To the Editor: I would like to add two points to the excellent review on starting insulin in patients with type 2 diabetes by Brateanu et al in the August 2015 issue.¹

First, in my practice, I review glucose patterns and recommend that mealtime insulin be started early after basal insulin is started and not simply wait for the next hemoglobin A_1c result. In my experience, basal insulin is often mindlessly up-titrated, month after month, to fix a high fasting glucose. During the first 2 to 3 weeks of basal insulin titration, I ask patients to test before breakfast, dinner, and bedtime, not just fasting. In so doing, I detect, in most patients, significant bedtime hyperglycemia arising from dinner, usually their largest meal. Then I prescribe dinnertime rapid-acting insulin to correct the bedtime hyperglycemia, and this in turn ameliorates the fasting hyperglycemia. Additional mealtime doses can be added if necessary.²

After all, why should we ignore hyperglycemia occurring at other times and focus only on fasting glucose? With blood glucose pattern review, we can detect those glucose elevations that need to be targeted regardless of when they occur. It has been repeatedly shown that up to almost 50% of patients will fail to reach a hemoglobin A_1c below 7%, even after months of up-titration of basal insulin.^3,4 Most patients will benefit by starting mealtime rapid-acting insulin early on.

And second, when adjusting mealtime rapid-acting injected insulin, there is no need to measure postprandial glucose in most patients with type 2 diabetes. A rigorous clinical trial⁵ showed that testing before the next meal or, in the case of dinner, before bedtime worked as well as or better than postprandial testing. By implementing the above steps, I think we all can provide better, more individualized therapy for our patients.

To the Editor: I would like to add two points to the excellent review on starting insulin in patients with type 2 diabetes by Brateanu et al in the August 2015 issue.¹

First, in my practice, I review glucose patterns and recommend that mealtime insulin be started early after basal insulin is started and not simply wait for the next hemoglobin A_1c result. In my experience, basal insulin is often mindlessly up-titrated, month after month, to fix a high fasting glucose. During the first 2 to 3 weeks of basal insulin titration, I ask patients to test before breakfast, dinner, and bedtime, not just fasting. In so doing, I detect, in most patients, significant bedtime hyperglycemia arising from dinner, usually their largest meal. Then I prescribe dinnertime rapid-acting insulin to correct the bedtime hyperglycemia, and this in turn ameliorates the fasting hyperglycemia. Additional mealtime doses can be added if necessary.²

After all, why should we ignore hyperglycemia occurring at other times and focus only on fasting glucose? With blood glucose pattern review, we can detect those glucose elevations that need to be targeted regardless of when they occur. It has been repeatedly shown that up to almost 50% of patients will fail to reach a hemoglobin A_1c below 7%, even after months of up-titration of basal insulin.^3,4 Most patients will benefit by starting mealtime rapid-acting insulin early on.

And second, when adjusting mealtime rapid-acting injected insulin, there is no need to measure postprandial glucose in most patients with type 2 diabetes. A rigorous clinical trial⁵ showed that testing before the next meal or, in the case of dinner, before bedtime worked as well as or better than postprandial testing. By implementing the above steps, I think we all can provide better, more individualized therapy for our patients.

To the Editor: I would like to add two points to the excellent review on starting insulin in patients with type 2 diabetes by Brateanu et al in the August 2015 issue.¹

First, in my practice, I review glucose patterns and recommend that mealtime insulin be started early after basal insulin is started and not simply wait for the next hemoglobin A_1c result. In my experience, basal insulin is often mindlessly up-titrated, month after month, to fix a high fasting glucose. During the first 2 to 3 weeks of basal insulin titration, I ask patients to test before breakfast, dinner, and bedtime, not just fasting. In so doing, I detect, in most patients, significant bedtime hyperglycemia arising from dinner, usually their largest meal. Then I prescribe dinnertime rapid-acting insulin to correct the bedtime hyperglycemia, and this in turn ameliorates the fasting hyperglycemia. Additional mealtime doses can be added if necessary.²

After all, why should we ignore hyperglycemia occurring at other times and focus only on fasting glucose? With blood glucose pattern review, we can detect those glucose elevations that need to be targeted regardless of when they occur. It has been repeatedly shown that up to almost 50% of patients will fail to reach a hemoglobin A_1c below 7%, even after months of up-titration of basal insulin.^3,4 Most patients will benefit by starting mealtime rapid-acting insulin early on.

And second, when adjusting mealtime rapid-acting injected insulin, there is no need to measure postprandial glucose in most patients with type 2 diabetes. A rigorous clinical trial⁵ showed that testing before the next meal or, in the case of dinner, before bedtime worked as well as or better than postprandial testing. By implementing the above steps, I think we all can provide better, more individualized therapy for our patients.

In Reply: We thank Dr. Weiss for his insightful comments and for the opportunity to clarify a number of points from our article.

We agree that controlling the fasting glucose should not take months. As mentioned in our article, adjusting the basal insulin dose should be done with 2 to 4 units every 2 to 3 days in order to reach the fasting glycemic goal. Applying this approach and systematically titrating the NPH, glargine, or detemir insulin will smoothly decrease the fasting glucose within 12 weeks, as described in the 24-week¹ and 52-week² treat-to-target trials in which basal insulin was added to the oral therapy in patients with type 2 diabetes.

When basal insulin is no longer sufficient to reach a target hemoglobin A_1c, a glucagon-like peptide-1 receptor agonist or prandial insulin can be used. The basal-bolus or twice-daily premixed insulin analogues can also be considered as the initial therapy, depending on the patient, disease, and drug characteristics.³ We agree that once a prandial insulin regimen is initiated, the dose titration can be done based on preprandial or postprandial blood glucose measurements, as shown in Table 2 in our article. However, adding the prandial insulin without first optimizing the basal therapy was considered a limitation of the Orals Plus Apidra and Lantus (OPAL) study,⁴ which investigated the addition of one prandial insulin injection to basal glargine insulin.⁵ As a consequence, the subsequent studies investigating the effects of initiating and titrating the preprandial rapid-acting insulin (as a single dose or using a stepwise approach) in patients inadequately controlled with once-daily basal insulin and oral antidiabetic drugs had run-in periods of 12 to 14 weeks, in order to optimize the basal insulin dosage and achieve target fasting blood glucose levels of 110 mg/dL or less. This approach had the additional benefit of achieving a target hemoglobin A_1c level of less than 7% in a significant number of patients (up to 37%),⁶ before starting the preprandial insulin.^6–8

Regardless of the regimen selected, titration of the insulin doses can only be achieved with understanding the pharmacodynamic characteristics of each type of insulin used.⁹

In Reply: We thank Dr. Weiss for his insightful comments and for the opportunity to clarify a number of points from our article.

We agree that controlling the fasting glucose should not take months. As mentioned in our article, adjusting the basal insulin dose should be done with 2 to 4 units every 2 to 3 days in order to reach the fasting glycemic goal. Applying this approach and systematically titrating the NPH, glargine, or detemir insulin will smoothly decrease the fasting glucose within 12 weeks, as described in the 24-week¹ and 52-week² treat-to-target trials in which basal insulin was added to the oral therapy in patients with type 2 diabetes.

When basal insulin is no longer sufficient to reach a target hemoglobin A_1c, a glucagon-like peptide-1 receptor agonist or prandial insulin can be used. The basal-bolus or twice-daily premixed insulin analogues can also be considered as the initial therapy, depending on the patient, disease, and drug characteristics.³ We agree that once a prandial insulin regimen is initiated, the dose titration can be done based on preprandial or postprandial blood glucose measurements, as shown in Table 2 in our article. However, adding the prandial insulin without first optimizing the basal therapy was considered a limitation of the Orals Plus Apidra and Lantus (OPAL) study,⁴ which investigated the addition of one prandial insulin injection to basal glargine insulin.⁵ As a consequence, the subsequent studies investigating the effects of initiating and titrating the preprandial rapid-acting insulin (as a single dose or using a stepwise approach) in patients inadequately controlled with once-daily basal insulin and oral antidiabetic drugs had run-in periods of 12 to 14 weeks, in order to optimize the basal insulin dosage and achieve target fasting blood glucose levels of 110 mg/dL or less. This approach had the additional benefit of achieving a target hemoglobin A_1c level of less than 7% in a significant number of patients (up to 37%),⁶ before starting the preprandial insulin.^6–8

Regardless of the regimen selected, titration of the insulin doses can only be achieved with understanding the pharmacodynamic characteristics of each type of insulin used.⁹

In Reply: We thank Dr. Weiss for his insightful comments and for the opportunity to clarify a number of points from our article.

We agree that controlling the fasting glucose should not take months. As mentioned in our article, adjusting the basal insulin dose should be done with 2 to 4 units every 2 to 3 days in order to reach the fasting glycemic goal. Applying this approach and systematically titrating the NPH, glargine, or detemir insulin will smoothly decrease the fasting glucose within 12 weeks, as described in the 24-week¹ and 52-week² treat-to-target trials in which basal insulin was added to the oral therapy in patients with type 2 diabetes.

When basal insulin is no longer sufficient to reach a target hemoglobin A_1c, a glucagon-like peptide-1 receptor agonist or prandial insulin can be used. The basal-bolus or twice-daily premixed insulin analogues can also be considered as the initial therapy, depending on the patient, disease, and drug characteristics.³ We agree that once a prandial insulin regimen is initiated, the dose titration can be done based on preprandial or postprandial blood glucose measurements, as shown in Table 2 in our article. However, adding the prandial insulin without first optimizing the basal therapy was considered a limitation of the Orals Plus Apidra and Lantus (OPAL) study,⁴ which investigated the addition of one prandial insulin injection to basal glargine insulin.⁵ As a consequence, the subsequent studies investigating the effects of initiating and titrating the preprandial rapid-acting insulin (as a single dose or using a stepwise approach) in patients inadequately controlled with once-daily basal insulin and oral antidiabetic drugs had run-in periods of 12 to 14 weeks, in order to optimize the basal insulin dosage and achieve target fasting blood glucose levels of 110 mg/dL or less. This approach had the additional benefit of achieving a target hemoglobin A_1c level of less than 7% in a significant number of patients (up to 37%),⁶ before starting the preprandial insulin.^6–8

Regardless of the regimen selected, titration of the insulin doses can only be achieved with understanding the pharmacodynamic characteristics of each type of insulin used.⁹

CASE › James A, age 68, presents to his family physician (FP) with anorexia, nausea, and vague upper abdominal pain that he’s had for 2 weeks. Mr. A has diabetes and hypertension, both of which are well controlled by medications. He also consumes more than 4 alcoholic beverages daily.

On examination, the FP notes icterus and tenderness in the right hypochondrium. Liver function testing reveals elevated liver enzyme levels: aspartate aminotransferase (AST), 864 IU/L (normal range: 10-40 IU/L); alanine aminotransferase (ALT), 1012 IU/L (normal range: 7-56 IU/L); serum bilirubin, 4.8 mg/dL (normal range: 0.3-1.9 mg/dL); and alkaline phosphatase (ALP), 200 IU/L (normal range: 44-147 IU/L). Mr. A’s coagulation profile is slightly abnormal. He is provisionally diagnosed with acute hepatitis. The FP sends blood samples to the lab to assess for viral markers, and starts symptomatic management.

If Mr. A were your patient, how would you proceed?

In the United States, drug-induced liver injury (DILI) is the most common cause of acute liver failure.^1,2 It can occur due to ingestion of any therapeutic drug, herbal product, or xenobiotic. Further complicating matters is the fact that it has an unpredictable and heterogeneous course, ranging from an asymptomatic rise in liver enzymes to acute liver failure. This article describes the risk factors, common causative agents, tools for early diagnosis, and effective management of DILI.

