Tears well up in my eyes. Not from pain, but frustration.

I pleaded with my 3‐year‐olds to come to me, so I could help them wash and dress for the day. Ordinarily, I would have come into their room, leaned over their beds, and whispered good morning into their ears.

Four days after surgery, I wasn't able to do that. Not without the crutches. Even with the crutches, I was moving slowly. I scooted up, put a few pillows behind my back, and carefully lifted up my leg. Putting on the knee immobilizer would take too long; I would only be crossing the hall.

Weighing less than 800 g, the immobilizer is an adjustable aluminum frame attached to foam rubber and 4 wide Velcro straps. It is a device of torment. I can never seem to find the proper fit. If it is too tight, my leg hurts and starts turning blue. When it is too loose, it pulls on my incision, multiplying the pain. You put it on while sitting, but you only discover whether it is too tight or too loose when you stand up.

With one foot on the floor at the edge of the bed, I took one crutch in hand, shifted to the left, and grabbed for the other crutch. I squeezed the handgrips of the crutches tightly and pulled myself up.

Put your weight on your hands, NOT your armpits, the instructions said. Easier said than done, because my armpits were now sore too.

Keep your crutches even with each other. I tried to remember to make an equilateral triangle with my good foot and 2 crutches, but the instructions only seemed to account for movement in a straight line.

Keep your elbows slightly bent and close to your sides to help keep the crutches under your arm. I am trying that too.

Lock your elbows. This instruction contradicts the previous one. Which should I follow?

Place your crutches 2 to 3 inches outside of each foot. How do I do this and keep my elbows close to my sides?

Swing your injured leg through first. But not too much, or I'll pole vault across the room.

After 3 steps, my leg started to throb, and my quadriceps went into a spasm. I needed to sit down, immediately.

Non‐weight‐bearing for next 4 weeks, was written on the doctor's note. Four weeks feels like an eternity. If my heel or toe even touched the ground, I felt an immediate throb of pain in my knee.

How do my orthopedic patients do it: those with broken hips and bad or broken knees, with hip replacements, or knee replacements? I was sensitive to their pain and could optimize control. Postoperatively, I could support gastrointestinal and other organ systems. I made sure that the basic weight‐bearing order was correct. I carefully followed the physical and/or occupational therapy recommendation for home, rehabilitation, or a nursing home. I spoke with families. Yet I did not dwell on activities of daily living nor how my patients felt to be dependent on others for simple things they needed. Some patients were non‐weight‐bearing for weeks, some for months, others never walked again. How can one deeply understand it if one has never experienced it?

According to Centers for Disease Control and Prevention (CDC) statistics,1 unintentional injuries are the leading cause of death between the ages of 1 and 44 years. Accidents are again the leading cause of death after age 75 years. More startling is the fact that these numbers have not been significantly reduced since these data were first collected. Nor do these numbers reveal the number of those debilitated, but still living. In my case, I was not playing basketball, water skiing, or rock climbing: I slipped and fell while stepping into a wading pool with my children, severing ligaments, tearing meniscus, and creating a hairline fracture of my tibia.

Expect to move slowly with the crutches. Yes, I am moving very slowly, only 1 to 2 feet with each stride. If I take a longer stride, I lose my balance.

Learn to sit down with the crutches. Learn to stand up. Learn to get into a car.

Learn to go up the stairs. Learn to go down the stairs.

Avoid wet surfaces. Otherwise you'll start skating and reinjure that knee.

It was effortless to think of patients and colleagues of mine. Mr. S., how do you do it? At age 30 years, he was quadriplegic from falling from a tree as a teenager. Mr. D, how about you, in a wheelchair, after being hit by a car and multiple postoperative leg infections and amputations: living in hotels, with estranged family and no social support. How did you do it, while we nagged you about controlling your glucose. Dr. J? The sadness fills my heart. At only 60 years old, my wonderful professor now made rounds in an electric wheelchair, the victim of amyotrophic lateral sclerosis (ALS). My fate, in comparison, is fortunate; my immobility only temporary. I can still think. And talk. And use a phone. And eat, as well as write this essay. And, best of all, read stories to my children. Be careful about this leg, I remind them. Don't come too close!

Maybe what life is trying to tell you is, slow down. In fact, it's forcing you to do that, a colleague and friend said. I had prided myself in thorough and compassionate doctoring. Now, having been a patient on crutches, I have a greater understanding of how limits to mobility can impact daily living on my patients after I discharge them. And the mundane subject of accident prevention has gained a new urgency.

Tears well up in my eyes. Not from pain, but frustration.

I pleaded with my 3‐year‐olds to come to me, so I could help them wash and dress for the day. Ordinarily, I would have come into their room, leaned over their beds, and whispered good morning into their ears.

Four days after surgery, I wasn't able to do that. Not without the crutches. Even with the crutches, I was moving slowly. I scooted up, put a few pillows behind my back, and carefully lifted up my leg. Putting on the knee immobilizer would take too long; I would only be crossing the hall.

Weighing less than 800 g, the immobilizer is an adjustable aluminum frame attached to foam rubber and 4 wide Velcro straps. It is a device of torment. I can never seem to find the proper fit. If it is too tight, my leg hurts and starts turning blue. When it is too loose, it pulls on my incision, multiplying the pain. You put it on while sitting, but you only discover whether it is too tight or too loose when you stand up.

With one foot on the floor at the edge of the bed, I took one crutch in hand, shifted to the left, and grabbed for the other crutch. I squeezed the handgrips of the crutches tightly and pulled myself up.

Put your weight on your hands, NOT your armpits, the instructions said. Easier said than done, because my armpits were now sore too.

Keep your crutches even with each other. I tried to remember to make an equilateral triangle with my good foot and 2 crutches, but the instructions only seemed to account for movement in a straight line.

Keep your elbows slightly bent and close to your sides to help keep the crutches under your arm. I am trying that too.

Lock your elbows. This instruction contradicts the previous one. Which should I follow?

Place your crutches 2 to 3 inches outside of each foot. How do I do this and keep my elbows close to my sides?

Swing your injured leg through first. But not too much, or I'll pole vault across the room.

After 3 steps, my leg started to throb, and my quadriceps went into a spasm. I needed to sit down, immediately.

Non‐weight‐bearing for next 4 weeks, was written on the doctor's note. Four weeks feels like an eternity. If my heel or toe even touched the ground, I felt an immediate throb of pain in my knee.

How do my orthopedic patients do it: those with broken hips and bad or broken knees, with hip replacements, or knee replacements? I was sensitive to their pain and could optimize control. Postoperatively, I could support gastrointestinal and other organ systems. I made sure that the basic weight‐bearing order was correct. I carefully followed the physical and/or occupational therapy recommendation for home, rehabilitation, or a nursing home. I spoke with families. Yet I did not dwell on activities of daily living nor how my patients felt to be dependent on others for simple things they needed. Some patients were non‐weight‐bearing for weeks, some for months, others never walked again. How can one deeply understand it if one has never experienced it?

According to Centers for Disease Control and Prevention (CDC) statistics,1 unintentional injuries are the leading cause of death between the ages of 1 and 44 years. Accidents are again the leading cause of death after age 75 years. More startling is the fact that these numbers have not been significantly reduced since these data were first collected. Nor do these numbers reveal the number of those debilitated, but still living. In my case, I was not playing basketball, water skiing, or rock climbing: I slipped and fell while stepping into a wading pool with my children, severing ligaments, tearing meniscus, and creating a hairline fracture of my tibia.

Expect to move slowly with the crutches. Yes, I am moving very slowly, only 1 to 2 feet with each stride. If I take a longer stride, I lose my balance.

Learn to sit down with the crutches. Learn to stand up. Learn to get into a car.

Learn to go up the stairs. Learn to go down the stairs.

Avoid wet surfaces. Otherwise you'll start skating and reinjure that knee.

It was effortless to think of patients and colleagues of mine. Mr. S., how do you do it? At age 30 years, he was quadriplegic from falling from a tree as a teenager. Mr. D, how about you, in a wheelchair, after being hit by a car and multiple postoperative leg infections and amputations: living in hotels, with estranged family and no social support. How did you do it, while we nagged you about controlling your glucose. Dr. J? The sadness fills my heart. At only 60 years old, my wonderful professor now made rounds in an electric wheelchair, the victim of amyotrophic lateral sclerosis (ALS). My fate, in comparison, is fortunate; my immobility only temporary. I can still think. And talk. And use a phone. And eat, as well as write this essay. And, best of all, read stories to my children. Be careful about this leg, I remind them. Don't come too close!

Maybe what life is trying to tell you is, slow down. In fact, it's forcing you to do that, a colleague and friend said. I had prided myself in thorough and compassionate doctoring. Now, having been a patient on crutches, I have a greater understanding of how limits to mobility can impact daily living on my patients after I discharge them. And the mundane subject of accident prevention has gained a new urgency.

Tears well up in my eyes. Not from pain, but frustration.

I pleaded with my 3‐year‐olds to come to me, so I could help them wash and dress for the day. Ordinarily, I would have come into their room, leaned over their beds, and whispered good morning into their ears.

Four days after surgery, I wasn't able to do that. Not without the crutches. Even with the crutches, I was moving slowly. I scooted up, put a few pillows behind my back, and carefully lifted up my leg. Putting on the knee immobilizer would take too long; I would only be crossing the hall.

Weighing less than 800 g, the immobilizer is an adjustable aluminum frame attached to foam rubber and 4 wide Velcro straps. It is a device of torment. I can never seem to find the proper fit. If it is too tight, my leg hurts and starts turning blue. When it is too loose, it pulls on my incision, multiplying the pain. You put it on while sitting, but you only discover whether it is too tight or too loose when you stand up.

