescribed to inpatients increases the cost of the hospitalization and places a further strain on the financial resources of many already troubled health care delivery systems. For example, a 1997 study found that the use of ranitidine for stress‐ulcer prophylaxis cost $84.81 per day and omeprazole cost $39.52 per day, and those costs would presumably be higher today.33 These costs increase more if patients are continued on such medications after discharge. Clinicians have an obligation to ensure that the therapies they prescribe do not result in increased cost or harm, unless there is at least a reasonable expectation for average net benefit. More information is needed to guide such judgments for stress‐ulcer prophylaxis in non‐ICU patients.

As with all reviews, this one had some limitations. Although we searched a wide body of medical literature, some relevant work may not have been considered. Any published work not indexed by the Medline database or not listed in the Cochrane database of controlled trials would not have been part of this review. In addition, articles written in a language other than English and unpublished works were not examined. Therefore, it is possible that others have investigated this topic and collected information that would alter our results. However, this seems unlikely given the paucity of relevant studies in the wide body of literature that was examined. Finally, the primary author was exclusively responsible for identifying which studies met the inclusion criteria. It is conceivable that additional reviewers would have considered other studies to be relevant to the analysis.

Because stress‐ulcer prophylaxis appears to be widely used in patients hospitalized outside the intensive care unit, it is necessary to determine the efficacy and safety of this practice. Unfortunately, research in this area is sparse. The only 2 trials evaluating this topic, although suggesting a benefit for prophylaxis in selected higher‐risk populations, did not provide guidance for prophylaxis among a broad population of hospitalized medical patients. The present body of evidence does not clearly support or refute the use of stress‐ulcer prophylaxis in a general medical population. An appropriately powered randomized, controlled trial in a diverse population of general medical patients would clarify this issue.

Patients suffering from a critical life‐threatening illness have long been known to have an increased risk of spontaneous upper gastrointestinal bleeding, even in the absence of previously known gastrointestinal pathology. This phenomenon is generally known as the stress‐ulcer syndrome or stress‐related mucosal disease. Although the incidence in critically ill patients has declined in recent years to less than 10%, the mortality rate in patients experiencing bleeding is often considered to be nearly 50%.1, 2 Various pathophysiological processes including respiratory failure, sepsis, coagulopathy, burns, and severe trauma have been implicated in the development of stress ulcers in critically ill patients.1, 3 The administration of acid‐suppressing medications such as histamine‐2 receptor antagonists, proton‐pump inhibitors, and sucralfate has been shown to decrease the risk of stress‐related gastrointestinal bleeding in these patients.46 As a result, it is standard practice in many intensive care units to use such medications, commonly referred to as stress‐ulcer prophylaxis, to reduce the production of gastric acid and raise intragastric pH. Many intensivists prescribe stress‐ulcer prophylaxis to all ICU patients, including those without risk factors.7

Patients admitted to general medical wards also experience gastrointestinal bleeding. There appears to be an association between stress‐ulcer bleeding in general medical patients and overall severity of illness, similar to that in critically ill patients. Risk factors may include ischemic heart disease, chronic renal failure, and a prior intensive care unit stay or mechanical ventilation.8, 9 Studies in limited populations found that 3% of patients admitted with acute stroke and 13% of patients admitted with renal failure have experienced bleeding. However, only about half these episodes were clinically significant.10, 11 A more recent review that included a much larger and medically diverse population found a rate of less than 1%. In this study mortality did not differ between patients with and without bleeding.12 An older report found that mortality in a set of 125 hospitalized patients with secondary gastrointestinal bleeding was 28%, but only a small fraction of the deaths was directly attributable to the bleeding episode.13

Widespread use of acid‐suppressive therapy for stress‐ulcer prophylaxis in general medical settings has been recognized, especially among patients cared for by medical residents. However, this practice has been significantly less well characterized than the use of stress‐ulcer prophylaxis in critical care settings.1416 This article reports a systematic review of the literature to answer 2 questions: (1) What is the frequency of prescription of acid‐suppressive therapy for stress‐ulcer prophylaxis among adult general medical inpatients? (2) What evidence exists to support this practice?

METHODS

RESULTS

The search criteria identified 3979 citations from the electronic databases and 106 references from the included studies. After eliminating non‐English‐language articles and articles that did not have human subjects, 2912 articles were examined. Of these, only 5 citations met the inclusion criteria (Fig. 1).

Figure 1

DISCUSSION

To our knowledge, this is the first systematic review of the literature that examined the use of acid‐suppressing medications as stress‐ulcer bleeding prophylaxis among general medical patients. Results indicate that there is widespread use of these medications among general medical patients, but little evidence demonstrating a reduction in clinically important gastrointestinal bleeding.