Two types of risk factors for DILI

Risk factors for DILI can be classified as drug-related (eg, dose, concomitant medications, polypharmacy) or host-related (eg, age, gender, alcohol intake, concomitant infections).^3-5

Drug-related factors. Hundreds of agents can lead to liver injury. In fact, the US National Library of Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases have created LiverTox (http://www.livertox.nih.gov/), an online database that provides detailed information on more than 600 such agents.⁶ Antibiotics are the most common cause of DILI, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, analgesics, antineoplastic drugs, and lipid-lowering agents.²

Among antibiotics, the specific medication most often responsible for DILI varies by geographical region. Amoxicillin/clavulanic acid is the most common causative antibiotic in the United States, whereas anti-tuberculosis agents such as isoniazid, rifampin, and pyrazinamide are the most common causative drugs in developing countries such as India, where the prevalence of tuberculosis is still high.^7,8 Herbal and dietary supplements are emerging as an important cause of DILI.^5,9,10

The use of multiple drugs further increases the risk of developing DILI.¹⁰ Drugs with a recommended daily dose of <50 mg are rarely associated with DILI.¹¹

Host-related factors. Vulnerability to DILI is influenced by a patient’s age and sex.^3,12 Very young and very old patients have an increased risk of developing DILI, and a patient’s age may make him or her particularly susceptible to the effects of certain medications.^3,12,13 For example, children are more susceptible to DILI as a result of taking valproate or aspirin, whereas older patients are more likely to experience DILI brought on by amoxicillin/clavulanic acid.¹³ The pattern of liver injury also varies by age. Younger patients present most commonly with a hepatocellular pattern of injury, whereas older patients mostly present with a cholestatic pattern of liver injury.³

Some studies have found that women have a greater risk of developing DILI than men.¹³ The presence of chronic liver diseases, alcoholism, and nonalcoholic fatty liver disease (NAFLD) increase the risk of developing DILI.¹⁴ Diabetes is an independent risk factor for DILI.³

Clinical presentation of DILI varies widely

Some degree of liver injury may occur in any patient who ingests a drug that is metabolized in the liver. The clinical presentation of a patient with DILI can vary from an asymptomatic rise in liver enzymes to acute liver failure. Unexplained transaminitis should raise the possibility of DILI, especially when the patient has started a new drug in the preceding 3 months. However, in most patients, an asymptomatic rise in liver enzymes is due to hepatic adaptation or tolerance. In such cases, liver enzyme levels tend to normalize even if the patient continues to take the drug in the same dose.¹⁵

Apart from nonspecific symptoms such as anorexia, nausea, and vomiting, a patient with DILI may exhibit right upper quadrant pain, skin rash, or itching. A patient with severe DILI might exhibit jaundice, ascites, or encephalopathy.¹⁵

A stepwise approach to evaluation

DILI is a diagnosis of exclusion.¹⁶ Guidelines from the American College of Gastroenterology (ACG) recommend a stepwise approach to evaluating a patient you suspect may have DILI (TABLE).¹⁶ First, take a detailed history regarding the onset of symptoms, time latency, and use of hepatotoxic and other drugs (dosage and duration of use). Also ask the patient about his or her use of herbal products, dietary supplements, and alcohol. Check the patient’s history for the presence of other liver diseases such as NAFLD.

Next, make sure initial laboratory testing includes liver function tests and an eosinophil count. In order to classify the pattern of liver injury as hepatocellular, cholestatic, or mixed, you’ll need to calculate the patient’s R value (ALGORITHM^16-18). This value is calculated by dividing the patient’s ALT level by the ALP, using the upper limit of the normal range (ULN) as follows: R = (ALT value ÷ ALT ULN) ÷ (ALP value ÷ ALP ULN).¹⁷ A hepatocellular pattern of liver injury is indicated by an R value >5, a cholestatic pattern is an R value <2, and a mixed pattern is suggested by an R value between 2 and 5.¹⁷

Antibiotics are the most common cause of drug-induced liver injury, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, and analgesics.

Quite often, the pattern of liver damage is characteristic of a particular drug or drug class. For example, DILI induced by amoxicillin/clavulanic acid typically will exhibit a cholestatic injury pattern, whereas DILI resulting from a nonsteroidal anti-inflammatory drug typically is associated with a hepatocellular injury pattern.¹⁶

Rule out other causes. Further investigations should be directed at ruling out other possible causes of liver injury. If a patient has a hepatocellular pattern of liver injury, order serological tests to rule out acute viral hepatitis (hepatitis A, B, C, and E). Such patients should also be evaluated for autoimmune hepatitis, Budd-Chiari syndrome, Wilson’s disease, and ischemic hepatitis.¹⁶ In patients with a predominant cholestatic pattern, imaging studies and other serological tests should be ordered to rule out pancreato-biliary diseases.

Once DILI is confirmed, identify offending agent, grade severity

Which medication is responsible for DILI is determined by the physician based on his or her clinical experience and judgment. Guiding points are improvement of liver function tests after stopping the suspected drug (more on that in a bit), exclusion of other possible causes of liver injury, and the results of liver biopsy. (See “Time for a biopsy?”¹⁶)

DILI severity can be graded as mild (1+) to fatal (5+).¹⁹ Mild forms of DILI are associated with increased levels of liver enzymes (AST, ALT, or ALP) without raised serum bilirubin or clinical jaundice, whereas moderately severe DILI is associated with clinical jaundice or hyperbilirubinemia (bilirubin >2 mg/dL).¹⁹ Severe forms of DILI are associated with features of hepatic failure, such as ascites, encephalopathy, and an elevated international normalized ratio (>1.5), in addition to hyperbilirubinemia or jaundice.

CASE › Mr. A’s lab results are negative for viral markers. On further questioning, he reveals that he had recovered from a sore throat 3 weeks earlier, for which he had been prescribed an unknown dose of amoxicillin/clavulanic acid. A review of Mr. A’s drug history finds that he is taking metformin, pioglitazone, telmisartan, and atorvastatin for his chronic conditions. The FP suspects DILI , and refers Mr. A to a liver specialist for further investigation.

For many patients, stopping the offending drug will be sufficient 

The first step in managing DILI is to stop the medication suspected of causing the liver injury.²⁰ Discontinuing the suspected medication may not always be necessary in patients who have only slightly elevated liver enzymes, but should be strongly considered for a patient who has a considerable increase in liver enzymes levels (ie, an AST, ALT, or serum bilirubin level more than 3 times the ULN or an ALP more than 1.5 times the ULN at any time after initiating a new drug).¹⁸ Certain drugs, such as those used to treat tuberculosis, are associated with hepatic adaptation, in which there is spontaneous resolution of the increased liver enzymes level even while the drug is continued in the same dose.

Diabetes is an independent risk factor for drug-induced liver injury.

In patients with mild to moderate DILI, stopping the offending drug typically results in normalization of liver enzyme levels.²⁰ Management of patients with moderate to severe DILI is mainly supportive; however, a patient with acute liver failure will require intensive care support.^21,22 Consider hospital admission for patients who exhibit severe symptoms, such as intractable vomiting or severe dehydration, those who experience bleeding due to coagulation failure, and those who develop hepatic encephalopathy.²¹

When more aggressive steps are needed

N-acetylcysteine (NAC) should be considered for all patients with DILI who present with acute liver failure.^12,23-25 NAC can be administered either orally or intravenously. The following 3 regimens have been well studied for patients with acetaminophen-induced liver injury:²⁶
• Oral 72-hour regimen: Loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours up to 72 hours
• Intravenous 72-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 418.75 mg/kg over 67 hours
• Intravenous 21-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours.

Of these regimens, the 72-hour IV regimen has been found to be more effective than the 21-hour regimen for patients with acetaminophen-induced liver toxicity.²⁶ A study of NAC administered as continuous infusion for 72 hours in patients with acute liver failure found that the transplant-free survival rate was 40% for NAC in comparison with 27% for placebo.²⁶

L-carnitine can be used to treat valproate-induced hepatotoxicity. In a case-control study of 92 patients with severe, symptomatic, valproate-induced hepatotoxicity, nearly half of 42 patients treated with L-carnitine survived, but only 10% of 50 patients treated solely with aggressive supportive care survived.²⁷ Greater benefit has been found for IV vs oral L-carnitine.^27,28

Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg, may be helpful for DILI patients with a cholestatic pattern of liver injury.

Other therapies. Steroids have no defined role in management of DILI except in autoimmune-type DILI. Other drugs, such as silymarin and antioxidants, have been used to treat other forms of hepatic toxicities and might be beneficial for patients with DILI.^29,30

Liver transplantation may be necessary to prevent death due to acute liver failure in patients with severe DILI. Various criteria, including Kings College criteria,³¹ can be used to select which patients may best benefit from liver transplantation.

For most patients, hospitalization will not be necessary

Generally, patients with DILI have a good prognosis.^20,30 About 70% of patients with DILI do not require hospitalization, and approximately 90% recover without reaching the threshold of acute liver failure. However, patients with acute liver failure have a poor prognosis; 40% will require liver transplantation.^16,20

A patient with a hepatocellular pattern of liver injury should receive serological tests to rule out acute viral hepatitis.

Traditionally, patients with a cholestatic pattern of liver injury have been considered to have a better prognosis than those with a hepatocellular pattern of liver injury. Patients whose DILI is the result of a hypersensitivity reaction to a drug also have a good prognosis. This may be because features such as skin rash prompt early diagnosis and discontinuation of the offending drugs.⁷

CASE › A liver specialist evaluates Mr. A and concludes that his liver injury was caused by his long-term heavy alcohol consumption and exacerbated by the amoxicillin/clavulanic acid he had recently been prescribed. After 2 days, Mr. A develops drowsiness and is admitted to the hospital for further management. He is managed in the intensive care unit under supervision of a gastroenterologist. A NAC infusion is started at a loading dose of 150 mg/kg to manage acute liver failure. Unfortunately, however, Mr. A succumbs to his illness.

CORRESPONDENCE
Piyush Ranjan, MD, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029; drpiyushaiims@gmail.com.

CASE › James A, age 68, presents to his family physician (FP) with anorexia, nausea, and vague upper abdominal pain that he’s had for 2 weeks. Mr. A has diabetes and hypertension, both of which are well controlled by medications. He also consumes more than 4 alcoholic beverages daily.

On examination, the FP notes icterus and tenderness in the right hypochondrium. Liver function testing reveals elevated liver enzyme levels: aspartate aminotransferase (AST), 864 IU/L (normal range: 10-40 IU/L); alanine aminotransferase (ALT), 1012 IU/L (normal range: 7-56 IU/L); serum bilirubin, 4.8 mg/dL (normal range: 0.3-1.9 mg/dL); and alkaline phosphatase (ALP), 200 IU/L (normal range: 44-147 IU/L). Mr. A’s coagulation profile is slightly abnormal. He is provisionally diagnosed with acute hepatitis. The FP sends blood samples to the lab to assess for viral markers, and starts symptomatic management.

If Mr. A were your patient, how would you proceed?

In the United States, drug-induced liver injury (DILI) is the most common cause of acute liver failure.^1,2 It can occur due to ingestion of any therapeutic drug, herbal product, or xenobiotic. Further complicating matters is the fact that it has an unpredictable and heterogeneous course, ranging from an asymptomatic rise in liver enzymes to acute liver failure. This article describes the risk factors, common causative agents, tools for early diagnosis, and effective management of DILI.

Two types of risk factors for DILI

Risk factors for DILI can be classified as drug-related (eg, dose, concomitant medications, polypharmacy) or host-related (eg, age, gender, alcohol intake, concomitant infections).^3-5

Drug-related factors. Hundreds of agents can lead to liver injury. In fact, the US National Library of Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases have created LiverTox (http://www.livertox.nih.gov/), an online database that provides detailed information on more than 600 such agents.⁶ Antibiotics are the most common cause of DILI, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, analgesics, antineoplastic drugs, and lipid-lowering agents.²

Among antibiotics, the specific medication most often responsible for DILI varies by geographical region. Amoxicillin/clavulanic acid is the most common causative antibiotic in the United States, whereas anti-tuberculosis agents such as isoniazid, rifampin, and pyrazinamide are the most common causative drugs in developing countries such as India, where the prevalence of tuberculosis is still high.^7,8 Herbal and dietary supplements are emerging as an important cause of DILI.^5,9,10

The use of multiple drugs further increases the risk of developing DILI.¹⁰ Drugs with a recommended daily dose of <50 mg are rarely associated with DILI.¹¹

Host-related factors. Vulnerability to DILI is influenced by a patient’s age and sex.^3,12 Very young and very old patients have an increased risk of developing DILI, and a patient’s age may make him or her particularly susceptible to the effects of certain medications.^3,12,13 For example, children are more susceptible to DILI as a result of taking valproate or aspirin, whereas older patients are more likely to experience DILI brought on by amoxicillin/clavulanic acid.¹³ The pattern of liver injury also varies by age. Younger patients present most commonly with a hepatocellular pattern of injury, whereas older patients mostly present with a cholestatic pattern of liver injury.³

Some studies have found that women have a greater risk of developing DILI than men.¹³ The presence of chronic liver diseases, alcoholism, and nonalcoholic fatty liver disease (NAFLD) increase the risk of developing DILI.¹⁴ Diabetes is an independent risk factor for DILI.³

Clinical presentation of DILI varies widely

Some degree of liver injury may occur in any patient who ingests a drug that is metabolized in the liver. The clinical presentation of a patient with DILI can vary from an asymptomatic rise in liver enzymes to acute liver failure. Unexplained transaminitis should raise the possibility of DILI, especially when the patient has started a new drug in the preceding 3 months. However, in most patients, an asymptomatic rise in liver enzymes is due to hepatic adaptation or tolerance. In such cases, liver enzyme levels tend to normalize even if the patient continues to take the drug in the same dose.¹⁵

Apart from nonspecific symptoms such as anorexia, nausea, and vomiting, a patient with DILI may exhibit right upper quadrant pain, skin rash, or itching. A patient with severe DILI might exhibit jaundice, ascites, or encephalopathy.¹⁵

A stepwise approach to evaluation

DILI is a diagnosis of exclusion.¹⁶ Guidelines from the American College of Gastroenterology (ACG) recommend a stepwise approach to evaluating a patient you suspect may have DILI (TABLE).¹⁶ First, take a detailed history regarding the onset of symptoms, time latency, and use of hepatotoxic and other drugs (dosage and duration of use). Also ask the patient about his or her use of herbal products, dietary supplements, and alcohol. Check the patient’s history for the presence of other liver diseases such as NAFLD.