With one foot on the floor at the edge of the bed, I took one crutch in hand, shifted to the left, and grabbed for the other crutch. I squeezed the handgrips of the crutches tightly and pulled myself up.

Put your weight on your hands, NOT your armpits, the instructions said. Easier said than done, because my armpits were now sore too.

Keep your crutches even with each other. I tried to remember to make an equilateral triangle with my good foot and 2 crutches, but the instructions only seemed to account for movement in a straight line.

Keep your elbows slightly bent and close to your sides to help keep the crutches under your arm. I am trying that too.

Lock your elbows. This instruction contradicts the previous one. Which should I follow?

Place your crutches 2 to 3 inches outside of each foot. How do I do this and keep my elbows close to my sides?

Swing your injured leg through first. But not too much, or I'll pole vault across the room.

After 3 steps, my leg started to throb, and my quadriceps went into a spasm. I needed to sit down, immediately.

Non‐weight‐bearing for next 4 weeks, was written on the doctor's note. Four weeks feels like an eternity. If my heel or toe even touched the ground, I felt an immediate throb of pain in my knee.

How do my orthopedic patients do it: those with broken hips and bad or broken knees, with hip replacements, or knee replacements? I was sensitive to their pain and could optimize control. Postoperatively, I could support gastrointestinal and other organ systems. I made sure that the basic weight‐bearing order was correct. I carefully followed the physical and/or occupational therapy recommendation for home, rehabilitation, or a nursing home. I spoke with families. Yet I did not dwell on activities of daily living nor how my patients felt to be dependent on others for simple things they needed. Some patients were non‐weight‐bearing for weeks, some for months, others never walked again. How can one deeply understand it if one has never experienced it?

According to Centers for Disease Control and Prevention (CDC) statistics,1 unintentional injuries are the leading cause of death between the ages of 1 and 44 years. Accidents are again the leading cause of death after age 75 years. More startling is the fact that these numbers have not been significantly reduced since these data were first collected. Nor do these numbers reveal the number of those debilitated, but still living. In my case, I was not playing basketball, water skiing, or rock climbing: I slipped and fell while stepping into a wading pool with my children, severing ligaments, tearing meniscus, and creating a hairline fracture of my tibia.

Expect to move slowly with the crutches. Yes, I am moving very slowly, only 1 to 2 feet with each stride. If I take a longer stride, I lose my balance.

Learn to sit down with the crutches. Learn to stand up. Learn to get into a car.

Learn to go up the stairs. Learn to go down the stairs.

Avoid wet surfaces. Otherwise you'll start skating and reinjure that knee.

It was effortless to think of patients and colleagues of mine. Mr. S., how do you do it? At age 30 years, he was quadriplegic from falling from a tree as a teenager. Mr. D, how about you, in a wheelchair, after being hit by a car and multiple postoperative leg infections and amputations: living in hotels, with estranged family and no social support. How did you do it, while we nagged you about controlling your glucose. Dr. J? The sadness fills my heart. At only 60 years old, my wonderful professor now made rounds in an electric wheelchair, the victim of amyotrophic lateral sclerosis (ALS). My fate, in comparison, is fortunate; my immobility only temporary. I can still think. And talk. And use a phone. And eat, as well as write this essay. And, best of all, read stories to my children. Be careful about this leg, I remind them. Don't come too close!

Maybe what life is trying to tell you is, slow down. In fact, it's forcing you to do that, a colleague and friend said. I had prided myself in thorough and compassionate doctoring. Now, having been a patient on crutches, I have a greater understanding of how limits to mobility can impact daily living on my patients after I discharge them. And the mundane subject of accident prevention has gained a new urgency.

Clostridium difficile colitis (CDC) is the most common cause of hospital‐acquired diarrhea.1 The incidence of CDC has sharply increased over the past decade despite increasing awareness among health care professionals.24 C. difficile pathogenic strains induce diarrhea through the elaboration and secretion of 2 exotoxins: toxin A and toxin B. Toxin A is an inflammatory toxin, leading to fluid secretion, increased mucosal permeability, and marked enteritis and colitis.5 Toxin B is cytotoxic, leading to cell injury and apoptosis.5 Combined, toxin A and toxin B can cause a wide spectrum of clinical presentations, ranging from mild diarrhea that resolves with the discontinuation of antibiotics to a fulminant colitis requiring surgical intervention.

The severity of clinical manifestations has been shown to be inversely proportional to the host anti‐toxin A antibody level in response to toxin exposure. Kyne et al.6 demonstrated that asymptomatic C. difficile carriers produced significantly higher anti‐toxin A immunoglobulin G (IgG) levels compared to symptomatic patients. Among the latter group, patients with mild disease had a higher antibody level compared to those with severe colitis.6, 7 Additional risk factors predisposing to severe colitis are advanced age, severe underlying illness,8 and immunocompromised state.9

Recently, a new C. difficile strain (BI/NAP1) with a mutated toxin A and toxin B promoter silencer, a binary toxin gene, and fluoroquinolone resistance has been described in Canada and the United States.3, 10 This strain has been associated with an increased incidence of CDC among hospitalized patients, especially the incidence of severe disease requiring colectomy. At the same time, several reports describing metronidazole treatment failure have been published.1114 These recent findings emphasize the importance of finding alternative treatments for CDC.

Intravenous immunoglobulin (IVIG) was used to treat CDC for the first time in 1991.15 Since then, 12 case reports and small case series, along with 1 case‐control study have been published documenting IVIG treatment outcomes.1527 However, only 5 reports to date examined patients with severe CDC.2125 In the present study, we report the largest series of patients with severe CDC treated with IVIG in the literature to our knowledge.

Patients and Methods

Results

Discussion

To our knowledge, the present study is the largest series published in the literature to date on the use of IVIG for severe CDC. It is also the first study to report a high mortality rate compared to the 5 previous smaller studies on this topic. In the first report on IVIG use for CDC, Leung et al.15 used IVIG to treat 5 pediatric patients suffering from chronic relapsing CDC. It was not until 7 years later, in 1997, that the first IVIG use for severe CDC was reported.22 Since then, a total of 13 works have been published on IVIG for CDC treatment, and only in 5 of these was IVIG administered for severe CDC treatment:2125 3 case reports, 1 case series, and 1 case‐control study. Although the 4 uncontrolled reports concluded that IVIG is beneficial for severe CDC, the only controlled study reported no significant difference between cases and controls for all‐cause mortality, length of stay, and colectomy rate.25

The definition of severe CDC varied between reports, making comparison difficult. McPherson et al.21 and Hassoun and Ibrahim24 defined severe disease as one causing pancolitis on CT scan either with or without megacolon. In the study by Juang et al.,25 disease severity was assessed using the modified criteria of Rubin et al.9 Salcedo et al.22 defined severe CDC as one causing pancolitis in one patient and thumbprinting on CT scan in another, whereas Chandrasekar et al.23 defined it as one causing shock requiring inotropic support and presence of pseudomembranes on colonoscopy.

The present report is unique in that it provided 2 scales to characterize disease in each patient. The first scale measured colonic involvement anatomically and physiologically using a combination of computerized axial tomography (CAT) scan findings, presence or absence of ileus or referral for possible colectomy. This is not a prognostic scale, however, since CAT scan findings have been previously shown to be poor predictors of treatment outcome.29 The second scale measured the severity of systemic involvement using a well‐validated and standardized scale, the APACHE II score. We have shown in this report that it is associated with prognosis in the context of IVIG use.

Our study reports a higher mortality rate than previously described, and suggests that risk stratification and patient selection are important before IVIG administration, since not all patients seem to benefit from this treatment as previously suggested by smaller case series. Previously, several physical findings and laboratory values were found to be associated with worse outcome in CDC. These were increasing age, immunosuppression, shock requiring vasopressors, peak white blood cell count, peak serum lactate level, hypoalbuminemia, a fall in serum albumin level of >1.1 g/dL at the onset of CDC symptoms, use of 3 or more antibiotics, comorbid disease, previous history of CDC, acute renal failure and hypotension, underlying altered or depressed mental status, abdominal pain or distention, white blood cell count over 20,000/mm³ or <1500/mm³ and/or a >10% band forms on the white blood cell differential count, and ascites or pneumatosis coli by abdominal imaging.9, 3033 Using the APACHE II scale for the same purpose has the advantage of utilizing a well‐validated and objective scale that is expected to measure the degree of systemic involvement more reliably compared to the clinical and laboratory values above.

Timing of IVIG infusion remains controversial. Due to the lack of randomized controlled trials, the current practice is guided by expert opinion, leading to wide variations between reports. Since the APACHE II score was positively associated with mortality in the setting of IVIG treatment, the same scale could be used to guide decisions regarding timing of IVIG infusion. Our results suggest that IVIG should be preferentially used while the APACHE II score is still relatively low. This association and the specific APACHE II score at which to initiate or hold treatment need to be validated in the setting of a randomized controlled study before being used in clinical practice.

Although the current study was not designed to test this theory, IVIG could be associated conceptually with treatment success for patients with severe disease that is still restricted to the colon (without other organ dysfunction or at least at an early stage of extracolonic organ failure and thus associated with a low APACHE II score) but not for severe colonic disease with secondary multiple organ failure (high APACHE II score). This may be because colonic disease is toxin‐mediated whereas secondary systemic involvement is mediated through toxin‐induced inflammatory mediators (interleukin‐8, macrophage‐inflammatory protein‐2, substance P, tumor necrosis factor‐alpha) released locally in the colon,3436 triggering a SIRS and hematogenous translocation of colonic bacteria,37 both of which are poorly responsive to immunoglobulin infusion. Along the same lines, waiting for failure of conventional therapy before IVIG use might result in IVIG treatment failure because of disease progression and secondary sepsis, at which point no treatment may be effective. No study thus far has addressed this issue specifically.