Nardino et al., Parente et al., and Gullota et al. indicated that acid‐suppressive therapies are prescribed to 29%‐54% of hospitalized inpatients. The most common indication for such therapy is stress‐ulcer prophylaxis in patients believed to be at low or no risk, which was true for 20%‐25% of all such patients. Interestingly, both Nardino et al. and Parente et al. assumed there were risk factors that place some general medical patients in a higher‐risk category. In their assessment, these patients warrant prophylaxis. This is somewhat problematic though, as such risk factors have yet to be firmly established. All studies were localized, and results should be confirmed in a larger series that spans multiple institutions. Widespread use of stress‐ulcer prophylaxis may be driven by fear of the previously reported high mortality rates associated with stress‐ulcer bleeding. This fear may be largely unjustified, as overall rates of bleeding episodes appear low.12 Furthermore, patients who die with stress‐ulcer‐related bleeding likely die from their underlying severe illness rather than the bleed itself.

We identified only 2 studies that tested the effectiveness of stress‐ulcer prophylaxis in general medical populations. Both indicated a relatively low risk of gastrointestinal bleeding in patients receiving prophylaxis. Most notably, the work by Estruch et al. comparing an antacid regimen (magaldrate) to placebo showed a significant reduction in bleeding in the active treatment group. However, these trials possess characteristics that limit their applicability to a broad medical population. In particular, these trials were designed to represent only patients with severe illness, many of whom possessed presumed risk factors for stress‐ulcer bleeding. Although all the patients in these 2 series were managed on a general medical ward, many (eg, heart failure patients requiring inotropic support) would likely qualify for intensive care at some institutions. The rate of minor gastrointestinal hemorrhages in the placebo group of the magaldrate trial was significantly higher than in previous observational trials, further suggesting that this population had greater severity of illness than a typical medical population. In addition, although the studies contributed some useful information about severely ill patients, both controlled trials had design limitations. Neither study described why the respective populations were chosen or how the sample sizes were derived. More important, neither was double‐blinded. In sum, given the small number of trials, the limited generalizability to more severely ill patients, and design limitations, the existing literature provides minimal guidance about stress‐ulcer prophylaxis in a diverse inpatient service.

There were no major drug‐related adverse effects reported in these trials, and all the acid‐suppressive drugs currently available are considered relatively safe. However, widespread prophylaxis could result in adverse outcomes on balance. For example, in intensive care populations, there is evidence of an increased risk of nosocomial pneumonia associated with universal acid suppression.27 Many of these patients, however, have other risk factors for pneumonia such as mechanical ventilation.28, 29 Similarly, there has been an association between proton‐pump inhibitor use and increased risk for Clostridium difficileassociated diarrhea.30, 31 Also, H2 receptor antagonists have been implicated in thrombocytopenia, but this is still somewhat controversial.32 Whether these or any other adverse events occur commonly in general medical patients is unclear. Finally, every medication prescribed to inpatients increases the cost of the hospitalization and places a further strain on the financial resources of many already troubled health care delivery systems. For example, a 1997 study found that the use of ranitidine for stress‐ulcer prophylaxis cost $84.81 per day and omeprazole cost $39.52 per day, and those costs would presumably be higher today.33 These costs increase more if patients are continued on such medications after discharge. Clinicians have an obligation to ensure that the therapies they prescribe do not result in increased cost or harm, unless there is at least a reasonable expectation for average net benefit. More information is needed to guide such judgments for stress‐ulcer prophylaxis in non‐ICU patients.

As with all reviews, this one had some limitations. Although we searched a wide body of medical literature, some relevant work may not have been considered. Any published work not indexed by the Medline database or not listed in the Cochrane database of controlled trials would not have been part of this review. In addition, articles written in a language other than English and unpublished works were not examined. Therefore, it is possible that others have investigated this topic and collected information that would alter our results. However, this seems unlikely given the paucity of relevant studies in the wide body of literature that was examined. Finally, the primary author was exclusively responsible for identifying which studies met the inclusion criteria. It is conceivable that additional reviewers would have considered other studies to be relevant to the analysis.

Because stress‐ulcer prophylaxis appears to be widely used in patients hospitalized outside the intensive care unit, it is necessary to determine the efficacy and safety of this practice. Unfortunately, research in this area is sparse. The only 2 trials evaluating this topic, although suggesting a benefit for prophylaxis in selected higher‐risk populations, did not provide guidance for prophylaxis among a broad population of hospitalized medical patients. The present body of evidence does not clearly support or refute the use of stress‐ulcer prophylaxis in a general medical population. An appropriately powered randomized, controlled trial in a diverse population of general medical patients would clarify this issue.