Next, make sure initial laboratory testing includes liver function tests and an eosinophil count. In order to classify the pattern of liver injury as hepatocellular, cholestatic, or mixed, you’ll need to calculate the patient’s R value (ALGORITHM^16-18). This value is calculated by dividing the patient’s ALT level by the ALP, using the upper limit of the normal range (ULN) as follows: R = (ALT value ÷ ALT ULN) ÷ (ALP value ÷ ALP ULN).¹⁷ A hepatocellular pattern of liver injury is indicated by an R value >5, a cholestatic pattern is an R value <2, and a mixed pattern is suggested by an R value between 2 and 5.¹⁷

Antibiotics are the most common cause of drug-induced liver injury, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, and analgesics.

Quite often, the pattern of liver damage is characteristic of a particular drug or drug class. For example, DILI induced by amoxicillin/clavulanic acid typically will exhibit a cholestatic injury pattern, whereas DILI resulting from a nonsteroidal anti-inflammatory drug typically is associated with a hepatocellular injury pattern.¹⁶

Rule out other causes. Further investigations should be directed at ruling out other possible causes of liver injury. If a patient has a hepatocellular pattern of liver injury, order serological tests to rule out acute viral hepatitis (hepatitis A, B, C, and E). Such patients should also be evaluated for autoimmune hepatitis, Budd-Chiari syndrome, Wilson’s disease, and ischemic hepatitis.¹⁶ In patients with a predominant cholestatic pattern, imaging studies and other serological tests should be ordered to rule out pancreato-biliary diseases.

Once DILI is confirmed, identify offending agent, grade severity

Which medication is responsible for DILI is determined by the physician based on his or her clinical experience and judgment. Guiding points are improvement of liver function tests after stopping the suspected drug (more on that in a bit), exclusion of other possible causes of liver injury, and the results of liver biopsy. (See “Time for a biopsy?”¹⁶)

DILI severity can be graded as mild (1+) to fatal (5+).¹⁹ Mild forms of DILI are associated with increased levels of liver enzymes (AST, ALT, or ALP) without raised serum bilirubin or clinical jaundice, whereas moderately severe DILI is associated with clinical jaundice or hyperbilirubinemia (bilirubin >2 mg/dL).¹⁹ Severe forms of DILI are associated with features of hepatic failure, such as ascites, encephalopathy, and an elevated international normalized ratio (>1.5), in addition to hyperbilirubinemia or jaundice.

CASE › Mr. A’s lab results are negative for viral markers. On further questioning, he reveals that he had recovered from a sore throat 3 weeks earlier, for which he had been prescribed an unknown dose of amoxicillin/clavulanic acid. A review of Mr. A’s drug history finds that he is taking metformin, pioglitazone, telmisartan, and atorvastatin for his chronic conditions. The FP suspects DILI , and refers Mr. A to a liver specialist for further investigation.

For many patients, stopping the offending drug will be sufficient 

The first step in managing DILI is to stop the medication suspected of causing the liver injury.²⁰ Discontinuing the suspected medication may not always be necessary in patients who have only slightly elevated liver enzymes, but should be strongly considered for a patient who has a considerable increase in liver enzymes levels (ie, an AST, ALT, or serum bilirubin level more than 3 times the ULN or an ALP more than 1.5 times the ULN at any time after initiating a new drug).¹⁸ Certain drugs, such as those used to treat tuberculosis, are associated with hepatic adaptation, in which there is spontaneous resolution of the increased liver enzymes level even while the drug is continued in the same dose.

Diabetes is an independent risk factor for drug-induced liver injury.

In patients with mild to moderate DILI, stopping the offending drug typically results in normalization of liver enzyme levels.²⁰ Management of patients with moderate to severe DILI is mainly supportive; however, a patient with acute liver failure will require intensive care support.^21,22 Consider hospital admission for patients who exhibit severe symptoms, such as intractable vomiting or severe dehydration, those who experience bleeding due to coagulation failure, and those who develop hepatic encephalopathy.²¹

When more aggressive steps are needed

N-acetylcysteine (NAC) should be considered for all patients with DILI who present with acute liver failure.^12,23-25 NAC can be administered either orally or intravenously. The following 3 regimens have been well studied for patients with acetaminophen-induced liver injury:²⁶
• Oral 72-hour regimen: Loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours up to 72 hours
• Intravenous 72-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 418.75 mg/kg over 67 hours
• Intravenous 21-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours.

Of these regimens, the 72-hour IV regimen has been found to be more effective than the 21-hour regimen for patients with acetaminophen-induced liver toxicity.²⁶ A study of NAC administered as continuous infusion for 72 hours in patients with acute liver failure found that the transplant-free survival rate was 40% for NAC in comparison with 27% for placebo.²⁶

L-carnitine can be used to treat valproate-induced hepatotoxicity. In a case-control study of 92 patients with severe, symptomatic, valproate-induced hepatotoxicity, nearly half of 42 patients treated with L-carnitine survived, but only 10% of 50 patients treated solely with aggressive supportive care survived.²⁷ Greater benefit has been found for IV vs oral L-carnitine.^27,28

Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg, may be helpful for DILI patients with a cholestatic pattern of liver injury.

Other therapies. Steroids have no defined role in management of DILI except in autoimmune-type DILI. Other drugs, such as silymarin and antioxidants, have been used to treat other forms of hepatic toxicities and might be beneficial for patients with DILI.^29,30

Liver transplantation may be necessary to prevent death due to acute liver failure in patients with severe DILI. Various criteria, including Kings College criteria,³¹ can be used to select which patients may best benefit from liver transplantation.

For most patients, hospitalization will not be necessary

Generally, patients with DILI have a good prognosis.^20,30 About 70% of patients with DILI do not require hospitalization, and approximately 90% recover without reaching the threshold of acute liver failure. However, patients with acute liver failure have a poor prognosis; 40% will require liver transplantation.^16,20

A patient with a hepatocellular pattern of liver injury should receive serological tests to rule out acute viral hepatitis.

Traditionally, patients with a cholestatic pattern of liver injury have been considered to have a better prognosis than those with a hepatocellular pattern of liver injury. Patients whose DILI is the result of a hypersensitivity reaction to a drug also have a good prognosis. This may be because features such as skin rash prompt early diagnosis and discontinuation of the offending drugs.⁷

CASE › A liver specialist evaluates Mr. A and concludes that his liver injury was caused by his long-term heavy alcohol consumption and exacerbated by the amoxicillin/clavulanic acid he had recently been prescribed. After 2 days, Mr. A develops drowsiness and is admitted to the hospital for further management. He is managed in the intensive care unit under supervision of a gastroenterologist. A NAC infusion is started at a loading dose of 150 mg/kg to manage acute liver failure. Unfortunately, however, Mr. A succumbs to his illness.

CORRESPONDENCE
Piyush Ranjan, MD, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029; drpiyushaiims@gmail.com.

CASE › James A, age 68, presents to his family physician (FP) with anorexia, nausea, and vague upper abdominal pain that he’s had for 2 weeks. Mr. A has diabetes and hypertension, both of which are well controlled by medications. He also consumes more than 4 alcoholic beverages daily.

On examination, the FP notes icterus and tenderness in the right hypochondrium. Liver function testing reveals elevated liver enzyme levels: aspartate aminotransferase (AST), 864 IU/L (normal range: 10-40 IU/L); alanine aminotransferase (ALT), 1012 IU/L (normal range: 7-56 IU/L); serum bilirubin, 4.8 mg/dL (normal range: 0.3-1.9 mg/dL); and alkaline phosphatase (ALP), 200 IU/L (normal range: 44-147 IU/L). Mr. A’s coagulation profile is slightly abnormal. He is provisionally diagnosed with acute hepatitis. The FP sends blood samples to the lab to assess for viral markers, and starts symptomatic management.

If Mr. A were your patient, how would you proceed?

In the United States, drug-induced liver injury (DILI) is the most common cause of acute liver failure.^1,2 It can occur due to ingestion of any therapeutic drug, herbal product, or xenobiotic. Further complicating matters is the fact that it has an unpredictable and heterogeneous course, ranging from an asymptomatic rise in liver enzymes to acute liver failure. This article describes the risk factors, common causative agents, tools for early diagnosis, and effective management of DILI.

Two types of risk factors for DILI

Risk factors for DILI can be classified as drug-related (eg, dose, concomitant medications, polypharmacy) or host-related (eg, age, gender, alcohol intake, concomitant infections).^3-5

Drug-related factors. Hundreds of agents can lead to liver injury. In fact, the US National Library of Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases have created LiverTox (http://www.livertox.nih.gov/), an online database that provides detailed information on more than 600 such agents.⁶ Antibiotics are the most common cause of DILI, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, analgesics, antineoplastic drugs, and lipid-lowering agents.²

Among antibiotics, the specific medication most often responsible for DILI varies by geographical region. Amoxicillin/clavulanic acid is the most common causative antibiotic in the United States, whereas anti-tuberculosis agents such as isoniazid, rifampin, and pyrazinamide are the most common causative drugs in developing countries such as India, where the prevalence of tuberculosis is still high.^7,8 Herbal and dietary supplements are emerging as an important cause of DILI.^5,9,10

The use of multiple drugs further increases the risk of developing DILI.¹⁰ Drugs with a recommended daily dose of <50 mg are rarely associated with DILI.¹¹

Host-related factors. Vulnerability to DILI is influenced by a patient’s age and sex.^3,12 Very young and very old patients have an increased risk of developing DILI, and a patient’s age may make him or her particularly susceptible to the effects of certain medications.^3,12,13 For example, children are more susceptible to DILI as a result of taking valproate or aspirin, whereas older patients are more likely to experience DILI brought on by amoxicillin/clavulanic acid.¹³ The pattern of liver injury also varies by age. Younger patients present most commonly with a hepatocellular pattern of injury, whereas older patients mostly present with a cholestatic pattern of liver injury.³

Some studies have found that women have a greater risk of developing DILI than men.¹³ The presence of chronic liver diseases, alcoholism, and nonalcoholic fatty liver disease (NAFLD) increase the risk of developing DILI.¹⁴ Diabetes is an independent risk factor for DILI.³

Clinical presentation of DILI varies widely

Some degree of liver injury may occur in any patient who ingests a drug that is metabolized in the liver. The clinical presentation of a patient with DILI can vary from an asymptomatic rise in liver enzymes to acute liver failure. Unexplained transaminitis should raise the possibility of DILI, especially when the patient has started a new drug in the preceding 3 months. However, in most patients, an asymptomatic rise in liver enzymes is due to hepatic adaptation or tolerance. In such cases, liver enzyme levels tend to normalize even if the patient continues to take the drug in the same dose.¹⁵

Apart from nonspecific symptoms such as anorexia, nausea, and vomiting, a patient with DILI may exhibit right upper quadrant pain, skin rash, or itching. A patient with severe DILI might exhibit jaundice, ascites, or encephalopathy.¹⁵

A stepwise approach to evaluation

DILI is a diagnosis of exclusion.¹⁶ Guidelines from the American College of Gastroenterology (ACG) recommend a stepwise approach to evaluating a patient you suspect may have DILI (TABLE).¹⁶ First, take a detailed history regarding the onset of symptoms, time latency, and use of hepatotoxic and other drugs (dosage and duration of use). Also ask the patient about his or her use of herbal products, dietary supplements, and alcohol. Check the patient’s history for the presence of other liver diseases such as NAFLD.

Next, make sure initial laboratory testing includes liver function tests and an eosinophil count. In order to classify the pattern of liver injury as hepatocellular, cholestatic, or mixed, you’ll need to calculate the patient’s R value (ALGORITHM^16-18). This value is calculated by dividing the patient’s ALT level by the ALP, using the upper limit of the normal range (ULN) as follows: R = (ALT value ÷ ALT ULN) ÷ (ALP value ÷ ALP ULN).¹⁷ A hepatocellular pattern of liver injury is indicated by an R value >5, a cholestatic pattern is an R value <2, and a mixed pattern is suggested by an R value between 2 and 5.¹⁷

Antibiotics are the most common cause of drug-induced liver injury, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, and analgesics.