Overall, the combined cohort of patients with severe CDC treated with IVIG in the literature includes 51 patients (Table 4). The current report contributes 41% of these patients. The patients' average age was 68 years, with a 2 to 1 female‐male ratio. The dose of IVIG used varied largely also, with 400 mg/kg being the mode (range, 75400 mg/kg from 1 to 5 doses). This dose is significantly below the doses used in the treatment of other diseases, like Guillain‐Barr syndrome, myasthenia gravis, Kawasaki disease, autoimmune hemolytic anemia, agammaglobulinemia, and hypogammaglobulinemia, where the usual dose is 400 mg/kg for 5 days. The resolution of diarrhea in these cases occurred after an average of 9 (range, 142) days. The index hospitalization survival rate varied from 43% to 100%. Patients received standard treatment for an average of 13 (range, 065) days before IVIG infusion. Thirty‐two of 51 patients survived their illness (63%). Neither total IgG nor anti‐toxin A IgG levels were measured in any of the reports. Of the 32 patients who had clinical resolution, 3 (10%) experienced symptoms recurrence in a follow‐up period of 1 to 13 months. This number is most probably an underestimation of the true recurrence rate resulting from an incomplete reporting because there was no uniform or active recurrence ascertainment mechanism in any of the studies. The recurrences were at 10, 14, and 30 days posttreatment. Since standard treatment was not discontinued in any of the reports once IVIG was given, the relative contribution and the ideal timing for IVIG infusion are still unclear.

The mechanism of action of IVIG is passive immunization (with anti‐toxin A and anti‐toxin B antibodies present in the pooled immunoglobulin) of a host who is usually unable to mount an adequate protective immune response.15, 22 IVIG is formed from pooling immunoglobulin from several random donors. It has been shown that many such donors express high anti‐toxin A and anti‐toxin B antibody serum titers.38, 39 In addition, high levels of anti‐toxin A and anti‐toxin B antibodies were present in the IVIG preparations and the recipients after infusion.1517, 22 Although constituting only a small fraction of the total IVIG administered, these antitoxin antibodies are believed to neutralize toxin A and B and help the host recover from the disease. In fact, Babcock et al.40 used an experimental hamster model of CDC to demonstrate a mortality reduction from 100% to 55% postinfusion of combined anti‐toxin A and anti‐toxin B antibodies. While some early reports indicated that anti‐toxin B antibodies were the major determinants of protection against colitis,41 later reports correlated disease severity pathologically42 and clinically43, 44 with anti‐toxin A levels. Anti‐toxin B antibodies were later shown to play an adjunctive role in conferring immunity against CDC40, 45, 46 when added to anti‐toxin A antibodies, but not to have any significant role on their own.

However, IVIG has been shown to contain IgG, but not IgA, anti‐toxin A and anti‐toxin B antibodies while it is only the IgA class of anti‐toxin A antibodies, and not the IgG class, that could neutralize toxin A in vitro and in vivo.47, 48 Babcock et al.40 solved this apparent dilemma by showing that a combination of 3 different monoclonal IgG anti‐toxin A antibodies could neutralize toxin A activity in vitro and prevent disease in the hamster model in vivo. Each of the 3 antibodies recognized a different toxin A domain: the first neutralized toxin A enzymatic activity, while the second prevented toxin A binding to its receptor on enterocytes, and the third prevented toxin internalization after binding to the receptor.

Thus, the mechanism of action of IVIG is most likely through the transfer of IgG anti‐toxin A antibodies that gain access to the intestinal lumen presumably secondary to inflammation‐induced mucosal damage and neutralize toxin A. Transfer of yet undetected IgA anti‐toxin A antibodies that prevent toxin A from binding to its receptor is much less likely, although possible.

The present study has limitations. As in all retrospective studies, selection bias was unavoidable. In addition, the decision to initiate IVIG administration was dependent on the attending physician, who also decided the dose, leading to heterogeneity in the total dose of IVIG infused. Such heterogeneity, however, is primarily the result of a lack of a standard dose for IVIG infusion for CDC in the published literature, as reported above. In addition, since IVIG is not yet approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe CDC, standard treatment was not discontinued in any of the reports to date, including ours.

Choosing appropriate controls for patients suffering from severe CDC is challenging. This patient population is usually frail, with severe and multiple underlying diseases. The deteriorating clinical condition (and subsequently the need for multiple antibiotics) may be either the result of or the cause of CDC. Furthermore, IVIG has been in short supply for several years and therefore it has been expensive, making its administration to the number of patients needed to design adequately‐powered controlled studies difficult. These are mainly the reasons no randomized, multicenter, placebo‐controlled trial on IVIG use in severe CDC has been conducted to date.

Conclusions

In the present study, we report the results of IVIG use for the treatment of 21 patients with severe CDC. This is the largest cohort to our knowledge in the literature. Unlike previous studies on the subject, the present report provided 2 scales for disease assessment: the first based on the extent of colonic involvement and the second measuring the severity of systemic involvement using the APACHE II score. The latter was positively associated with mortality in this context. Of the 21 study patients treated with IVIG, only 9 patients (43%) survived their illness. This is the highest reported mortality rate among all studies on this subject so far. Further studies on the ideal timing of IVIG infusion, dose, and patient selection are needed before accepting IVIG as a standard of care for severe CDC treatment. The role of APACHE II score in the decision to use IVIG is promising and should be validated in randomized controlled trials.

Clostridium difficile colitis (CDC) is the most common cause of hospital‐acquired diarrhea.1 The incidence of CDC has sharply increased over the past decade despite increasing awareness among health care professionals.24 C. difficile pathogenic strains induce diarrhea through the elaboration and secretion of 2 exotoxins: toxin A and toxin B. Toxin A is an inflammatory toxin, leading to fluid secretion, increased mucosal permeability, and marked enteritis and colitis.5 Toxin B is cytotoxic, leading to cell injury and apoptosis.5 Combined, toxin A and toxin B can cause a wide spectrum of clinical presentations, ranging from mild diarrhea that resolves with the discontinuation of antibiotics to a fulminant colitis requiring surgical intervention.

The severity of clinical manifestations has been shown to be inversely proportional to the host anti‐toxin A antibody level in response to toxin exposure. Kyne et al.6 demonstrated that asymptomatic C. difficile carriers produced significantly higher anti‐toxin A immunoglobulin G (IgG) levels compared to symptomatic patients. Among the latter group, patients with mild disease had a higher antibody level compared to those with severe colitis.6, 7 Additional risk factors predisposing to severe colitis are advanced age, severe underlying illness,8 and immunocompromised state.9

Recently, a new C. difficile strain (BI/NAP1) with a mutated toxin A and toxin B promoter silencer, a binary toxin gene, and fluoroquinolone resistance has been described in Canada and the United States.3, 10 This strain has been associated with an increased incidence of CDC among hospitalized patients, especially the incidence of severe disease requiring colectomy. At the same time, several reports describing metronidazole treatment failure have been published.1114 These recent findings emphasize the importance of finding alternative treatments for CDC.

Intravenous immunoglobulin (IVIG) was used to treat CDC for the first time in 1991.15 Since then, 12 case reports and small case series, along with 1 case‐control study have been published documenting IVIG treatment outcomes.1527 However, only 5 reports to date examined patients with severe CDC.2125 In the present study, we report the largest series of patients with severe CDC treated with IVIG in the literature to our knowledge.

Patients and Methods

Results

Discussion

To our knowledge, the present study is the largest series published in the literature to date on the use of IVIG for severe CDC. It is also the first study to report a high mortality rate compared to the 5 previous smaller studies on this topic. In the first report on IVIG use for CDC, Leung et al.15 used IVIG to treat 5 pediatric patients suffering from chronic relapsing CDC. It was not until 7 years later, in 1997, that the first IVIG use for severe CDC was reported.22 Since then, a total of 13 works have been published on IVIG for CDC treatment, and only in 5 of these was IVIG administered for severe CDC treatment:2125 3 case reports, 1 case series, and 1 case‐control study. Although the 4 uncontrolled reports concluded that IVIG is beneficial for severe CDC, the only controlled study reported no significant difference between cases and controls for all‐cause mortality, length of stay, and colectomy rate.25

The definition of severe CDC varied between reports, making comparison difficult. McPherson et al.21 and Hassoun and Ibrahim24 defined severe disease as one causing pancolitis on CT scan either with or without megacolon. In the study by Juang et al.,25 disease severity was assessed using the modified criteria of Rubin et al.9 Salcedo et al.22 defined severe CDC as one causing pancolitis in one patient and thumbprinting on CT scan in another, whereas Chandrasekar et al.23 defined it as one causing shock requiring inotropic support and presence of pseudomembranes on colonoscopy.

The present report is unique in that it provided 2 scales to characterize disease in each patient. The first scale measured colonic involvement anatomically and physiologically using a combination of computerized axial tomography (CAT) scan findings, presence or absence of ileus or referral for possible colectomy. This is not a prognostic scale, however, since CAT scan findings have been previously shown to be poor predictors of treatment outcome.29 The second scale measured the severity of systemic involvement using a well‐validated and standardized scale, the APACHE II score. We have shown in this report that it is associated with prognosis in the context of IVIG use.