Patients suffering from a critical life‐threatening illness have long been known to have an increased risk of spontaneous upper gastrointestinal bleeding, even in the absence of previously known gastrointestinal pathology. This phenomenon is generally known as the stress‐ulcer syndrome or stress‐related mucosal disease. Although the incidence in critically ill patients has declined in recent years to less than 10%, the mortality rate in patients experiencing bleeding is often considered to be nearly 50%.1, 2 Various pathophysiological processes including respiratory failure, sepsis, coagulopathy, burns, and severe trauma have been implicated in the development of stress ulcers in critically ill patients.1, 3 The administration of acid‐suppressing medications such as histamine‐2 receptor antagonists, proton‐pump inhibitors, and sucralfate has been shown to decrease the risk of stress‐related gastrointestinal bleeding in these patients.46 As a result, it is standard practice in many intensive care units to use such medications, commonly referred to as stress‐ulcer prophylaxis, to reduce the production of gastric acid and raise intragastric pH. Many intensivists prescribe stress‐ulcer prophylaxis to all ICU patients, including those without risk factors.7

Patients admitted to general medical wards also experience gastrointestinal bleeding. There appears to be an association between stress‐ulcer bleeding in general medical patients and overall severity of illness, similar to that in critically ill patients. Risk factors may include ischemic heart disease, chronic renal failure, and a prior intensive care unit stay or mechanical ventilation.8, 9 Studies in limited populations found that 3% of patients admitted with acute stroke and 13% of patients admitted with renal failure have experienced bleeding. However, only about half these episodes were clinically significant.10, 11 A more recent review that included a much larger and medically diverse population found a rate of less than 1%. In this study mortality did not differ between patients with and without bleeding.12 An older report found that mortality in a set of 125 hospitalized patients with secondary gastrointestinal bleeding was 28%, but only a small fraction of the deaths was directly attributable to the bleeding episode.13

Widespread use of acid‐suppressive therapy for stress‐ulcer prophylaxis in general medical settings has been recognized, especially among patients cared for by medical residents. However, this practice has been significantly less well characterized than the use of stress‐ulcer prophylaxis in critical care settings.1416 This article reports a systematic review of the literature to answer 2 questions: (1) What is the frequency of prescription of acid‐suppressive therapy for stress‐ulcer prophylaxis among adult general medical inpatients? (2) What evidence exists to support this practice?

METHODS

RESULTS

The search criteria identified 3979 citations from the electronic databases and 106 references from the included studies. After eliminating non‐English‐language articles and articles that did not have human subjects, 2912 articles were examined. Of these, only 5 citations met the inclusion criteria (Fig. 1).

Figure 1

DISCUSSION

To our knowledge, this is the first systematic review of the literature that examined the use of acid‐suppressing medications as stress‐ulcer bleeding prophylaxis among general medical patients. Results indicate that there is widespread use of these medications among general medical patients, but little evidence demonstrating a reduction in clinically important gastrointestinal bleeding.

Nardino et al., Parente et al., and Gullota et al. indicated that acid‐suppressive therapies are prescribed to 29%‐54% of hospitalized inpatients. The most common indication for such therapy is stress‐ulcer prophylaxis in patients believed to be at low or no risk, which was true for 20%‐25% of all such patients. Interestingly, both Nardino et al. and Parente et al. assumed there were risk factors that place some general medical patients in a higher‐risk category. In their assessment, these patients warrant prophylaxis. This is somewhat problematic though, as such risk factors have yet to be firmly established. All studies were localized, and results should be confirmed in a larger series that spans multiple institutions. Widespread use of stress‐ulcer prophylaxis may be driven by fear of the previously reported high mortality rates associated with stress‐ulcer bleeding. This fear may be largely unjustified, as overall rates of bleeding episodes appear low.12 Furthermore, patients who die with stress‐ulcer‐related bleeding likely die from their underlying severe illness rather than the bleed itself.

We identified only 2 studies that tested the effectiveness of stress‐ulcer prophylaxis in general medical populations. Both indicated a relatively low risk of gastrointestinal bleeding in patients receiving prophylaxis. Most notably, the work by Estruch et al. comparing an antacid regimen (magaldrate) to placebo showed a significant reduction in bleeding in the active treatment group. However, these trials possess characteristics that limit their applicability to a broad medical population. In particular, these trials were designed to represent only patients with severe illness, many of whom possessed presumed risk factors for stress‐ulcer bleeding. Although all the patients in these 2 series were managed on a general medical ward, many (eg, heart failure patients requiring inotropic support) would likely qualify for intensive care at some institutions. The rate of minor gastrointestinal hemorrhages in the placebo group of the magaldrate trial was significantly higher than in previous observational trials, further suggesting that this population had greater severity of illness than a typical medical population. In addition, although the studies contributed some useful information about severely ill patients, both controlled trials had design limitations. Neither study described why the respective populations were chosen or how the sample sizes were derived. More important, neither was double‐blinded. In sum, given the small number of trials, the limited generalizability to more severely ill patients, and design limitations, the existing literature provides minimal guidance about stress‐ulcer prophylaxis in a diverse inpatient service.