Quite often, the pattern of liver damage is characteristic of a particular drug or drug class. For example, DILI induced by amoxicillin/clavulanic acid typically will exhibit a cholestatic injury pattern, whereas DILI resulting from a nonsteroidal anti-inflammatory drug typically is associated with a hepatocellular injury pattern.¹⁶

Rule out other causes. Further investigations should be directed at ruling out other possible causes of liver injury. If a patient has a hepatocellular pattern of liver injury, order serological tests to rule out acute viral hepatitis (hepatitis A, B, C, and E). Such patients should also be evaluated for autoimmune hepatitis, Budd-Chiari syndrome, Wilson’s disease, and ischemic hepatitis.¹⁶ In patients with a predominant cholestatic pattern, imaging studies and other serological tests should be ordered to rule out pancreato-biliary diseases.

Once DILI is confirmed, identify offending agent, grade severity

Which medication is responsible for DILI is determined by the physician based on his or her clinical experience and judgment. Guiding points are improvement of liver function tests after stopping the suspected drug (more on that in a bit), exclusion of other possible causes of liver injury, and the results of liver biopsy. (See “Time for a biopsy?”¹⁶)

DILI severity can be graded as mild (1+) to fatal (5+).¹⁹ Mild forms of DILI are associated with increased levels of liver enzymes (AST, ALT, or ALP) without raised serum bilirubin or clinical jaundice, whereas moderately severe DILI is associated with clinical jaundice or hyperbilirubinemia (bilirubin >2 mg/dL).¹⁹ Severe forms of DILI are associated with features of hepatic failure, such as ascites, encephalopathy, and an elevated international normalized ratio (>1.5), in addition to hyperbilirubinemia or jaundice.

CASE › Mr. A’s lab results are negative for viral markers. On further questioning, he reveals that he had recovered from a sore throat 3 weeks earlier, for which he had been prescribed an unknown dose of amoxicillin/clavulanic acid. A review of Mr. A’s drug history finds that he is taking metformin, pioglitazone, telmisartan, and atorvastatin for his chronic conditions. The FP suspects DILI , and refers Mr. A to a liver specialist for further investigation.

For many patients, stopping the offending drug will be sufficient 

The first step in managing DILI is to stop the medication suspected of causing the liver injury.²⁰ Discontinuing the suspected medication may not always be necessary in patients who have only slightly elevated liver enzymes, but should be strongly considered for a patient who has a considerable increase in liver enzymes levels (ie, an AST, ALT, or serum bilirubin level more than 3 times the ULN or an ALP more than 1.5 times the ULN at any time after initiating a new drug).¹⁸ Certain drugs, such as those used to treat tuberculosis, are associated with hepatic adaptation, in which there is spontaneous resolution of the increased liver enzymes level even while the drug is continued in the same dose.

Diabetes is an independent risk factor for drug-induced liver injury.

In patients with mild to moderate DILI, stopping the offending drug typically results in normalization of liver enzyme levels.²⁰ Management of patients with moderate to severe DILI is mainly supportive; however, a patient with acute liver failure will require intensive care support.^21,22 Consider hospital admission for patients who exhibit severe symptoms, such as intractable vomiting or severe dehydration, those who experience bleeding due to coagulation failure, and those who develop hepatic encephalopathy.²¹

When more aggressive steps are needed

N-acetylcysteine (NAC) should be considered for all patients with DILI who present with acute liver failure.^12,23-25 NAC can be administered either orally or intravenously. The following 3 regimens have been well studied for patients with acetaminophen-induced liver injury:²⁶
• Oral 72-hour regimen: Loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours up to 72 hours
• Intravenous 72-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 418.75 mg/kg over 67 hours
• Intravenous 21-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours.

Of these regimens, the 72-hour IV regimen has been found to be more effective than the 21-hour regimen for patients with acetaminophen-induced liver toxicity.²⁶ A study of NAC administered as continuous infusion for 72 hours in patients with acute liver failure found that the transplant-free survival rate was 40% for NAC in comparison with 27% for placebo.²⁶

L-carnitine can be used to treat valproate-induced hepatotoxicity. In a case-control study of 92 patients with severe, symptomatic, valproate-induced hepatotoxicity, nearly half of 42 patients treated with L-carnitine survived, but only 10% of 50 patients treated solely with aggressive supportive care survived.²⁷ Greater benefit has been found for IV vs oral L-carnitine.^27,28

Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg, may be helpful for DILI patients with a cholestatic pattern of liver injury.

Other therapies. Steroids have no defined role in management of DILI except in autoimmune-type DILI. Other drugs, such as silymarin and antioxidants, have been used to treat other forms of hepatic toxicities and might be beneficial for patients with DILI.^29,30

Liver transplantation may be necessary to prevent death due to acute liver failure in patients with severe DILI. Various criteria, including Kings College criteria,³¹ can be used to select which patients may best benefit from liver transplantation.

For most patients, hospitalization will not be necessary

Generally, patients with DILI have a good prognosis.^20,30 About 70% of patients with DILI do not require hospitalization, and approximately 90% recover without reaching the threshold of acute liver failure. However, patients with acute liver failure have a poor prognosis; 40% will require liver transplantation.^16,20

A patient with a hepatocellular pattern of liver injury should receive serological tests to rule out acute viral hepatitis.

Traditionally, patients with a cholestatic pattern of liver injury have been considered to have a better prognosis than those with a hepatocellular pattern of liver injury. Patients whose DILI is the result of a hypersensitivity reaction to a drug also have a good prognosis. This may be because features such as skin rash prompt early diagnosis and discontinuation of the offending drugs.⁷

CASE › A liver specialist evaluates Mr. A and concludes that his liver injury was caused by his long-term heavy alcohol consumption and exacerbated by the amoxicillin/clavulanic acid he had recently been prescribed. After 2 days, Mr. A develops drowsiness and is admitted to the hospital for further management. He is managed in the intensive care unit under supervision of a gastroenterologist. A NAC infusion is started at a loading dose of 150 mg/kg to manage acute liver failure. Unfortunately, however, Mr. A succumbs to his illness.

CORRESPONDENCE
Piyush Ranjan, MD, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029; drpiyushaiims@gmail.com.

Blood samples

Photo by Graham Colm

New research has revealed a microRNA (miRNA) signature in the bone marrow of patients with multiple myeloma (MM) that is also detectable in peripheral blood.

Investigators believe this signature may mark the onset of MM and predict progression to MM in patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM).

This research has been published in The Journal of Molecular Diagnostics.

“Currently, there is no single factor that can predict patients with MGUS or SMM who are likely to progress to myeloma,” said Katherine R. Calvo, MD, PhD, of the National Institutes of Health in Bethesda, Maryland.

“A biomarker of disease progression in the peripheral blood could assist in the early identification of patients evolving to multiple myeloma.”

With this in mind, Dr Calvo and her colleagues studied miRNAs as possible biomarkers of MM. Previous research has shown increased levels of specific miRNAs in the blood and plasma of MM patients.

In this study, the investigators analyzed bone marrow, plasma, and serum samples from healthy controls and patients with MM, MGUS, or SMM.

The team analyzed fluid from the bone marrow of 20 patients with MM and identified 111 miRNAs that showed a 2-fold or greater difference from levels observed in 8 control samples. Sixty-nine of the miRNAs were downregulated, and 42 were upregulated.

Further analysis revealed a unique miRNA signature indicative of MM. The bone marrow signature included 8 members of the let-7 family of miRNAs, each of which showed significant decreases ranging from 6-fold to 17-fold (P<0.03) in patients with MM.

Other experiments revealed the miRNA profiles characteristic of MM in peripheral blood, serum, and plasma samples.

Using quantitative real-time PCR, the investigators identified 18 miRNAs that were significantly decreased in bone marrow MM samples. Of these, 11 (60%) miRNAs were also significantly decreased in serum samples, and 6 of the 11 were also found to be lower in plasma samples (including 3 members of the let-7 miRNA family).

The investigators further explored whether the miRNA pattern of MM in precursor diseases changes as the disease progresses. They analyzed serum samples in 17 patients with MGUS, 17 with SMM, 13 with MM, and 12 healthy controls.

Only 4 of the 11 miRNAs (36%) that were reduced in the MM serum samples were lower in the MGUS samples.

“This suggests that aberrant expression of these [4] miRNAs may be associated with early events in plasma cell neoplasia,” Dr Calvo said.

Eight of the 11 (73%) miRNAs were decreased in SMM plasma samples. However, 3 (27%) were significantly reduced only in the MM samples, suggesting that downregulation of this group of miRNAs may be related to later events during evolution from precursor disease to MM.

“Our findings suggest that the antiproliferative and proapoptotic miRNAs, such as the let-7 family members, are downregulated in multiple myeloma’s microenvironment,” Dr Calvo said.

“These findings suggest that measuring expression of miRNAs associated with myeloma progression in the peripheral blood may hold promise for predicting disease progression in MGUS and SMM.”

Blood samples

Photo by Graham Colm

New research has revealed a microRNA (miRNA) signature in the bone marrow of patients with multiple myeloma (MM) that is also detectable in peripheral blood.

Investigators believe this signature may mark the onset of MM and predict progression to MM in patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM).

This research has been published in The Journal of Molecular Diagnostics.

“Currently, there is no single factor that can predict patients with MGUS or SMM who are likely to progress to myeloma,” said Katherine R. Calvo, MD, PhD, of the National Institutes of Health in Bethesda, Maryland.

“A biomarker of disease progression in the peripheral blood could assist in the early identification of patients evolving to multiple myeloma.”

With this in mind, Dr Calvo and her colleagues studied miRNAs as possible biomarkers of MM. Previous research has shown increased levels of specific miRNAs in the blood and plasma of MM patients.

In this study, the investigators analyzed bone marrow, plasma, and serum samples from healthy controls and patients with MM, MGUS, or SMM.

The team analyzed fluid from the bone marrow of 20 patients with MM and identified 111 miRNAs that showed a 2-fold or greater difference from levels observed in 8 control samples. Sixty-nine of the miRNAs were downregulated, and 42 were upregulated.

Further analysis revealed a unique miRNA signature indicative of MM. The bone marrow signature included 8 members of the let-7 family of miRNAs, each of which showed significant decreases ranging from 6-fold to 17-fold (P<0.03) in patients with MM.

Other experiments revealed the miRNA profiles characteristic of MM in peripheral blood, serum, and plasma samples.

Using quantitative real-time PCR, the investigators identified 18 miRNAs that were significantly decreased in bone marrow MM samples. Of these, 11 (60%) miRNAs were also significantly decreased in serum samples, and 6 of the 11 were also found to be lower in plasma samples (including 3 members of the let-7 miRNA family).

The investigators further explored whether the miRNA pattern of MM in precursor diseases changes as the disease progresses. They analyzed serum samples in 17 patients with MGUS, 17 with SMM, 13 with MM, and 12 healthy controls.

Only 4 of the 11 miRNAs (36%) that were reduced in the MM serum samples were lower in the MGUS samples.

“This suggests that aberrant expression of these [4] miRNAs may be associated with early events in plasma cell neoplasia,” Dr Calvo said.

Eight of the 11 (73%) miRNAs were decreased in SMM plasma samples. However, 3 (27%) were significantly reduced only in the MM samples, suggesting that downregulation of this group of miRNAs may be related to later events during evolution from precursor disease to MM.

“Our findings suggest that the antiproliferative and proapoptotic miRNAs, such as the let-7 family members, are downregulated in multiple myeloma’s microenvironment,” Dr Calvo said.

“These findings suggest that measuring expression of miRNAs associated with myeloma progression in the peripheral blood may hold promise for predicting disease progression in MGUS and SMM.”

Blood samples

Photo by Graham Colm

New research has revealed a microRNA (miRNA) signature in the bone marrow of patients with multiple myeloma (MM) that is also detectable in peripheral blood.

Investigators believe this signature may mark the onset of MM and predict progression to MM in patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM).

This research has been published in The Journal of Molecular Diagnostics.

“Currently, there is no single factor that can predict patients with MGUS or SMM who are likely to progress to myeloma,” said Katherine R. Calvo, MD, PhD, of the National Institutes of Health in Bethesda, Maryland.

“A biomarker of disease progression in the peripheral blood could assist in the early identification of patients evolving to multiple myeloma.”

With this in mind, Dr Calvo and her colleagues studied miRNAs as possible biomarkers of MM. Previous research has shown increased levels of specific miRNAs in the blood and plasma of MM patients.

In this study, the investigators analyzed bone marrow, plasma, and serum samples from healthy controls and patients with MM, MGUS, or SMM.