Our study reports a higher mortality rate than previously described, and suggests that risk stratification and patient selection are important before IVIG administration, since not all patients seem to benefit from this treatment as previously suggested by smaller case series. Previously, several physical findings and laboratory values were found to be associated with worse outcome in CDC. These were increasing age, immunosuppression, shock requiring vasopressors, peak white blood cell count, peak serum lactate level, hypoalbuminemia, a fall in serum albumin level of >1.1 g/dL at the onset of CDC symptoms, use of 3 or more antibiotics, comorbid disease, previous history of CDC, acute renal failure and hypotension, underlying altered or depressed mental status, abdominal pain or distention, white blood cell count over 20,000/mm³ or <1500/mm³ and/or a >10% band forms on the white blood cell differential count, and ascites or pneumatosis coli by abdominal imaging.9, 3033 Using the APACHE II scale for the same purpose has the advantage of utilizing a well‐validated and objective scale that is expected to measure the degree of systemic involvement more reliably compared to the clinical and laboratory values above.

Timing of IVIG infusion remains controversial. Due to the lack of randomized controlled trials, the current practice is guided by expert opinion, leading to wide variations between reports. Since the APACHE II score was positively associated with mortality in the setting of IVIG treatment, the same scale could be used to guide decisions regarding timing of IVIG infusion. Our results suggest that IVIG should be preferentially used while the APACHE II score is still relatively low. This association and the specific APACHE II score at which to initiate or hold treatment need to be validated in the setting of a randomized controlled study before being used in clinical practice.

Although the current study was not designed to test this theory, IVIG could be associated conceptually with treatment success for patients with severe disease that is still restricted to the colon (without other organ dysfunction or at least at an early stage of extracolonic organ failure and thus associated with a low APACHE II score) but not for severe colonic disease with secondary multiple organ failure (high APACHE II score). This may be because colonic disease is toxin‐mediated whereas secondary systemic involvement is mediated through toxin‐induced inflammatory mediators (interleukin‐8, macrophage‐inflammatory protein‐2, substance P, tumor necrosis factor‐alpha) released locally in the colon,3436 triggering a SIRS and hematogenous translocation of colonic bacteria,37 both of which are poorly responsive to immunoglobulin infusion. Along the same lines, waiting for failure of conventional therapy before IVIG use might result in IVIG treatment failure because of disease progression and secondary sepsis, at which point no treatment may be effective. No study thus far has addressed this issue specifically.

Overall, the combined cohort of patients with severe CDC treated with IVIG in the literature includes 51 patients (Table 4). The current report contributes 41% of these patients. The patients' average age was 68 years, with a 2 to 1 female‐male ratio. The dose of IVIG used varied largely also, with 400 mg/kg being the mode (range, 75400 mg/kg from 1 to 5 doses). This dose is significantly below the doses used in the treatment of other diseases, like Guillain‐Barr syndrome, myasthenia gravis, Kawasaki disease, autoimmune hemolytic anemia, agammaglobulinemia, and hypogammaglobulinemia, where the usual dose is 400 mg/kg for 5 days. The resolution of diarrhea in these cases occurred after an average of 9 (range, 142) days. The index hospitalization survival rate varied from 43% to 100%. Patients received standard treatment for an average of 13 (range, 065) days before IVIG infusion. Thirty‐two of 51 patients survived their illness (63%). Neither total IgG nor anti‐toxin A IgG levels were measured in any of the reports. Of the 32 patients who had clinical resolution, 3 (10%) experienced symptoms recurrence in a follow‐up period of 1 to 13 months. This number is most probably an underestimation of the true recurrence rate resulting from an incomplete reporting because there was no uniform or active recurrence ascertainment mechanism in any of the studies. The recurrences were at 10, 14, and 30 days posttreatment. Since standard treatment was not discontinued in any of the reports once IVIG was given, the relative contribution and the ideal timing for IVIG infusion are still unclear.

The mechanism of action of IVIG is passive immunization (with anti‐toxin A and anti‐toxin B antibodies present in the pooled immunoglobulin) of a host who is usually unable to mount an adequate protective immune response.15, 22 IVIG is formed from pooling immunoglobulin from several random donors. It has been shown that many such donors express high anti‐toxin A and anti‐toxin B antibody serum titers.38, 39 In addition, high levels of anti‐toxin A and anti‐toxin B antibodies were present in the IVIG preparations and the recipients after infusion.1517, 22 Although constituting only a small fraction of the total IVIG administered, these antitoxin antibodies are believed to neutralize toxin A and B and help the host recover from the disease. In fact, Babcock et al.40 used an experimental hamster model of CDC to demonstrate a mortality reduction from 100% to 55% postinfusion of combined anti‐toxin A and anti‐toxin B antibodies. While some early reports indicated that anti‐toxin B antibodies were the major determinants of protection against colitis,41 later reports correlated disease severity pathologically42 and clinically43, 44 with anti‐toxin A levels. Anti‐toxin B antibodies were later shown to play an adjunctive role in conferring immunity against CDC40, 45, 46 when added to anti‐toxin A antibodies, but not to have any significant role on their own.

However, IVIG has been shown to contain IgG, but not IgA, anti‐toxin A and anti‐toxin B antibodies while it is only the IgA class of anti‐toxin A antibodies, and not the IgG class, that could neutralize toxin A in vitro and in vivo.47, 48 Babcock et al.40 solved this apparent dilemma by showing that a combination of 3 different monoclonal IgG anti‐toxin A antibodies could neutralize toxin A activity in vitro and prevent disease in the hamster model in vivo. Each of the 3 antibodies recognized a different toxin A domain: the first neutralized toxin A enzymatic activity, while the second prevented toxin A binding to its receptor on enterocytes, and the third prevented toxin internalization after binding to the receptor.

Thus, the mechanism of action of IVIG is most likely through the transfer of IgG anti‐toxin A antibodies that gain access to the intestinal lumen presumably secondary to inflammation‐induced mucosal damage and neutralize toxin A. Transfer of yet undetected IgA anti‐toxin A antibodies that prevent toxin A from binding to its receptor is much less likely, although possible.

The present study has limitations. As in all retrospective studies, selection bias was unavoidable. In addition, the decision to initiate IVIG administration was dependent on the attending physician, who also decided the dose, leading to heterogeneity in the total dose of IVIG infused. Such heterogeneity, however, is primarily the result of a lack of a standard dose for IVIG infusion for CDC in the published literature, as reported above. In addition, since IVIG is not yet approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe CDC, standard treatment was not discontinued in any of the reports to date, including ours.

Choosing appropriate controls for patients suffering from severe CDC is challenging. This patient population is usually frail, with severe and multiple underlying diseases. The deteriorating clinical condition (and subsequently the need for multiple antibiotics) may be either the result of or the cause of CDC. Furthermore, IVIG has been in short supply for several years and therefore it has been expensive, making its administration to the number of patients needed to design adequately‐powered controlled studies difficult. These are mainly the reasons no randomized, multicenter, placebo‐controlled trial on IVIG use in severe CDC has been conducted to date.

Conclusions

In the present study, we report the results of IVIG use for the treatment of 21 patients with severe CDC. This is the largest cohort to our knowledge in the literature. Unlike previous studies on the subject, the present report provided 2 scales for disease assessment: the first based on the extent of colonic involvement and the second measuring the severity of systemic involvement using the APACHE II score. The latter was positively associated with mortality in this context. Of the 21 study patients treated with IVIG, only 9 patients (43%) survived their illness. This is the highest reported mortality rate among all studies on this subject so far. Further studies on the ideal timing of IVIG infusion, dose, and patient selection are needed before accepting IVIG as a standard of care for severe CDC treatment. The role of APACHE II score in the decision to use IVIG is promising and should be validated in randomized controlled trials.

Clostridium difficile colitis (CDC) is the most common cause of hospital‐acquired diarrhea.1 The incidence of CDC has sharply increased over the past decade despite increasing awareness among health care professionals.24 C. difficile pathogenic strains induce diarrhea through the elaboration and secretion of 2 exotoxins: toxin A and toxin B. Toxin A is an inflammatory toxin, leading to fluid secretion, increased mucosal permeability, and marked enteritis and colitis.5 Toxin B is cytotoxic, leading to cell injury and apoptosis.5 Combined, toxin A and toxin B can cause a wide spectrum of clinical presentations, ranging from mild diarrhea that resolves with the discontinuation of antibiotics to a fulminant colitis requiring surgical intervention.

The severity of clinical manifestations has been shown to be inversely proportional to the host anti‐toxin A antibody level in response to toxin exposure. Kyne et al.6 demonstrated that asymptomatic C. difficile carriers produced significantly higher anti‐toxin A immunoglobulin G (IgG) levels compared to symptomatic patients. Among the latter group, patients with mild disease had a higher antibody level compared to those with severe colitis.6, 7 Additional risk factors predisposing to severe colitis are advanced age, severe underlying illness,8 and immunocompromised state.9

Recently, a new C. difficile strain (BI/NAP1) with a mutated toxin A and toxin B promoter silencer, a binary toxin gene, and fluoroquinolone resistance has been described in Canada and the United States.3, 10 This strain has been associated with an increased incidence of CDC among hospitalized patients, especially the incidence of severe disease requiring colectomy. At the same time, several reports describing metronidazole treatment failure have been published.1114 These recent findings emphasize the importance of finding alternative treatments for CDC.

Intravenous immunoglobulin (IVIG) was used to treat CDC for the first time in 1991.15 Since then, 12 case reports and small case series, along with 1 case‐control study have been published documenting IVIG treatment outcomes.1527 However, only 5 reports to date examined patients with severe CDC.2125 In the present study, we report the largest series of patients with severe CDC treated with IVIG in the literature to our knowledge.