There were no major drug‐related adverse effects reported in these trials, and all the acid‐suppressive drugs currently available are considered relatively safe. However, widespread prophylaxis could result in adverse outcomes on balance. For example, in intensive care populations, there is evidence of an increased risk of nosocomial pneumonia associated with universal acid suppression.27 Many of these patients, however, have other risk factors for pneumonia such as mechanical ventilation.28, 29 Similarly, there has been an association between proton‐pump inhibitor use and increased risk for Clostridium difficileassociated diarrhea.30, 31 Also, H2 receptor antagonists have been implicated in thrombocytopenia, but this is still somewhat controversial.32 Whether these or any other adverse events occur commonly in general medical patients is unclear. Finally, every medication prescribed to inpatients increases the cost of the hospitalization and places a further strain on the financial resources of many already troubled health care delivery systems. For example, a 1997 study found that the use of ranitidine for stress‐ulcer prophylaxis cost $84.81 per day and omeprazole cost $39.52 per day, and those costs would presumably be higher today.33 These costs increase more if patients are continued on such medications after discharge. Clinicians have an obligation to ensure that the therapies they prescribe do not result in increased cost or harm, unless there is at least a reasonable expectation for average net benefit. More information is needed to guide such judgments for stress‐ulcer prophylaxis in non‐ICU patients.

As with all reviews, this one had some limitations. Although we searched a wide body of medical literature, some relevant work may not have been considered. Any published work not indexed by the Medline database or not listed in the Cochrane database of controlled trials would not have been part of this review. In addition, articles written in a language other than English and unpublished works were not examined. Therefore, it is possible that others have investigated this topic and collected information that would alter our results. However, this seems unlikely given the paucity of relevant studies in the wide body of literature that was examined. Finally, the primary author was exclusively responsible for identifying which studies met the inclusion criteria. It is conceivable that additional reviewers would have considered other studies to be relevant to the analysis.

Because stress‐ulcer prophylaxis appears to be widely used in patients hospitalized outside the intensive care unit, it is necessary to determine the efficacy and safety of this practice. Unfortunately, research in this area is sparse. The only 2 trials evaluating this topic, although suggesting a benefit for prophylaxis in selected higher‐risk populations, did not provide guidance for prophylaxis among a broad population of hospitalized medical patients. The present body of evidence does not clearly support or refute the use of stress‐ulcer prophylaxis in a general medical population. An appropriately powered randomized, controlled trial in a diverse population of general medical patients would clarify this issue.

In 10 short years, the explosive growth in the number of hospitalists has made hospital medicine programs the cornerstone of many innovations that support the institutions they serve: expanded inpatient care, developing consultative and comanagement services, hospital capacity management, improved patient quality and safety practices, and more. Hospitalist teams have demonstrated a genuine commitment to improving the hospital system, with literature supporting that hospitalists can positively affect cost, length of stay, quality of care, and, at academic institutions, education.1 To the casual observer, these hospitalist groups and the solutions they bring may seem fairly uniform; however, to the discerning eye, nothing could be farther from the truth. Hospital medicine programs, and their innovations, are as varied as the hospitals they serve.

Although the challenges encountered in hospital systems have clear, institution‐specific elements, common themes are often encountered by clinicians that parallel those seen at other facilities. Unfortunately, widely disseminated articles from peer‐reviewed journals on hospital‐based innovations have not been available for other hospitalists to use and glean ideas from for use at their home institutionsuntil now. The Journal of Hospital Medicine is pleased to announce the creation of that opportunity.

This year, the Journal of Hospital Medicine will publish articles on and later a supplement dedicated to innovations in hospital medicine. We invite authors to submit manuscripts related to any successful innovation they initiated in their hospital. We will consider any original work that pertains to hospital medicine, including but not limited to clinical innovations, educational programs, quality and safety initiatives, and administrative or academic issues. When available and appropriate, we encourage outcomes to be reported.

To be able to publish articles on a significant number of innovations, we request manuscripts be a maximum of 1500 words with no more than 2 tables or figures and fewer than 15 references. The deadline for submissions is August 1, 2007. All submitted manuscripts will undergo both editorial review by JHM staff and peer review. Authors should consult JHM's instructions for authors2 for guidelines on manuscript submission and preparation.