The team analyzed fluid from the bone marrow of 20 patients with MM and identified 111 miRNAs that showed a 2-fold or greater difference from levels observed in 8 control samples. Sixty-nine of the miRNAs were downregulated, and 42 were upregulated.

Further analysis revealed a unique miRNA signature indicative of MM. The bone marrow signature included 8 members of the let-7 family of miRNAs, each of which showed significant decreases ranging from 6-fold to 17-fold (P<0.03) in patients with MM.

Other experiments revealed the miRNA profiles characteristic of MM in peripheral blood, serum, and plasma samples.

Using quantitative real-time PCR, the investigators identified 18 miRNAs that were significantly decreased in bone marrow MM samples. Of these, 11 (60%) miRNAs were also significantly decreased in serum samples, and 6 of the 11 were also found to be lower in plasma samples (including 3 members of the let-7 miRNA family).

The investigators further explored whether the miRNA pattern of MM in precursor diseases changes as the disease progresses. They analyzed serum samples in 17 patients with MGUS, 17 with SMM, 13 with MM, and 12 healthy controls.

Only 4 of the 11 miRNAs (36%) that were reduced in the MM serum samples were lower in the MGUS samples.

“This suggests that aberrant expression of these [4] miRNAs may be associated with early events in plasma cell neoplasia,” Dr Calvo said.

Eight of the 11 (73%) miRNAs were decreased in SMM plasma samples. However, 3 (27%) were significantly reduced only in the MM samples, suggesting that downregulation of this group of miRNAs may be related to later events during evolution from precursor disease to MM.

“Our findings suggest that the antiproliferative and proapoptotic miRNAs, such as the let-7 family members, are downregulated in multiple myeloma’s microenvironment,” Dr Calvo said.

“These findings suggest that measuring expression of miRNAs associated with myeloma progression in the peripheral blood may hold promise for predicting disease progression in MGUS and SMM.”

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the recombinant factor VIII Fc fusion protein efmoroctocog alfa (Elocta) to treat patients with hemophilia A.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to

deliver its final decision within 3 months.

If approved by the EC, efmoroctocog alfa would be the first hemophilia A treatment with prolonged circulation available in the European Union (plus Iceland, Lichtenstein, and Norway).

The CHMP’s positive opinion of efmoroctocog alfa was based on results from 2 phase 3 studies—A-LONG and Kids A-LONG.

A-LONG

The A-LONG study included 165 previously treated males 12 years of age and older with severe hemophilia A. Researchers evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes and on-demand dosing to treat bleeding episodes.

Prophylaxis with efmoroctocog alfa resulted in low annualized bleeding rates, and a majority of bleeding episodes were controlled with a single injection of efmoroctocog alfa.

None of the patients developed neutralizing antibodies, efmoroctocog alfa was considered well-tolerated, and the product had a prolonged half-life when compared with rFVIII.

Kids A-LONG

The Kids A-LONG study included 71 boys (younger than 12) with severe hemophilia A who had at least 50 prior exposure days to FVIII therapies.

The children saw their median annualized bleeding rate decrease with efmoroctocog alfa, and close to half of the children did not have any bleeding episodes while they were receiving efmoroctocog alfa.

None of the patients developed inhibitors, and researchers said adverse events were typical of a pediatric hemophilia population.

ASPIRE

Participants in both the A-LONG and Kids A-LONG trials were able to enroll in ASPIRE, a phase 3 extension study evaluating the long-term safety and efficacy of efmoroctocog alfa.

Interim results of ASPIRE suggested that extended treatment with efmoroctocog alfa was largely safe and effective.

Efmoroctocog alfa development

Elocta is the European trade name for efmoroctocog alfa, which is known as Eloctate in the US, Canada, Australia, New Zealand, and Japan, where it is approved for the treatment of hemophilia A.

Biogen and Sobi are collaboration partners in the development and commercialization of efmoroctocog alfa for hemophilia A.

Last year, Sobi exercised its opt-in right to assume final development and commercialization of efmoroctocog alfa in the Sobi territories (essentially, Europe, North Africa, Russia, and certain countries in the Middle East). Biogen leads development for efmoroctocog alfa, has manufacturing rights, and has commercialization rights in North America and all other regions in the world excluding the Sobi territories.

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the recombinant factor VIII Fc fusion protein efmoroctocog alfa (Elocta) to treat patients with hemophilia A.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to

deliver its final decision within 3 months.

If approved by the EC, efmoroctocog alfa would be the first hemophilia A treatment with prolonged circulation available in the European Union (plus Iceland, Lichtenstein, and Norway).

The CHMP’s positive opinion of efmoroctocog alfa was based on results from 2 phase 3 studies—A-LONG and Kids A-LONG.

A-LONG

The A-LONG study included 165 previously treated males 12 years of age and older with severe hemophilia A. Researchers evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes and on-demand dosing to treat bleeding episodes.

Prophylaxis with efmoroctocog alfa resulted in low annualized bleeding rates, and a majority of bleeding episodes were controlled with a single injection of efmoroctocog alfa.

None of the patients developed neutralizing antibodies, efmoroctocog alfa was considered well-tolerated, and the product had a prolonged half-life when compared with rFVIII.

Kids A-LONG

The Kids A-LONG study included 71 boys (younger than 12) with severe hemophilia A who had at least 50 prior exposure days to FVIII therapies.

The children saw their median annualized bleeding rate decrease with efmoroctocog alfa, and close to half of the children did not have any bleeding episodes while they were receiving efmoroctocog alfa.

None of the patients developed inhibitors, and researchers said adverse events were typical of a pediatric hemophilia population.

ASPIRE

Participants in both the A-LONG and Kids A-LONG trials were able to enroll in ASPIRE, a phase 3 extension study evaluating the long-term safety and efficacy of efmoroctocog alfa.

Interim results of ASPIRE suggested that extended treatment with efmoroctocog alfa was largely safe and effective.

Efmoroctocog alfa development

Elocta is the European trade name for efmoroctocog alfa, which is known as Eloctate in the US, Canada, Australia, New Zealand, and Japan, where it is approved for the treatment of hemophilia A.

Biogen and Sobi are collaboration partners in the development and commercialization of efmoroctocog alfa for hemophilia A.

Last year, Sobi exercised its opt-in right to assume final development and commercialization of efmoroctocog alfa in the Sobi territories (essentially, Europe, North Africa, Russia, and certain countries in the Middle East). Biogen leads development for efmoroctocog alfa, has manufacturing rights, and has commercialization rights in North America and all other regions in the world excluding the Sobi territories.

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the recombinant factor VIII Fc fusion protein efmoroctocog alfa (Elocta) to treat patients with hemophilia A.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to

deliver its final decision within 3 months.

If approved by the EC, efmoroctocog alfa would be the first hemophilia A treatment with prolonged circulation available in the European Union (plus Iceland, Lichtenstein, and Norway).

The CHMP’s positive opinion of efmoroctocog alfa was based on results from 2 phase 3 studies—A-LONG and Kids A-LONG.

A-LONG

The A-LONG study included 165 previously treated males 12 years of age and older with severe hemophilia A. Researchers evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes and on-demand dosing to treat bleeding episodes.

Prophylaxis with efmoroctocog alfa resulted in low annualized bleeding rates, and a majority of bleeding episodes were controlled with a single injection of efmoroctocog alfa.

None of the patients developed neutralizing antibodies, efmoroctocog alfa was considered well-tolerated, and the product had a prolonged half-life when compared with rFVIII.

Kids A-LONG

The Kids A-LONG study included 71 boys (younger than 12) with severe hemophilia A who had at least 50 prior exposure days to FVIII therapies.

The children saw their median annualized bleeding rate decrease with efmoroctocog alfa, and close to half of the children did not have any bleeding episodes while they were receiving efmoroctocog alfa.

None of the patients developed inhibitors, and researchers said adverse events were typical of a pediatric hemophilia population.

ASPIRE

Participants in both the A-LONG and Kids A-LONG trials were able to enroll in ASPIRE, a phase 3 extension study evaluating the long-term safety and efficacy of efmoroctocog alfa.

Interim results of ASPIRE suggested that extended treatment with efmoroctocog alfa was largely safe and effective.

Efmoroctocog alfa development

Elocta is the European trade name for efmoroctocog alfa, which is known as Eloctate in the US, Canada, Australia, New Zealand, and Japan, where it is approved for the treatment of hemophilia A.

Biogen and Sobi are collaboration partners in the development and commercialization of efmoroctocog alfa for hemophilia A.

Last year, Sobi exercised its opt-in right to assume final development and commercialization of efmoroctocog alfa in the Sobi territories (essentially, Europe, North Africa, Russia, and certain countries in the Middle East). Biogen leads development for efmoroctocog alfa, has manufacturing rights, and has commercialization rights in North America and all other regions in the world excluding the Sobi territories.

Ursula Seidel

NEW YORK—Researchers have developed a pharmaceutical-grade, third-generation, CD19-specific antibody that reduced minimal residual disease (MRD) in pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

This chimerized, Fc-optimized antibody—4G7SDIE—was used on a compassionate-need basis in 14 patients with relapsed or refractory BCP-ALL. Nine of the patients had prior stem cell transplants.

Ursula JE Seidel, a PhD candidate at University Children’s Hospital Tubingen in Germany, discussed early results with the new antibody (poster B144) during the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

Patients received 4G7SDIE infusions ranging from 5 mg/m² to 50 mg/m² twice a week for a year or longer.

They rarely experienced fever, nausea, or headache, according to the investigators, and all had B-cell depletion.

“The good thing about this antibody is it has a very low toxicity profile,” Seidel noted.

Upon discontinuation of therapy, B-cell counts recovered rapidly to normal levels.

The researchers followed the patients for a median of 543 days after transplant (range, 208–1137) and a median of 720 days after administration of 4G7SDIE (range, 264–1115).

Nine of the 14 patients had a reduction in MRD by 1 log or more, 2 of whom were receiving additional therapy with tyrosine kinase inhibitors.

Five patients had a reduction in MRD below the quantifiable level, and 2 patients became MRD-negative.

Six patients relapsed, and 5 of them died from relapsed disease. Two patients died of sepsis or chemotoxicity while in complete molecular remission. And 6 patients remain in complete molecular remission.

Functional characterization of 4G7SDIE

Through analysis of cells from healthy volunteers and BCP-ALL blasts of untreated and treated patients, the researchers determined that 4G7SDIE mediates enhanced antibody‑dependent cellular cytotoxicity through its improved capability to recruit FcγRIIIa-bearing effector cells.

They identified natural killer cells and γδ T cells as the main effector cells. And they determined that the FcγRIIIa-V158F polymorphism did not influence the effect of 4G7SDIE-mediated antibody‑dependent cellular cytotoxicity.

The researchers believe that the promising anti-leukemic effects of 4G7SDIE both in vitro and in vivo call for additional exploration. They are currently planning a phase 1/2 study to further assess the therapeutic activity of 4G7SDIE.

Ursula Seidel

NEW YORK—Researchers have developed a pharmaceutical-grade, third-generation, CD19-specific antibody that reduced minimal residual disease (MRD) in pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

This chimerized, Fc-optimized antibody—4G7SDIE—was used on a compassionate-need basis in 14 patients with relapsed or refractory BCP-ALL. Nine of the patients had prior stem cell transplants.

Ursula JE Seidel, a PhD candidate at University Children’s Hospital Tubingen in Germany, discussed early results with the new antibody (poster B144) during the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

Patients received 4G7SDIE infusions ranging from 5 mg/m² to 50 mg/m² twice a week for a year or longer.

They rarely experienced fever, nausea, or headache, according to the investigators, and all had B-cell depletion.

“The good thing about this antibody is it has a very low toxicity profile,” Seidel noted.

Upon discontinuation of therapy, B-cell counts recovered rapidly to normal levels.

The researchers followed the patients for a median of 543 days after transplant (range, 208–1137) and a median of 720 days after administration of 4G7SDIE (range, 264–1115).

Nine of the 14 patients had a reduction in MRD by 1 log or more, 2 of whom were receiving additional therapy with tyrosine kinase inhibitors.

Five patients had a reduction in MRD below the quantifiable level, and 2 patients became MRD-negative.

Six patients relapsed, and 5 of them died from relapsed disease. Two patients died of sepsis or chemotoxicity while in complete molecular remission. And 6 patients remain in complete molecular remission.

Functional characterization of 4G7SDIE

Through analysis of cells from healthy volunteers and BCP-ALL blasts of untreated and treated patients, the researchers determined that 4G7SDIE mediates enhanced antibody‑dependent cellular cytotoxicity through its improved capability to recruit FcγRIIIa-bearing effector cells.

They identified natural killer cells and γδ T cells as the main effector cells. And they determined that the FcγRIIIa-V158F polymorphism did not influence the effect of 4G7SDIE-mediated antibody‑dependent cellular cytotoxicity.