Patients and Methods

Results

Discussion

To our knowledge, the present study is the largest series published in the literature to date on the use of IVIG for severe CDC. It is also the first study to report a high mortality rate compared to the 5 previous smaller studies on this topic. In the first report on IVIG use for CDC, Leung et al.15 used IVIG to treat 5 pediatric patients suffering from chronic relapsing CDC. It was not until 7 years later, in 1997, that the first IVIG use for severe CDC was reported.22 Since then, a total of 13 works have been published on IVIG for CDC treatment, and only in 5 of these was IVIG administered for severe CDC treatment:2125 3 case reports, 1 case series, and 1 case‐control study. Although the 4 uncontrolled reports concluded that IVIG is beneficial for severe CDC, the only controlled study reported no significant difference between cases and controls for all‐cause mortality, length of stay, and colectomy rate.25

The definition of severe CDC varied between reports, making comparison difficult. McPherson et al.21 and Hassoun and Ibrahim24 defined severe disease as one causing pancolitis on CT scan either with or without megacolon. In the study by Juang et al.,25 disease severity was assessed using the modified criteria of Rubin et al.9 Salcedo et al.22 defined severe CDC as one causing pancolitis in one patient and thumbprinting on CT scan in another, whereas Chandrasekar et al.23 defined it as one causing shock requiring inotropic support and presence of pseudomembranes on colonoscopy.

The present report is unique in that it provided 2 scales to characterize disease in each patient. The first scale measured colonic involvement anatomically and physiologically using a combination of computerized axial tomography (CAT) scan findings, presence or absence of ileus or referral for possible colectomy. This is not a prognostic scale, however, since CAT scan findings have been previously shown to be poor predictors of treatment outcome.29 The second scale measured the severity of systemic involvement using a well‐validated and standardized scale, the APACHE II score. We have shown in this report that it is associated with prognosis in the context of IVIG use.

Our study reports a higher mortality rate than previously described, and suggests that risk stratification and patient selection are important before IVIG administration, since not all patients seem to benefit from this treatment as previously suggested by smaller case series. Previously, several physical findings and laboratory values were found to be associated with worse outcome in CDC. These were increasing age, immunosuppression, shock requiring vasopressors, peak white blood cell count, peak serum lactate level, hypoalbuminemia, a fall in serum albumin level of >1.1 g/dL at the onset of CDC symptoms, use of 3 or more antibiotics, comorbid disease, previous history of CDC, acute renal failure and hypotension, underlying altered or depressed mental status, abdominal pain or distention, white blood cell count over 20,000/mm³ or <1500/mm³ and/or a >10% band forms on the white blood cell differential count, and ascites or pneumatosis coli by abdominal imaging.9, 3033 Using the APACHE II scale for the same purpose has the advantage of utilizing a well‐validated and objective scale that is expected to measure the degree of systemic involvement more reliably compared to the clinical and laboratory values above.

Timing of IVIG infusion remains controversial. Due to the lack of randomized controlled trials, the current practice is guided by expert opinion, leading to wide variations between reports. Since the APACHE II score was positively associated with mortality in the setting of IVIG treatment, the same scale could be used to guide decisions regarding timing of IVIG infusion. Our results suggest that IVIG should be preferentially used while the APACHE II score is still relatively low. This association and the specific APACHE II score at which to initiate or hold treatment need to be validated in the setting of a randomized controlled study before being used in clinical practice.

Although the current study was not designed to test this theory, IVIG could be associated conceptually with treatment success for patients with severe disease that is still restricted to the colon (without other organ dysfunction or at least at an early stage of extracolonic organ failure and thus associated with a low APACHE II score) but not for severe colonic disease with secondary multiple organ failure (high APACHE II score). This may be because colonic disease is toxin‐mediated whereas secondary systemic involvement is mediated through toxin‐induced inflammatory mediators (interleukin‐8, macrophage‐inflammatory protein‐2, substance P, tumor necrosis factor‐alpha) released locally in the colon,3436 triggering a SIRS and hematogenous translocation of colonic bacteria,37 both of which are poorly responsive to immunoglobulin infusion. Along the same lines, waiting for failure of conventional therapy before IVIG use might result in IVIG treatment failure because of disease progression and secondary sepsis, at which point no treatment may be effective. No study thus far has addressed this issue specifically.

Overall, the combined cohort of patients with severe CDC treated with IVIG in the literature includes 51 patients (Table 4). The current report contributes 41% of these patients. The patients' average age was 68 years, with a 2 to 1 female‐male ratio. The dose of IVIG used varied largely also, with 400 mg/kg being the mode (range, 75400 mg/kg from 1 to 5 doses). This dose is significantly below the doses used in the treatment of other diseases, like Guillain‐Barr syndrome, myasthenia gravis, Kawasaki disease, autoimmune hemolytic anemia, agammaglobulinemia, and hypogammaglobulinemia, where the usual dose is 400 mg/kg for 5 days. The resolution of diarrhea in these cases occurred after an average of 9 (range, 142) days. The index hospitalization survival rate varied from 43% to 100%. Patients received standard treatment for an average of 13 (range, 065) days before IVIG infusion. Thirty‐two of 51 patients survived their illness (63%). Neither total IgG nor anti‐toxin A IgG levels were measured in any of the reports. Of the 32 patients who had clinical resolution, 3 (10%) experienced symptoms recurrence in a follow‐up period of 1 to 13 months. This number is most probably an underestimation of the true recurrence rate resulting from an incomplete reporting because there was no uniform or active recurrence ascertainment mechanism in any of the studies. The recurrences were at 10, 14, and 30 days posttreatment. Since standard treatment was not discontinued in any of the reports once IVIG was given, the relative contribution and the ideal timing for IVIG infusion are still unclear.

The mechanism of action of IVIG is passive immunization (with anti‐toxin A and anti‐toxin B antibodies present in the pooled immunoglobulin) of a host who is usually unable to mount an adequate protective immune response.15, 22 IVIG is formed from pooling immunoglobulin from several random donors. It has been shown that many such donors express high anti‐toxin A and anti‐toxin B antibody serum titers.38, 39 In addition, high levels of anti‐toxin A and anti‐toxin B antibodies were present in the IVIG preparations and the recipients after infusion.1517, 22 Although constituting only a small fraction of the total IVIG administered, these antitoxin antibodies are believed to neutralize toxin A and B and help the host recover from the disease. In fact, Babcock et al.40 used an experimental hamster model of CDC to demonstrate a mortality reduction from 100% to 55% postinfusion of combined anti‐toxin A and anti‐toxin B antibodies. While some early reports indicated that anti‐toxin B antibodies were the major determinants of protection against colitis,41 later reports correlated disease severity pathologically42 and clinically43, 44 with anti‐toxin A levels. Anti‐toxin B antibodies were later shown to play an adjunctive role in conferring immunity against CDC40, 45, 46 when added to anti‐toxin A antibodies, but not to have any significant role on their own.

However, IVIG has been shown to contain IgG, but not IgA, anti‐toxin A and anti‐toxin B antibodies while it is only the IgA class of anti‐toxin A antibodies, and not the IgG class, that could neutralize toxin A in vitro and in vivo.47, 48 Babcock et al.40 solved this apparent dilemma by showing that a combination of 3 different monoclonal IgG anti‐toxin A antibodies could neutralize toxin A activity in vitro and prevent disease in the hamster model in vivo. Each of the 3 antibodies recognized a different toxin A domain: the first neutralized toxin A enzymatic activity, while the second prevented toxin A binding to its receptor on enterocytes, and the third prevented toxin internalization after binding to the receptor.

Thus, the mechanism of action of IVIG is most likely through the transfer of IgG anti‐toxin A antibodies that gain access to the intestinal lumen presumably secondary to inflammation‐induced mucosal damage and neutralize toxin A. Transfer of yet undetected IgA anti‐toxin A antibodies that prevent toxin A from binding to its receptor is much less likely, although possible.

The present study has limitations. As in all retrospective studies, selection bias was unavoidable. In addition, the decision to initiate IVIG administration was dependent on the attending physician, who also decided the dose, leading to heterogeneity in the total dose of IVIG infused. Such heterogeneity, however, is primarily the result of a lack of a standard dose for IVIG infusion for CDC in the published literature, as reported above. In addition, since IVIG is not yet approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe CDC, standard treatment was not discontinued in any of the reports to date, including ours.

Choosing appropriate controls for patients suffering from severe CDC is challenging. This patient population is usually frail, with severe and multiple underlying diseases. The deteriorating clinical condition (and subsequently the need for multiple antibiotics) may be either the result of or the cause of CDC. Furthermore, IVIG has been in short supply for several years and therefore it has been expensive, making its administration to the number of patients needed to design adequately‐powered controlled studies difficult. These are mainly the reasons no randomized, multicenter, placebo‐controlled trial on IVIG use in severe CDC has been conducted to date.

Conclusions

In the present study, we report the results of IVIG use for the treatment of 21 patients with severe CDC. This is the largest cohort to our knowledge in the literature. Unlike previous studies on the subject, the present report provided 2 scales for disease assessment: the first based on the extent of colonic involvement and the second measuring the severity of systemic involvement using the APACHE II score. The latter was positively associated with mortality in this context. Of the 21 study patients treated with IVIG, only 9 patients (43%) survived their illness. This is the highest reported mortality rate among all studies on this subject so far. Further studies on the ideal timing of IVIG infusion, dose, and patient selection are needed before accepting IVIG as a standard of care for severe CDC treatment. The role of APACHE II score in the decision to use IVIG is promising and should be validated in randomized controlled trials.

Pretest probability assessment is an important first step in the diagnosis of venous thromboembolism (VTE) and models incorporating Wells criteria1 can be used accurately in emergency department (ED) and inpatient settings.2 Gestalt has the disadvantage of poor interobserver reliability,3 and use of clinical prediction rules has been advocated instead.4 In academic institutions, trainees frequently first evaluate patients with suspected VTE, and although gestalt improves with degree of experience, the performance of gestalt in 1 study5 was better for attendings than interns or residents (for whom it was equivalent), suggesting that structured pretest probability assessment may be more important for trainees.

From an imaging perspective, multidetector computed tomography (CT),6 is more accurate than ventilation perfusion (VP) scanning7, 8 in diagnosing VTE in any setting, including the critically ill.9, 10 Lower extremity CT venography (LECTV) has comparable sensitivity to contrast venography and sonography,11 and in combination with computed tomographic pulmonary angiography (CTPA) is important when imaging results are discordant with pretest probability.12 Guidelines for diagnostic pathways in VTE based on published literature incorporating D‐dimer testing have been updated recently,13 the degree of adoption and use of diagnostic algorithms among trainees has been understudied.

Clinical trials14, 15 have confirmed the safety and efficacy of low molecular weight heparin (LMWH) in the treatment of pulmonary embolism (PE) in inpatients, but the degree of adoption of this therapy is unclear. The primary objective of our survey of was to assess the knowledge, attitudes, practices, and preferences of trainees and attendings who order and evaluate the results of diagnostic studies in the management of VTE. A secondary objective was to assess willingness to use LMWH to treat VTE in the inpatient setting among non‐ED respondents.

Methods

Results

Table 1 lists the characteristics of respondents. Medical attendings reported practicing in up to 5 different institutions, and residents reported rotating through up to 10 different institutions during their residency. Students reported rotating through up to 11 different institutions.

Discussion

Conclusions

Our survey identifies the use of evidence‐based strategies in the management of VTE among trainees, a perspective that has been lacking in other studies of physicians in practice.16, 24, 27 Substantial variability in attending practice identified in this survey may impede the adoption of a structured approach to the diagnosis of VTE among trainees, and this survey raises major concerns about mechanisms of diagnosis of VTE. Caprini et al.29 believe that physician knowledge, attitudes, and beliefs are partially responsible for the gap between actual practice and international guidelines.27 The results of our survey extend this suggestion to trainees and imply that supervisor attitudes may negatively influence trainee practices. Development of written protocols or standardized pathway order sets based on published evidence‐based guidelines13 in the management of VTE could improve the use of structured pretest probability determination and use of evidence‐based strategies among trainees. Finally, comparisons of outcomes using algorithms and usual practice could provide valuable, clinically important data that could inform clinical practice.

Pretest probability assessment is an important first step in the diagnosis of venous thromboembolism (VTE) and models incorporating Wells criteria1 can be used accurately in emergency department (ED) and inpatient settings.2 Gestalt has the disadvantage of poor interobserver reliability,3 and use of clinical prediction rules has been advocated instead.4 In academic institutions, trainees frequently first evaluate patients with suspected VTE, and although gestalt improves with degree of experience, the performance of gestalt in 1 study5 was better for attendings than interns or residents (for whom it was equivalent), suggesting that structured pretest probability assessment may be more important for trainees.

From an imaging perspective, multidetector computed tomography (CT),6 is more accurate than ventilation perfusion (VP) scanning7, 8 in diagnosing VTE in any setting, including the critically ill.9, 10 Lower extremity CT venography (LECTV) has comparable sensitivity to contrast venography and sonography,11 and in combination with computed tomographic pulmonary angiography (CTPA) is important when imaging results are discordant with pretest probability.12 Guidelines for diagnostic pathways in VTE based on published literature incorporating D‐dimer testing have been updated recently,13 the degree of adoption and use of diagnostic algorithms among trainees has been understudied.

Clinical trials14, 15 have confirmed the safety and efficacy of low molecular weight heparin (LMWH) in the treatment of pulmonary embolism (PE) in inpatients, but the degree of adoption of this therapy is unclear. The primary objective of our survey of was to assess the knowledge, attitudes, practices, and preferences of trainees and attendings who order and evaluate the results of diagnostic studies in the management of VTE. A secondary objective was to assess willingness to use LMWH to treat VTE in the inpatient setting among non‐ED respondents.

Methods

Results

Table 1 lists the characteristics of respondents. Medical attendings reported practicing in up to 5 different institutions, and residents reported rotating through up to 10 different institutions during their residency. Students reported rotating through up to 11 different institutions.

Discussion

Conclusions

Our survey identifies the use of evidence‐based strategies in the management of VTE among trainees, a perspective that has been lacking in other studies of physicians in practice.16, 24, 27 Substantial variability in attending practice identified in this survey may impede the adoption of a structured approach to the diagnosis of VTE among trainees, and this survey raises major concerns about mechanisms of diagnosis of VTE. Caprini et al.29 believe that physician knowledge, attitudes, and beliefs are partially responsible for the gap between actual practice and international guidelines.27 The results of our survey extend this suggestion to trainees and imply that supervisor attitudes may negatively influence trainee practices. Development of written protocols or standardized pathway order sets based on published evidence‐based guidelines13 in the management of VTE could improve the use of structured pretest probability determination and use of evidence‐based strategies among trainees. Finally, comparisons of outcomes using algorithms and usual practice could provide valuable, clinically important data that could inform clinical practice.

Pretest probability assessment is an important first step in the diagnosis of venous thromboembolism (VTE) and models incorporating Wells criteria1 can be used accurately in emergency department (ED) and inpatient settings.2 Gestalt has the disadvantage of poor interobserver reliability,3 and use of clinical prediction rules has been advocated instead.4 In academic institutions, trainees frequently first evaluate patients with suspected VTE, and although gestalt improves with degree of experience, the performance of gestalt in 1 study5 was better for attendings than interns or residents (for whom it was equivalent), suggesting that structured pretest probability assessment may be more important for trainees.

From an imaging perspective, multidetector computed tomography (CT),6 is more accurate than ventilation perfusion (VP) scanning7, 8 in diagnosing VTE in any setting, including the critically ill.9, 10 Lower extremity CT venography (LECTV) has comparable sensitivity to contrast venography and sonography,11 and in combination with computed tomographic pulmonary angiography (CTPA) is important when imaging results are discordant with pretest probability.12 Guidelines for diagnostic pathways in VTE based on published literature incorporating D‐dimer testing have been updated recently,13 the degree of adoption and use of diagnostic algorithms among trainees has been understudied.

Clinical trials14, 15 have confirmed the safety and efficacy of low molecular weight heparin (LMWH) in the treatment of pulmonary embolism (PE) in inpatients, but the degree of adoption of this therapy is unclear. The primary objective of our survey of was to assess the knowledge, attitudes, practices, and preferences of trainees and attendings who order and evaluate the results of diagnostic studies in the management of VTE. A secondary objective was to assess willingness to use LMWH to treat VTE in the inpatient setting among non‐ED respondents.

Methods

Results

Table 1 lists the characteristics of respondents. Medical attendings reported practicing in up to 5 different institutions, and residents reported rotating through up to 10 different institutions during their residency. Students reported rotating through up to 11 different institutions.

Discussion

Conclusions

Our survey identifies the use of evidence‐based strategies in the management of VTE among trainees, a perspective that has been lacking in other studies of physicians in practice.16, 24, 27 Substantial variability in attending practice identified in this survey may impede the adoption of a structured approach to the diagnosis of VTE among trainees, and this survey raises major concerns about mechanisms of diagnosis of VTE. Caprini et al.29 believe that physician knowledge, attitudes, and beliefs are partially responsible for the gap between actual practice and international guidelines.27 The results of our survey extend this suggestion to trainees and imply that supervisor attitudes may negatively influence trainee practices. Development of written protocols or standardized pathway order sets based on published evidence‐based guidelines13 in the management of VTE could improve the use of structured pretest probability determination and use of evidence‐based strategies among trainees. Finally, comparisons of outcomes using algorithms and usual practice could provide valuable, clinically important data that could inform clinical practice.

The term stroke is defined by the World Health Organization as rapidly developed clinical signs of focal (or global) disturbance of cerebral function lasting more than 24 hours (unless interrupted by surgery or death), with no apparent cause other than a vascular origin; it includes patients presenting clinical signs and symptoms suggestive of subarachnoid hemorrhage (SAH), intracerebral hemorrhage, or cerebral ischemic necrosis.1 Stroke is 1 of the leading causes of death and the number 1 cause of long‐term disability in the United States, with over 700,000 strokes and over 150,000 stroke deaths each year.2

Given the projections of 30,000 hospitalists nationally by 2010 (http://www.hospitalmedicine.org) and only 12,000 neurologists,3 coupled with an aging population, it is important now that the practicing hospitalist is facile in the treatment of patients with cerebrovascular diseaseand it is likely to become progressively more important over time.

Case Presentation

A 76‐year‐old right‐handed male with a history of hyperlipidemia and myocardial infarction was found at 7 _AM with right‐sided paralysis and poor responsiveness on the morning of admission. He seemed to prefer looking to the left and to understand what was being said to him, but had great difficulty speaking. When he went to bed at 9 _PM, he was at his neurological baseline. Upon finding him that morning, his wife called 911.

With increased knowledge regarding the pathophysiology of stroke, it has become clear that timeliness is of utmost importance (time is brain) and that acute stroke should be regarded as an acute medical/neurological emergency.

This article reviews the approach in evaluating an acute stroke patient, management strategies, and treatment options. Where not otherwise referenced, data to support our comments come from the recently updated and exhaustive American Heart Association (AHA)/American Stroke Association (ASA) Guidelines for the Early Management of Adults With Ischemic Stroke and will be referred to herein as the Guidelines.4 Harborview Medical Center in Seattle is a Joint Commissioncertified Primary Stroke Center and the home hospital of 2 of the authors (C.L.E., D.L.T.); it is referred to herein as Harborview.