The researchers believe that the promising anti-leukemic effects of 4G7SDIE both in vitro and in vivo call for additional exploration. They are currently planning a phase 1/2 study to further assess the therapeutic activity of 4G7SDIE.

Ursula Seidel

NEW YORK—Researchers have developed a pharmaceutical-grade, third-generation, CD19-specific antibody that reduced minimal residual disease (MRD) in pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

This chimerized, Fc-optimized antibody—4G7SDIE—was used on a compassionate-need basis in 14 patients with relapsed or refractory BCP-ALL. Nine of the patients had prior stem cell transplants.

Ursula JE Seidel, a PhD candidate at University Children’s Hospital Tubingen in Germany, discussed early results with the new antibody (poster B144) during the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

Patients received 4G7SDIE infusions ranging from 5 mg/m² to 50 mg/m² twice a week for a year or longer.

They rarely experienced fever, nausea, or headache, according to the investigators, and all had B-cell depletion.

“The good thing about this antibody is it has a very low toxicity profile,” Seidel noted.

Upon discontinuation of therapy, B-cell counts recovered rapidly to normal levels.

The researchers followed the patients for a median of 543 days after transplant (range, 208–1137) and a median of 720 days after administration of 4G7SDIE (range, 264–1115).

Nine of the 14 patients had a reduction in MRD by 1 log or more, 2 of whom were receiving additional therapy with tyrosine kinase inhibitors.

Five patients had a reduction in MRD below the quantifiable level, and 2 patients became MRD-negative.

Six patients relapsed, and 5 of them died from relapsed disease. Two patients died of sepsis or chemotoxicity while in complete molecular remission. And 6 patients remain in complete molecular remission.

Functional characterization of 4G7SDIE

Through analysis of cells from healthy volunteers and BCP-ALL blasts of untreated and treated patients, the researchers determined that 4G7SDIE mediates enhanced antibody‑dependent cellular cytotoxicity through its improved capability to recruit FcγRIIIa-bearing effector cells.

They identified natural killer cells and γδ T cells as the main effector cells. And they determined that the FcγRIIIa-V158F polymorphism did not influence the effect of 4G7SDIE-mediated antibody‑dependent cellular cytotoxicity.

The researchers believe that the promising anti-leukemic effects of 4G7SDIE both in vitro and in vivo call for additional exploration. They are currently planning a phase 1/2 study to further assess the therapeutic activity of 4G7SDIE.

Radiation therapist preparing

woman for radiotherapy

Photo by Rhoda Baer

VIENNA—Millions of people throughout the world are dying from potentially treatable cancers because of a chronic underinvestment in radiotherapy resources, according to a new report.

The report suggests that expanding access to radiotherapy services will require a sizeable investment upfront, but that investment could bring economic benefits of up to $365 billion in developing countries over the next 20 years.

The report was published in The Lancet Oncology and presented at the 2015 European Cancer Congress.

The report estimates that 204 million fractions of radiotherapy will be needed to treat the 12 million cancer patients worldwide who could benefit from treatment in 2035.

But the cost per fraction is highly cost-effective and low compared to the price of many new cancer drugs, according to the report’s authors.

They estimate that full access to radiotherapy could be achieved for all patients in need in low-and middle income countries (LMIC) by 2035 for $97 billion, with potential health benefits of 27 million life-years saved and economic benefits ranging from $278 billion to $365 billion over the next 20 years.

“There is a widespread misconception that the costs of providing radiotherapy put it beyond the reach of all but the richest countries, [but] nothing could be further from the truth,” said Rifat Atun, MBBS, of Harvard University in Boston, Massachusetts.

“Our work . . .  clearly shows that not only can this essential service be deployed safely and high quality treatment delivered in low- and middle-income countries, but that scale-up of radiotherapy capacity is a feasible and highly cost-effective investment.”

The report provides details on access to radiotherapy services across the world, on a country-by-country basis. The authors calculated the costs and benefits of meeting the worldwide shortfall in resources and bridging the gap in access to effective treatment.

Estimates suggest that, at present, about 40% to 60% of cancer patients worldwide have access to radiotherapy. Even in high-income countries like Canada, Australia, and the UK, numbers of radiotherapy facilities, equipment, and trained staff are inadequate.

Access is worst in low-income countries, where as many as 9 out of 10 people cannot access radiotherapy. The problem of access is especially acute in Africa. In most African countries, radiotherapy is virtually non-existent. Forty countries have no radiotherapy facilities at all.

“The time has come to agree and implement immediate actions to tackle the global shortfall in radiotherapy services and the crisis of access to this highly effective treatment,” Dr Atun said.

With that in mind, he and his colleagues called for the following 6 targets to be met.

By 2020:

• 80% of countries to have comprehensive cancer plans that include radiotherapy.
• Each LMIC to create 1 new center for treatment and training.
• 80% of LMICs to include radiotherapy services in their universal health coverage plans.

By 2025:

• A 25% increase in radiotherapy treatment capacity.
• LMICs to train 7500 radiation oncologists, 20,000 radiotherapy radiographers, and 6000 medical physicists.
• $46 billion of upfront investment to be raised to establish radiotherapy infrastructure and training in LMICs (with help from international banks and the private sector).

“The evidence outlined in the [report] reinforces the case for investing in radiotherapy as an essential component of cancer control,” said Mary Gospodarowicz, MD, co-chair of the UICC Global Task Force on Radiotherapy for Cancer Control.

“The building of radiotherapy capacity will require large initial investment. However, the treatment is more cost-effective than chemotherapy and surgery for treating cancer, and the health and economic benefits will be realized in just 10 to 15 years.”

Radiation therapist preparing

woman for radiotherapy

Photo by Rhoda Baer

VIENNA—Millions of people throughout the world are dying from potentially treatable cancers because of a chronic underinvestment in radiotherapy resources, according to a new report.

The report suggests that expanding access to radiotherapy services will require a sizeable investment upfront, but that investment could bring economic benefits of up to $365 billion in developing countries over the next 20 years.

The report was published in The Lancet Oncology and presented at the 2015 European Cancer Congress.

The report estimates that 204 million fractions of radiotherapy will be needed to treat the 12 million cancer patients worldwide who could benefit from treatment in 2035.

But the cost per fraction is highly cost-effective and low compared to the price of many new cancer drugs, according to the report’s authors.

They estimate that full access to radiotherapy could be achieved for all patients in need in low-and middle income countries (LMIC) by 2035 for $97 billion, with potential health benefits of 27 million life-years saved and economic benefits ranging from $278 billion to $365 billion over the next 20 years.

“There is a widespread misconception that the costs of providing radiotherapy put it beyond the reach of all but the richest countries, [but] nothing could be further from the truth,” said Rifat Atun, MBBS, of Harvard University in Boston, Massachusetts.

“Our work . . .  clearly shows that not only can this essential service be deployed safely and high quality treatment delivered in low- and middle-income countries, but that scale-up of radiotherapy capacity is a feasible and highly cost-effective investment.”

The report provides details on access to radiotherapy services across the world, on a country-by-country basis. The authors calculated the costs and benefits of meeting the worldwide shortfall in resources and bridging the gap in access to effective treatment.

Estimates suggest that, at present, about 40% to 60% of cancer patients worldwide have access to radiotherapy. Even in high-income countries like Canada, Australia, and the UK, numbers of radiotherapy facilities, equipment, and trained staff are inadequate.

Access is worst in low-income countries, where as many as 9 out of 10 people cannot access radiotherapy. The problem of access is especially acute in Africa. In most African countries, radiotherapy is virtually non-existent. Forty countries have no radiotherapy facilities at all.

“The time has come to agree and implement immediate actions to tackle the global shortfall in radiotherapy services and the crisis of access to this highly effective treatment,” Dr Atun said.

With that in mind, he and his colleagues called for the following 6 targets to be met.

By 2020:

• 80% of countries to have comprehensive cancer plans that include radiotherapy.
• Each LMIC to create 1 new center for treatment and training.
• 80% of LMICs to include radiotherapy services in their universal health coverage plans.

By 2025:

• A 25% increase in radiotherapy treatment capacity.
• LMICs to train 7500 radiation oncologists, 20,000 radiotherapy radiographers, and 6000 medical physicists.
• $46 billion of upfront investment to be raised to establish radiotherapy infrastructure and training in LMICs (with help from international banks and the private sector).

“The evidence outlined in the [report] reinforces the case for investing in radiotherapy as an essential component of cancer control,” said Mary Gospodarowicz, MD, co-chair of the UICC Global Task Force on Radiotherapy for Cancer Control.

“The building of radiotherapy capacity will require large initial investment. However, the treatment is more cost-effective than chemotherapy and surgery for treating cancer, and the health and economic benefits will be realized in just 10 to 15 years.”

Radiation therapist preparing

woman for radiotherapy

Photo by Rhoda Baer

VIENNA—Millions of people throughout the world are dying from potentially treatable cancers because of a chronic underinvestment in radiotherapy resources, according to a new report.

The report suggests that expanding access to radiotherapy services will require a sizeable investment upfront, but that investment could bring economic benefits of up to $365 billion in developing countries over the next 20 years.

The report was published in The Lancet Oncology and presented at the 2015 European Cancer Congress.

The report estimates that 204 million fractions of radiotherapy will be needed to treat the 12 million cancer patients worldwide who could benefit from treatment in 2035.

But the cost per fraction is highly cost-effective and low compared to the price of many new cancer drugs, according to the report’s authors.

They estimate that full access to radiotherapy could be achieved for all patients in need in low-and middle income countries (LMIC) by 2035 for $97 billion, with potential health benefits of 27 million life-years saved and economic benefits ranging from $278 billion to $365 billion over the next 20 years.

“There is a widespread misconception that the costs of providing radiotherapy put it beyond the reach of all but the richest countries, [but] nothing could be further from the truth,” said Rifat Atun, MBBS, of Harvard University in Boston, Massachusetts.

“Our work . . .  clearly shows that not only can this essential service be deployed safely and high quality treatment delivered in low- and middle-income countries, but that scale-up of radiotherapy capacity is a feasible and highly cost-effective investment.”

The report provides details on access to radiotherapy services across the world, on a country-by-country basis. The authors calculated the costs and benefits of meeting the worldwide shortfall in resources and bridging the gap in access to effective treatment.

Estimates suggest that, at present, about 40% to 60% of cancer patients worldwide have access to radiotherapy. Even in high-income countries like Canada, Australia, and the UK, numbers of radiotherapy facilities, equipment, and trained staff are inadequate.

Access is worst in low-income countries, where as many as 9 out of 10 people cannot access radiotherapy. The problem of access is especially acute in Africa. In most African countries, radiotherapy is virtually non-existent. Forty countries have no radiotherapy facilities at all.

“The time has come to agree and implement immediate actions to tackle the global shortfall in radiotherapy services and the crisis of access to this highly effective treatment,” Dr Atun said.

With that in mind, he and his colleagues called for the following 6 targets to be met.

By 2020:

• 80% of countries to have comprehensive cancer plans that include radiotherapy.
• Each LMIC to create 1 new center for treatment and training.
• 80% of LMICs to include radiotherapy services in their universal health coverage plans.

By 2025:

• A 25% increase in radiotherapy treatment capacity.
• LMICs to train 7500 radiation oncologists, 20,000 radiotherapy radiographers, and 6000 medical physicists.
• $46 billion of upfront investment to be raised to establish radiotherapy infrastructure and training in LMICs (with help from international banks and the private sector).

“The evidence outlined in the [report] reinforces the case for investing in radiotherapy as an essential component of cancer control,” said Mary Gospodarowicz, MD, co-chair of the UICC Global Task Force on Radiotherapy for Cancer Control.

“The building of radiotherapy capacity will require large initial investment. However, the treatment is more cost-effective than chemotherapy and surgery for treating cancer, and the health and economic benefits will be realized in just 10 to 15 years.”

Patients with inflammatory bowel disease (IBD) were about five to eight times more likely to die after emergency intestinal resection as opposed to elective surgery, a large meta-analysis found.

Overall mortality rates after emergency intestinal resection were 5.3% for patients with ulcerative colitis (UC) and 3.6% for patients with Crohn’s disease (CD), said Dr. Sunny Singh and his associates at the University of Calgary in Alberta, Canada. In contrast, only 0.6%-0.7% of patients died after elective resection, the researchers reported in the October issue of Gastroenterology (2015 Jun 5. doi: 10.1053/j.gastro.2015.06.001).

Clinicians should optimize medical management to avoid emergency resection, seek ways to reduce associated mortality, and use the data when counseling patients and weighing medical and surgical management options, they added.