Emergency Room Care (see Acute Stroke Algorithm, Figure 1)

The First 15 Minutes

After assuring stable airway, breathing, and circulation, immediate (STAT) blood draws should be performed, including full complete blood count (CBC) with platelets, international normalized ratio/prothrombin time/partial thromboplastin time (INR/PT/PTT), full electrolytes, and glucose (finger‐stick blood glucose also recommended). Glasgow Coma Scale (GCS) score and NIH Stroke Scale (NIHSS) score should be established via a focused history and physical exam. The GCS is most appropriate for patients with a significantly depressed level of consciousness, while the NIHSS can be scored for any stroke patient (1‐page version of NIHSS used at Harborview is shown in Figure 2). By quantifying stroke severity, the NIHSS score helps both to facilitate communication about neurologic deficit as well as serve as a documented baseline in case of subsequent clinical change. Emergency department (ED) physicians, hospitalists, neurologists, and nursing staff regularly caring for acute stroke patients would be well‐served by obtaining certification in the NIHSS (available free online at http://www.nihstrokescale.org). Two large‐bore intravenous lines (IVs) should be placed and a computed tomography (CT) scanner should be cleared (if not already done). The pharmacy should be alerted to the possible need for tissue plasminogen activator (tPA) if the patient presents within the 3‐hour window.

Figure 1

Figure 2

Our case patient's initial NIHSS score was 15, with points given for drowsiness, inability to answer questions, partial facial palsy, no movement in right arm or leg, mild‐moderate aphasia, and mild‐moderate dysarthria (Figure 2).

Differential Diagnosis

Many acute conditions can mimic stroke, and 1 of the goals of the initial emergency room (ER) evaluation is to rule out such stroke mimics. A report of 411 initial ER stroke diagnoses identified 19% as stroke mimics; the most common mimic diagnoses were seizure, systemic infection, brain tumor, and toxic‐metabolic.5 The same study identified decreased level of alertness as associated with a final mimic diagnosis and history of angina as associated with a final diagnosis of stroke. Another study looked at 350 presentations with an initial stroke diagnosis and found 31% stroke mimics; similarly, the main alternative diagnoses were seizure, sepsis, toxic‐metabolic, space‐occupying lesion, and syncope/presyncope.6 Findings associated with a mimic diagnosis included no cognitive impairment and abnormal findings in any other system, while findings associated with a stroke diagnosis were a definite history of focal neurological symptoms, NIHSS score, stroke type classification possible, an exact onset that could be determined, and abnormal vascular findings on imaging.6

Initial Imaging

The patient should receive a STAT noncontrast head CT to evaluate for the presence or absence of blood. At this time, magnetic resonance imaging (MRI) is not essential to confirm the diagnosis of ischemic stroke, as diagnosis is based on clinical suspicion. MRI is more sensitive at imaging acute ischemia (on diffusion‐weighted sequences) and recently has been shown to be equally sensitive in identifying acute blood (previously thought to be a relative advantage of CT).7, 8 Practical and pervasive barriers to emergent MRI include study duration, significant patient cooperation, and that few hospitals are currently set up to perform such rapid MRIS. The Guidelines specifically state that In most instances, CT will provide the information to make decisions about emergency management (p. 1668),4 that vascular imaging should not delay treatment of patients whose symptoms started <3 hours ago and who have acute ischemic stroke, and that emergency treatment of stroke should not be delayed in order to obtain multimodal imaging studies (p. 1669).4

Our case patient's initial imaging, a noncontrast head CT (Supporting Figures 1 and 2), showed subtle clues consistent with the diagnosis of acute ischemic stroke. These include a hyperdense middle cerebral artery (MCA) sign (presumably representing thrombus), possible obscuration of the basal ganglia, and, importantly, no acute intraparenchymal (IPH), SAH, or subdural hemorrhage.

Acute Treatments

After the patient's head CT is completed, the next steps are dependent upon what was seen on the scan and the time from symptom onset.

Blood on the CT Scan

If the initial brain imaging reveals IPH or SAH, further diagnostic testing and early treatments are quite different than for ischemic stroke. New guidelines are available for IPH management,9 and there have been recent review articles of care for SAH.1012 At the authors' institutions, early care of such patients always involves aggressive reversal of any antithrombotic medications the patient was taking prior to presentation. Our approach to warfarin reversal includes vitamin K and fresh frozen plasma (FFP) to achieve an INR 1.4; others have used prothrombin complex concentrate (PCC).13 Blood pressure (BP) treatment goals are generally more aggressive than for ischemic stroke, while supportive care to avoid aspiration, hyperglycemia, fever, and venous thrombosis (here initially with sequential compression devices alone) are similar. Early estimation of prognosis for these patients with IPH and SAH and discussions with families about continued aggressive care are of utmost importance, and should involve providers with sufficient expertise. Care should be taken to avoid overly pessimistic early prognostication, as early do not resuscitate (DNR) decisions in intercranial hemorrhage (ICH) can become a self‐fulfilling prophecy.1416 If the decision is to continue aggressive and supportive care, or if an appropriately expert consultation is not available at the presentation hospital, IPH and SAH patients should be considered for transfer to a hospital with the appropriate resources (including emergency access to neurosurgeons) or be evaluated by such an expert by telemedicine if available.

No Blood on the CT Scan, Results Back in <3 Hours From Symptom Onset

If such a patient is not rapidly resolving their symptoms, and the diagnosis continues to remain clear, inclusion/exclusion criteria for IV tPA should be reviewed (Table 1). Consent should be obtained much like any other procedure with significant risk. As many consider tPA to be standard of care, it is reasonable to proceed in cases of unobtainable consent as one would with any other emergent therapy. This situation is a topic of ongoing debate.17, 18 The Guidelines state that although written consent is not necessary before administration of recombinant tPA (rtPA) for treatment of stroke, a full discussion of the potential risks and benefits of treatment with rtPA with the family and the patient if possible is recommended (p. 1676).4 After tPA is given in the ER, the patient should be admitted to an intensive care unit (ICU) setting for 24 hours for careful monitoring of BP, avoidance of invasive procedures, and no use of antithrombotic medications during that period of time.

Table 1.IV tPA Inclusion and Exclusion Criteria

	Comments (from the authors)
NOTE: From the Guidelines, page 1676.4 * From the Guidelines, page 1671.4 Abbreviations: aPTT, activated plasma thromboplastin time; CT, computed tomography; DVT, deep vein thrombosis; ER, emergency room; INR, international normalized ratio; IV, intravenous; LDL, low‐density lipoprotein; NIHSS, National Institutes of Health Stroke Scale; NINDS, National Institute of Neurological Disorders and Stroke; PO, by mouth; tPA, tissue plasminogen activator.
Inclusion criteria
Diagnosis of ischemic stroke causing measurable neurological deficit	Usually NIHSS > 4
Neurological signs should not be clearing spontaneously	Such a patient may do well without tPA, but there is debate82
Neurological signs should not be minor and isolated.
Onset of symptoms >3 hours before beginning treatment
Patient or family members understand the potential risks and benefits from treatment	Debated, as tPA considered standard of care by many
Cautionary criteria
Caution should be exercised in treating a patient with major deficits	Higher risk of hemorrhage, but still may benefit from treatment
Exclusion criteria
Symptoms of stroke should not be suggestive of subarachnoid hemorrhage
No head trauma or prior stroke in previous 3 months
No myocardial infarction in the previous 3 months
No gastrointestinal or urinary tract hemorrhage in previous 21 days
No major surgery in the previous 14 days
No arterial puncture at a noncompressible site in the previous 7 days
No history of previous intracranial hemorrhage
Blood pressure not elevated (systolic >185 mm Hg or diastolic 110 mm Hg)	Okay to bring down with labetolol, nitropaste, or nicardipine*
No evidence of active bleeding or acute trauma (fracture) on examination
Not taking an oral anticoagulant or, if anticoagulant being taken, INR 1.7
If receiving heparin in previous 48 hours, aPTT must be in normal range
Platelet count <100,000 mm3
Blood glucose concentration <50 mg/dL (2.7 mmol/L)
Seizure with postictal residual neurological impairments	Not absolute if treating physician feels stroke also present, or if confirmed by imaging
CT does not show a multilobar infarction (hypodensity >1/3 cerebral hemisphere)	Not strictly evidence based, in NINDS trial this finding did not preclude benefit of tPA

Based mainly on the results of the National Institute of Neurological Disorders and Stroke (NINDS) tPA trial,19 and recently supported by a large Phase IV observational study from the European Union,20 IV tPA for acute ischemic stroke is approved for use in many countries and is endorsed for the treatment of carefully selected ischemic stroke patients in a number of practice guidelines.4 Despite this, the emergency medicine community has been less enthusiastic about the use of IV tPA.21, 22 Although the risk of hemorrhagic complications is greater in certain subgroups of patients (ie, the most severe strokes, significant early CT changes, older age), there is no definitive evidence to suggest that these groups do not still benefit from the treatment.23 It is also clear that if patients are not carefully selected, meeting strict inclusion and exclusion criteria, the rate of complications is increased.24 Thus, as summarized in a practice statement of the American College of Emergency Physicians, There is insufficient evidence at this time to endorse the use of intravenous tPA in clinical practice when systems are not in place to ensure that the inclusion/exclusion criteria established by the NINDS guidelines for tPA use in acute stroke are followed.21 When counseling patients and their families about the benefits and risks of IV tPA, one should keep in mind that the NINDS trial demonstrated increased odds of excellent outcomes despite a significant 10‐fold increase in the risk of symptomatic intracranial hemorrhage (6.4% vs. 0.6%), and did not alter 30‐day mortality. The largest Phase IV cohort study of IV tPA treatment, Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS‐MOST) was mandated by the European Union upon approval of the medication for use in acute ischemic stroke.20 The results in 6483 patients showed that tPA, when used in strict accordance with published inclusion and exclusion criteria, could perform as well as it did in randomized trials.