Intestinal resection is less common among patients with IBD than in decades past, but almost half of CD patients undergo the surgery within 10 years of diagnosis, as do 16% of UC patients, according to another meta-analysis (Gastroenterology 2013;145:996-1006). Past studies have reported divergent rates of death after these surgeries, the researchers noted. To better understand mortality rates and relevant risk factors, they reviewed 18 original research articles and three abstracts published between 1990 and 2015, all of which were indexed in Medline, EMBASE, or PubMed. The studies included 67,057 UC patients and 75,971 CD patients from 15 countries.

Rates of mortality after elective resection were significantly lower than after emergency resection, whether patients had CD (elective, 0.6%; 95% confidence interval, 0.2%-1.7%; emergency, 3.6%; 1.8%-6.9%) or UC (elective, 0.7%; 0.6%-0.9%; emergency, 5.3%; 3.8%-7.3%), the researchers found. Death rates did not significantly differ based on disease type. Postoperative mortality dropped significantly after the 1990s among CD patients only, perhaps because emergency surgery has become less common in Calgary since 1997, the researchers said. However, they were unable to compare changes in death rates over time by surgery type, they said.

Several factors could explain the high fatality rates after emergency intestinal resection, the researchers said. Patients tended to have worse disease activity and higher rates of intestinal obstruction, intra-abdominal abscess, toxic megacolon, preoperative clostridial diarrhea, venous thromboembolism, malnourishment, or prolonged treatment with intravenous corticosteroids, they said. General surgeons are more likely to perform emergency resections than elective cases, which are typically handled by more experienced colorectal surgeons, they added. Emergency resections also are less likely to be performed laparoscopically than are elective resections, they noted. “The low risk of death associated with elective intestinal resections for CD and UC could be used as a quality assurance benchmark to compare outcomes between hospitals and surgeons,” they added.

The research was funded by the Canadian Institute of Health Research, Alberta-Innovates Health-Solutions, the Alberta IBD Consortium. Dr. Singh reported no conflicts of interest. Senior author Dr. Gilaad Kaplan and four coauthors disclosed speaker, advisory board, and funding relationships with a number of pharmaceutical companies.

Patients with inflammatory bowel disease (IBD) were about five to eight times more likely to die after emergency intestinal resection as opposed to elective surgery, a large meta-analysis found.

Overall mortality rates after emergency intestinal resection were 5.3% for patients with ulcerative colitis (UC) and 3.6% for patients with Crohn’s disease (CD), said Dr. Sunny Singh and his associates at the University of Calgary in Alberta, Canada. In contrast, only 0.6%-0.7% of patients died after elective resection, the researchers reported in the October issue of Gastroenterology (2015 Jun 5. doi: 10.1053/j.gastro.2015.06.001).

Clinicians should optimize medical management to avoid emergency resection, seek ways to reduce associated mortality, and use the data when counseling patients and weighing medical and surgical management options, they added.

Intestinal resection is less common among patients with IBD than in decades past, but almost half of CD patients undergo the surgery within 10 years of diagnosis, as do 16% of UC patients, according to another meta-analysis (Gastroenterology 2013;145:996-1006). Past studies have reported divergent rates of death after these surgeries, the researchers noted. To better understand mortality rates and relevant risk factors, they reviewed 18 original research articles and three abstracts published between 1990 and 2015, all of which were indexed in Medline, EMBASE, or PubMed. The studies included 67,057 UC patients and 75,971 CD patients from 15 countries.

Rates of mortality after elective resection were significantly lower than after emergency resection, whether patients had CD (elective, 0.6%; 95% confidence interval, 0.2%-1.7%; emergency, 3.6%; 1.8%-6.9%) or UC (elective, 0.7%; 0.6%-0.9%; emergency, 5.3%; 3.8%-7.3%), the researchers found. Death rates did not significantly differ based on disease type. Postoperative mortality dropped significantly after the 1990s among CD patients only, perhaps because emergency surgery has become less common in Calgary since 1997, the researchers said. However, they were unable to compare changes in death rates over time by surgery type, they said.

Several factors could explain the high fatality rates after emergency intestinal resection, the researchers said. Patients tended to have worse disease activity and higher rates of intestinal obstruction, intra-abdominal abscess, toxic megacolon, preoperative clostridial diarrhea, venous thromboembolism, malnourishment, or prolonged treatment with intravenous corticosteroids, they said. General surgeons are more likely to perform emergency resections than elective cases, which are typically handled by more experienced colorectal surgeons, they added. Emergency resections also are less likely to be performed laparoscopically than are elective resections, they noted. “The low risk of death associated with elective intestinal resections for CD and UC could be used as a quality assurance benchmark to compare outcomes between hospitals and surgeons,” they added.

The research was funded by the Canadian Institute of Health Research, Alberta-Innovates Health-Solutions, the Alberta IBD Consortium. Dr. Singh reported no conflicts of interest. Senior author Dr. Gilaad Kaplan and four coauthors disclosed speaker, advisory board, and funding relationships with a number of pharmaceutical companies.

Patients with inflammatory bowel disease (IBD) were about five to eight times more likely to die after emergency intestinal resection as opposed to elective surgery, a large meta-analysis found.

Overall mortality rates after emergency intestinal resection were 5.3% for patients with ulcerative colitis (UC) and 3.6% for patients with Crohn’s disease (CD), said Dr. Sunny Singh and his associates at the University of Calgary in Alberta, Canada. In contrast, only 0.6%-0.7% of patients died after elective resection, the researchers reported in the October issue of Gastroenterology (2015 Jun 5. doi: 10.1053/j.gastro.2015.06.001).

Clinicians should optimize medical management to avoid emergency resection, seek ways to reduce associated mortality, and use the data when counseling patients and weighing medical and surgical management options, they added.

Intestinal resection is less common among patients with IBD than in decades past, but almost half of CD patients undergo the surgery within 10 years of diagnosis, as do 16% of UC patients, according to another meta-analysis (Gastroenterology 2013;145:996-1006). Past studies have reported divergent rates of death after these surgeries, the researchers noted. To better understand mortality rates and relevant risk factors, they reviewed 18 original research articles and three abstracts published between 1990 and 2015, all of which were indexed in Medline, EMBASE, or PubMed. The studies included 67,057 UC patients and 75,971 CD patients from 15 countries.

Rates of mortality after elective resection were significantly lower than after emergency resection, whether patients had CD (elective, 0.6%; 95% confidence interval, 0.2%-1.7%; emergency, 3.6%; 1.8%-6.9%) or UC (elective, 0.7%; 0.6%-0.9%; emergency, 5.3%; 3.8%-7.3%), the researchers found. Death rates did not significantly differ based on disease type. Postoperative mortality dropped significantly after the 1990s among CD patients only, perhaps because emergency surgery has become less common in Calgary since 1997, the researchers said. However, they were unable to compare changes in death rates over time by surgery type, they said.

Several factors could explain the high fatality rates after emergency intestinal resection, the researchers said. Patients tended to have worse disease activity and higher rates of intestinal obstruction, intra-abdominal abscess, toxic megacolon, preoperative clostridial diarrhea, venous thromboembolism, malnourishment, or prolonged treatment with intravenous corticosteroids, they said. General surgeons are more likely to perform emergency resections than elective cases, which are typically handled by more experienced colorectal surgeons, they added. Emergency resections also are less likely to be performed laparoscopically than are elective resections, they noted. “The low risk of death associated with elective intestinal resections for CD and UC could be used as a quality assurance benchmark to compare outcomes between hospitals and surgeons,” they added.

The research was funded by the Canadian Institute of Health Research, Alberta-Innovates Health-Solutions, the Alberta IBD Consortium. Dr. Singh reported no conflicts of interest. Senior author Dr. Gilaad Kaplan and four coauthors disclosed speaker, advisory board, and funding relationships with a number of pharmaceutical companies.

Case

A 17-year-old adolescent girl with a history of depression and opioid dependence, for which she was taking buprenorphine until 2 weeks earlier, presented to the ED via emergency medical services (EMS) after her father found her lying on the couch unresponsive and with shallow respirations. Naloxone was administered by EMS and her mental status improved.

At presentation, the patient admitted to insufflation of an unknown amount of heroin and ingestion of 2 mg of alprazolam earlier in the day. She denied any past or current use of intravenous (IV) drugs. During monitoring, she began to complain of numbness in her legs and an inability to urinate. Examination revealed paralysis and decreased sensation of her bilateral lower extremities to the midthigh, with decreased rectal tone. Because of the patient’s history of drug use and temporal association with the heroin overdose, both neurosurgery and toxicology services were consulted.

What can cause lower extremity paralysis in a drug user?

The differential diagnosis for the patient at this point included toxin-induced myelopathy, Guillain-Barré syndrome, hypokalemic periodic paralysis, spinal compression, epidural abscess, cerebrovascular accident, spinal lesion, and spinal artery dissection or infarction.

Although Guillain-Barré syndrome presents with ascending paralysis, there is usually an antecedent respiratory or gastrointestinal infection. While epidural abscess with spinal compression is associated with IV drug use and can present similarly, the patient in this case denied IV use. In the absence of any risk factors, cerebrovascular accident and spinal artery dissection were also unlikely.

Case Continuation

A bladder catheter was placed due to the patient’s inability to urinate, and approximately 1 L of urine output was retrieved. Immediate magnetic resonance imaging (MRI) demonstrated increased T2 signal intensity and expansion of the distal thoracic cord and conus without mass lesion, consistent with transverse myelitis (TM).

What is transverse myelitis and why does it occur?

Transverse myelitis is an inflammatory demyelinating disorder that focally affects the spinal cord, resulting in a specific pattern of motor, sensory, and autonomic dysfunction.¹ Signs and symptoms include paresthesia, paralysis of the extremities, and loss of bladder and bowel control. The level of the spinal cord affected determines the clinical effects. Demyelination typically occurs at the thoracic segment, producing findings in the legs, as well as bladder and bowel dysfunction. 

The exact cause of TM is unknown, but the inflammation may result from a viral complication or an abnormal immune response. Infectious viral agents suspected of causing TM include varicella zoster, herpes simplex, cytomegalovirus, Epstein-Barr, influenza, human immunodeficiency virus, hepatitis A, and rubella. It has also been postulated that an autoimmune reaction is responsible for the condition.

In some individuals, TM represents the first manifestation of an underlying demyelinating disorder such as multiple sclerosis or neuromyelitis optica. A diagnosis of TM is made through patient history, physical examination, and characteristic findings on neuroimaging, specifically MRI.

Heroin use has long been associated with the development of TM, and is usually associated with IV administration of the drug after a period of abstinence.² This association strengthens the basis for an immunologic etiology—an initial sensitization and subsequent reexposure causing the effects of TM. There have also been cases of TM coexisting with rhabdomyolysis due to the patient being found in a contorted position.³ Another theory of the etiology of heroin-associated TM is a reaction to a possible adulterant or contaminant in the heroin.⁴

What is the treatment and prognosis of transverse myelitis?

Since there is no cure for TM, treatment is directed at reducing inflammation in the spinal cord. Initial therapy generally includes corticosteroids. In patients with a minimal response to corticosteroids, plasma exchange can be attempted. There are also limited data to suggest a beneficial role for the use of IV immunoglobulin.⁵ In addition to treatment, general supportive care must also be optimized, such as the use of prophylaxis for thrombophlebitis due to immobility and physical therapy, if possible.

The prognosis of patients with TM is variable, and up to two thirds of patients will have moderate-to-severe residual neurological disability.⁶ Recovery is slow, with most patients beginning to show improvement within the first 2 to 12 weeks from treatment and supportive care. The recovery process can continue for 2 years. However, if no improvement is made within the first 3 to 6 months, recovery is unlikely.⁷ Cases of heroin-associated TM may have a more favorable prognosis.⁸

A majority of individuals will only experience this clinical entity once, but there are rare causes of recurrent or relapsing TM.⁷ In these situations, a search for underlying demyelinating diseases should be performed.

Case Conclusion 

The patient was immediately started on IV corticosteroids, but as there was no improvement after 5 days, plasmapheresis was performed. She received 5 cycles of plasmapheresis and a 5-day course of IV immunoglobulin but still without any improvement. A repeat MRI of the thoracic spine was performed and raised the possibility of cord infarct, but infectious or inflammatory myelitis remained within differential consideration. The patient continued to make minimal improvement with physical therapy and, after a 3-week hospital course, she was transferred to inpatient rehabilitation for further care. Over the next 2 months, the loss of sensation and motor ability of her legs did not improve, but she did regain control of her bowels and bladder.

Dr Regina is a medical toxicology fellow in the department of emergency medicine at North Shore Long Island Jewish Health System, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

Case

A 17-year-old adolescent girl with a history of depression and opioid dependence, for which she was taking buprenorphine until 2 weeks earlier, presented to the ED via emergency medical services (EMS) after her father found her lying on the couch unresponsive and with shallow respirations. Naloxone was administered by EMS and her mental status improved.