The recently published European Cooperative Acute Stroke Study3 (ECASS‐3) trial demonstrated that IV tPA has efficacy with adequate safety up to 4.5 hours after the onset of symptoms. A total of 821 patients were enrolled and 375 received tPA. Exclusion criteria included diabetes being treated with medication with a history of prior stroke, an NIHSS score >25, or treatment with warfarin. The rates of hemorrhage (27.0% vs. 17.6%, P = 0.001) were in line with those of the SITS‐MOST study patients who were treated within the 3‐hour time window. There was no significant difference in mortality (7.7% tPA vs. 8.4% placebo). This study is relatively new; therefore, the data have not been reviewed by guideline committees.25

No Blood on the CT Scan, Results Back in >3 Hours, but 8 Hours, From Symptom Onset

Unfortunately as with our patient, most people do not present to an ER in a timely fashion. Nonetheless, there may be other treatments and interventions possible. If the patient arrives <8 hours from onset of symptoms, intraarterial (IA) interventions are a possibility. In such a case, a CT angiogram (CTA) of the neck from the arch of the aorta to the circle of Willis is recommended (barring any contraindications such as renal failure or iodine allergy). The rationale behind this study is that other treatment options, such as IA tPA or mechanical thrombectomy may be considered if a large arterial occlusion is identified. CTA is preferred over magnetic resonance angiography (MRA) due to the same time and patient cooperation issues mentioned above, though some expert centers may be set up to perform MRI and MRA rapidly in the acute setting. CTA or MRA is of great value early on in the emergent assessment of ischemic stroke patients, as it allows detailed evaluation of the cerebral vasculature; this knowledge helps define the pathophysiology of the ongoing stroke (eg, is there a larger artery occlusion?) and can help inform the approach to subsequent therapies.

The Guidelines (p. 1678)4 recommend IA thrombolysis as a treatment option if it can be started within 6 hours, based on results from the Prolyse in Acute Cerebral Thromboembolism (PROACT) II trial. This study involved angiography with identification of the occluded vessel (the proximal MCA‐M1 in this study) and administration of recombinant pro‐urokinase to the clot with functional outcome as the primary endpoint.26 At 3 months, patients who received the IA thrombolytic had a 40% chance of slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance or better (ie, a modified Rankin Scale score of 2) vs. 25% of those not receiving the IA thrombolytic. Pro‐urokinase is not available in the United States; therefore, many institutions substitute IA tPA. The Guidelines further state that IA thrombolysis can be considered for use in some patients with contraindications to IV tPA (eg, recent surgery), but should not be used instead of IV tPA in patients otherwise eligible (p. 1678).4

There are now two U.S. Food and Drug Administration (FDA)‐approved devices for mechanical cerebral vasculature thrombectomy for use up to 8 hours from symptom onset. The mechanical embolus removal in cerebral ischemia (MERCI) clot retrieval device was originally approved by the FDA in August 2004 for restoring blood flow in the neurovasculature by removing thrombus in patients experiencing ischemic stroke. Modified devices have been approved as recently as January 2007.27 The Penumbra System was FDA‐approved in December 2007 for revascularization of patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease.28 In both cases, the FDA approval was based on demonstration of safety in case series of patients treated with the devices.2931 No randomized trials have shown the use of these devices improves outcomes for stroke patients. The Guidelines state that Although the MERCI device is a reasonable intervention for extraction of IA thrombi in carefully selected patients, the panel also recognizes that the utility of the device in improving outcomes after stroke is unclear (p. 1684);4 this statement applies similarly to the Penumbra device.

More complex imaging techniques, including multimodal CT (CT, CTA, and CT perfusion) and MR (MRI with diffusion, MRA, and MR perfusion) are being used in some stroke centers to make decisions about acute ischemic stroke treatments.32, 33 The theory is that by using these techniques, one can determine the presence or absence of a mismatch, whereby the perfusion imaging suggests more tissue at risk of infarction than is seen as already abnormal on MR diffusion‐weighted images or compared to a clinical assessment. These mismatch patients are then seen as appropriate candidates for the more aggressive interventions (ie, late IV tPA or IA interventions).34 Unfortunately, the 2 largest randomized trials to look at this issue with respect to >3‐hour IV tPA both failed to show a benefit for patients selected in this manner.35, 36 Standardized definitions of mismatch are still needed, and larger randomized trials are needed before this approach can be suggested for routine care.3739

More complex interventions, available only at tertiary or comprehensive stroke centers, include a bridging approach in which IV tPA (at 2/3 standard dose) is followed by IA tPA, IV tPA with transcranial Doppler (TCD)‐enhanced thrombolysis or IA rescue thrombectomy when vascular imaging after IV tPA shows a persistent large artery occlusion. The Guidelines suggests that these more complex combinations of interventions to restore perfusion cannot be recommended outside the setting of clinical trials (p. 1685).4

No Blood on the CT Scan, Results Back in >8 Hours From Symptom Onset (or if Contraindications to Above Interventions)

This time frame takes the more aggressive interventions off the table. Per the Guidelines, 325 mg of aspirin is the default antiplatelet agent for use, and has been shown in 2 very large randomized trials to reduce early death and longer‐term disability vs. placebo after acute ischemic stroke.40, 41 Importantly, all patients who do not qualify for thrombolysis in the 0‐hour to 8‐hour time window should receive aspirin.

Although a number of small or pilot studies suggest a benefit of the addition of clopidogrel to aspirin for a period (13 months) immediately after ischemic stroke,4244 this more aggressive antiplatelet intervention is not an endorsed standard of care. As described below, the long‐term use of this antiplatelet combination has been consistently associated with a higher risk of hemorrhagic complications. There are no published data regarding the use of aspirin plus dipyridamole in the acute stroke setting. A number of randomized trials have now been performed that have consistently failed to show a benefit of heparin, or heparin‐like medications, for the routine treatment of acute ischemic stroke. Despite this, a number of exceptions exist, based more on tradition and theory than on evidence. These exceptions, for which an IV heparin drip will at times still be considered, include acute ischemic stroke due to dissection of the carotid or vertebral arteries, cardioembolic stroke with fresh clot seen on echocardiogram (ECHO), and a clinically progressive syndrome suggestive of basilar artery occlusion (see below).45, 46 Good evidence exists to specifically recommend the use of full‐dose heparin in the setting of cerebral venous sinus thrombosis.47

Basilar Artery Occlusion Syndromes

Basilar artery occlusion syndromes warrant special mention. These may involve patients who present with quadriparesis, altered mental status, vertigo, diplopia, and other brainstem signs. Conventional treatment of basilar artery occlusion has been associated with 40% mortality with 65% of survivors having severe disability.48 If suspected, an urgent CTA can usually confirm the diagnosis, and urge the clinician to expeditiously consider aggressive intervention. Only case series have been reported regarding basilar artery thrombosis and acute treatments. Based on these studies, it is generally agreed upon that patients who appear comatose or quadriplegic for more than 3 hours will likely have a very poor functional outcome regardless of treatment, and interventional treatment is withheld. If a basilar occlusion patient presents within the 3‐hour time window for IV tPA, they are thus treated, with follow‐up vascular imaging, and possible rescue IA mechanical thrombectomy if recanalization from the IV tPA does not occur. However, if the patient still has preserved neurologic function, or is waxing and waning, there is no clear time limit for IA interventions and they may be useful a day or more after presentation. For basilar occlusion patients with severe stenoses not responsive to lysis, or continuing to be symptomatic, angioplasty and stenting has also been used.46 Despite a lack of evidence, many stroke clinicians will use an IV heparin drip for treatment of acute basilar occlusive disease.

Malignant Middle Cerebral Artery (MCA) Infarction

Malignant MCA infarction is another specific clinical syndrome worthy of special consideration. It is most generally defined as a large infarction (1/2 or 2/3) of the MCA territory, somewhat depressed level of consciousness, and high stroke scale scores (ie, severe deficits) that goes on to severe cerebral edema, mass effect, and often herniation with death.49, 50 Associated patient characteristics include younger age, abnormal (incomplete) ipsilateral collateral circulation, and internal carotid artery occlusion.51 Maximal edema occurs 2 to 5 days from stroke onset and, despite best intensive therapy, has been associated with mortality rates of 70% to 80%.49, 50 A recent pooling of 3 small randomized trials of early decompressive hemicraniectomy and durotomy showed a 50% absolute risk reduction for mortality and a 23% absolute benefit in long‐term independence (modified Rankin scale 3).49 This treatment option should be strongly considered in carefully selected patients., Transfer to an appropriately equipped facility should be offered if not available at your hospital.

Returning to our case patient, upon arrival to the ED with symptoms of partial aphasia, right hemiplegia, and left gaze preference, there was a high suspicion for a left MCA stroke. Unfortunately, he was excluded from receiving IV tPA or any other interventions, as the last time he was known to be neurologically intact was the prior evening, which is taken to be the time of onset. Antiplatelet therapy was continued, and the patient was admitted for further workup.

The initial care of the patient with a cerebrovascular event is often quite complicated. Assimilation of a great deal of data must occur and decisions around therapy must be made in a timely fashion. In prior years there was little to offer in the way of therapy, which also meant there was little initial potential for iatrogenic complication. Both diagnostic and therapeutic options are evolving rapidly. We now have much to offer these patients both emergently and in areas of secondary prevention. In part 2 of this article, the patient's inpatient course and therapy will be reviewed.