At presentation, the patient admitted to insufflation of an unknown amount of heroin and ingestion of 2 mg of alprazolam earlier in the day. She denied any past or current use of intravenous (IV) drugs. During monitoring, she began to complain of numbness in her legs and an inability to urinate. Examination revealed paralysis and decreased sensation of her bilateral lower extremities to the midthigh, with decreased rectal tone. Because of the patient’s history of drug use and temporal association with the heroin overdose, both neurosurgery and toxicology services were consulted.

What can cause lower extremity paralysis in a drug user?

The differential diagnosis for the patient at this point included toxin-induced myelopathy, Guillain-Barré syndrome, hypokalemic periodic paralysis, spinal compression, epidural abscess, cerebrovascular accident, spinal lesion, and spinal artery dissection or infarction.

Although Guillain-Barré syndrome presents with ascending paralysis, there is usually an antecedent respiratory or gastrointestinal infection. While epidural abscess with spinal compression is associated with IV drug use and can present similarly, the patient in this case denied IV use. In the absence of any risk factors, cerebrovascular accident and spinal artery dissection were also unlikely.

Case Continuation

A bladder catheter was placed due to the patient’s inability to urinate, and approximately 1 L of urine output was retrieved. Immediate magnetic resonance imaging (MRI) demonstrated increased T2 signal intensity and expansion of the distal thoracic cord and conus without mass lesion, consistent with transverse myelitis (TM).

What is transverse myelitis and why does it occur?

Transverse myelitis is an inflammatory demyelinating disorder that focally affects the spinal cord, resulting in a specific pattern of motor, sensory, and autonomic dysfunction.¹ Signs and symptoms include paresthesia, paralysis of the extremities, and loss of bladder and bowel control. The level of the spinal cord affected determines the clinical effects. Demyelination typically occurs at the thoracic segment, producing findings in the legs, as well as bladder and bowel dysfunction. 

The exact cause of TM is unknown, but the inflammation may result from a viral complication or an abnormal immune response. Infectious viral agents suspected of causing TM include varicella zoster, herpes simplex, cytomegalovirus, Epstein-Barr, influenza, human immunodeficiency virus, hepatitis A, and rubella. It has also been postulated that an autoimmune reaction is responsible for the condition.

In some individuals, TM represents the first manifestation of an underlying demyelinating disorder such as multiple sclerosis or neuromyelitis optica. A diagnosis of TM is made through patient history, physical examination, and characteristic findings on neuroimaging, specifically MRI.

Heroin use has long been associated with the development of TM, and is usually associated with IV administration of the drug after a period of abstinence.² This association strengthens the basis for an immunologic etiology—an initial sensitization and subsequent reexposure causing the effects of TM. There have also been cases of TM coexisting with rhabdomyolysis due to the patient being found in a contorted position.³ Another theory of the etiology of heroin-associated TM is a reaction to a possible adulterant or contaminant in the heroin.⁴

What is the treatment and prognosis of transverse myelitis?

Since there is no cure for TM, treatment is directed at reducing inflammation in the spinal cord. Initial therapy generally includes corticosteroids. In patients with a minimal response to corticosteroids, plasma exchange can be attempted. There are also limited data to suggest a beneficial role for the use of IV immunoglobulin.⁵ In addition to treatment, general supportive care must also be optimized, such as the use of prophylaxis for thrombophlebitis due to immobility and physical therapy, if possible.

The prognosis of patients with TM is variable, and up to two thirds of patients will have moderate-to-severe residual neurological disability.⁶ Recovery is slow, with most patients beginning to show improvement within the first 2 to 12 weeks from treatment and supportive care. The recovery process can continue for 2 years. However, if no improvement is made within the first 3 to 6 months, recovery is unlikely.⁷ Cases of heroin-associated TM may have a more favorable prognosis.⁸

A majority of individuals will only experience this clinical entity once, but there are rare causes of recurrent or relapsing TM.⁷ In these situations, a search for underlying demyelinating diseases should be performed.

Case Conclusion 

The patient was immediately started on IV corticosteroids, but as there was no improvement after 5 days, plasmapheresis was performed. She received 5 cycles of plasmapheresis and a 5-day course of IV immunoglobulin but still without any improvement. A repeat MRI of the thoracic spine was performed and raised the possibility of cord infarct, but infectious or inflammatory myelitis remained within differential consideration. The patient continued to make minimal improvement with physical therapy and, after a 3-week hospital course, she was transferred to inpatient rehabilitation for further care. Over the next 2 months, the loss of sensation and motor ability of her legs did not improve, but she did regain control of her bowels and bladder.

Dr Regina is a medical toxicology fellow in the department of emergency medicine at North Shore Long Island Jewish Health System, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

Case

A 17-year-old adolescent girl with a history of depression and opioid dependence, for which she was taking buprenorphine until 2 weeks earlier, presented to the ED via emergency medical services (EMS) after her father found her lying on the couch unresponsive and with shallow respirations. Naloxone was administered by EMS and her mental status improved.

At presentation, the patient admitted to insufflation of an unknown amount of heroin and ingestion of 2 mg of alprazolam earlier in the day. She denied any past or current use of intravenous (IV) drugs. During monitoring, she began to complain of numbness in her legs and an inability to urinate. Examination revealed paralysis and decreased sensation of her bilateral lower extremities to the midthigh, with decreased rectal tone. Because of the patient’s history of drug use and temporal association with the heroin overdose, both neurosurgery and toxicology services were consulted.

What can cause lower extremity paralysis in a drug user?

The differential diagnosis for the patient at this point included toxin-induced myelopathy, Guillain-Barré syndrome, hypokalemic periodic paralysis, spinal compression, epidural abscess, cerebrovascular accident, spinal lesion, and spinal artery dissection or infarction.

Although Guillain-Barré syndrome presents with ascending paralysis, there is usually an antecedent respiratory or gastrointestinal infection. While epidural abscess with spinal compression is associated with IV drug use and can present similarly, the patient in this case denied IV use. In the absence of any risk factors, cerebrovascular accident and spinal artery dissection were also unlikely.

Case Continuation

A bladder catheter was placed due to the patient’s inability to urinate, and approximately 1 L of urine output was retrieved. Immediate magnetic resonance imaging (MRI) demonstrated increased T2 signal intensity and expansion of the distal thoracic cord and conus without mass lesion, consistent with transverse myelitis (TM).

What is transverse myelitis and why does it occur?

Transverse myelitis is an inflammatory demyelinating disorder that focally affects the spinal cord, resulting in a specific pattern of motor, sensory, and autonomic dysfunction.¹ Signs and symptoms include paresthesia, paralysis of the extremities, and loss of bladder and bowel control. The level of the spinal cord affected determines the clinical effects. Demyelination typically occurs at the thoracic segment, producing findings in the legs, as well as bladder and bowel dysfunction. 

The exact cause of TM is unknown, but the inflammation may result from a viral complication or an abnormal immune response. Infectious viral agents suspected of causing TM include varicella zoster, herpes simplex, cytomegalovirus, Epstein-Barr, influenza, human immunodeficiency virus, hepatitis A, and rubella. It has also been postulated that an autoimmune reaction is responsible for the condition.

In some individuals, TM represents the first manifestation of an underlying demyelinating disorder such as multiple sclerosis or neuromyelitis optica. A diagnosis of TM is made through patient history, physical examination, and characteristic findings on neuroimaging, specifically MRI.

Heroin use has long been associated with the development of TM, and is usually associated with IV administration of the drug after a period of abstinence.² This association strengthens the basis for an immunologic etiology—an initial sensitization and subsequent reexposure causing the effects of TM. There have also been cases of TM coexisting with rhabdomyolysis due to the patient being found in a contorted position.³ Another theory of the etiology of heroin-associated TM is a reaction to a possible adulterant or contaminant in the heroin.⁴

What is the treatment and prognosis of transverse myelitis?

Since there is no cure for TM, treatment is directed at reducing inflammation in the spinal cord. Initial therapy generally includes corticosteroids. In patients with a minimal response to corticosteroids, plasma exchange can be attempted. There are also limited data to suggest a beneficial role for the use of IV immunoglobulin.⁵ In addition to treatment, general supportive care must also be optimized, such as the use of prophylaxis for thrombophlebitis due to immobility and physical therapy, if possible.

The prognosis of patients with TM is variable, and up to two thirds of patients will have moderate-to-severe residual neurological disability.⁶ Recovery is slow, with most patients beginning to show improvement within the first 2 to 12 weeks from treatment and supportive care. The recovery process can continue for 2 years. However, if no improvement is made within the first 3 to 6 months, recovery is unlikely.⁷ Cases of heroin-associated TM may have a more favorable prognosis.⁸

A majority of individuals will only experience this clinical entity once, but there are rare causes of recurrent or relapsing TM.⁷ In these situations, a search for underlying demyelinating diseases should be performed.

Case Conclusion 

The patient was immediately started on IV corticosteroids, but as there was no improvement after 5 days, plasmapheresis was performed. She received 5 cycles of plasmapheresis and a 5-day course of IV immunoglobulin but still without any improvement. A repeat MRI of the thoracic spine was performed and raised the possibility of cord infarct, but infectious or inflammatory myelitis remained within differential consideration. The patient continued to make minimal improvement with physical therapy and, after a 3-week hospital course, she was transferred to inpatient rehabilitation for further care. Over the next 2 months, the loss of sensation and motor ability of her legs did not improve, but she did regain control of her bowels and bladder.

Dr Regina is a medical toxicology fellow in the department of emergency medicine at North Shore Long Island Jewish Health System, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

The patient’s physical examination was unremarkable. His vital signs were normal, and there was no obvious external evidence of trauma. The posterior cervical spine was tender to palpation in the midline, but no step-off signs were appreciated. The neurological examination, including strength and sensation in all four extremities, was normal.

Since the patient’s only complaint was neck pain and his physical examination and history were otherwise normal, the emergency physician (EP) ordered radiographs of the cervical spine. The imaging studies were interpreted as showing advanced degenerative changes but no fractures, and the patient was prescribed an analgesic and discharged home.

When the patient woke up the next morning, he was unable to move his extremities, and returned to the same ED via EMS. He was placed in a cervical collar and found to have flaccid extremities on examination. A computed tomography (CT) scan of the cervical spine revealed a transverse fracture through the C6 vertebra. Radiology services also reviewed the cervical spine X-rays from the previous day, noting the presence of fracture.

The patient was taken to the operating room by neurosurgery services but remained paralyzed postoperatively. He never recovered from his injury and died 6 months later. His family sued the EP and the hospital for missed diagnosis of cervical spine fracture at the first ED presentation and the resulting paralysis. The case was settled for $1.3 million prior to trial.

Discussion

The evaluation of suspected cervical spine injury secondary to blunt trauma is a frequent and important skill practiced by EPs. Motor vehicle accidents are the most common cause of spinal cord injury in the United States (42%), followed by falls (27%), acts of violence (15%), and sports-related injuries (8%).¹ A review by Sekon and Fehlings² showed that 55% of all spinal injuries involve the cervical spine. Interestingly, the majority of cervical spine injuries occur at the upper or lower ends of the cervical spine; C2 vertebral fractures account for 33%, while C6 and C7 vertebral fractures account for approximately 50%.¹

There are two commonly used criteria to clinically clear the cervical spine (ie, no imaging studies necessary) in blunt-trauma patients. The first is the National Emergency X-Radiography Use Study (NEXUS), which has a sensitivity of 99.6% of identifying cervical spine fractures.¹ According to the NEXUS criteria, no imaging studies are required if: (1) there is no midline cervical spine tenderness; (2) there are no focal neurological deficits; (3) the patient exhibits a normal level of alertness; (4) the patient is not intoxicated; and (5) there is no distracting injury.¹

The other set of criteria used to clear the cervical spine is the Canadian Cervical Spine Rule. In these criteria, a patient is considered at very low risk for cervical spine fracture in the following cases: (1) the patient is fully alert with a Glasgow Coma scale of 15; (2) the patient has no high-risk factors (ie, age >65 years, dangerous mechanism of injury, fall greater than five stairs, axial load to the head, high-speed vehicular crash, bicycle or motorcycle crash, or the presence of paresthesias in the extremities); (3) the patient has low-risk factors (eg, simple vehicle crash, sitting position in the ED, ambulatory at any time, delayed onset of neck pain, and the absence of midline cervical tenderness); and (4) the patient can actively rotate his or her neck 45 degrees to the left and to the right. The Canadian group found the above criteria to have 100% sensitivity for predicting the absence of cervical spine injury.¹

The patient in this case failed both sets of criteria (ie, presence of cervical spine tenderness and age >65 years) and therefore required imaging. Historically, cervical spine X-ray (three views, anteroposterior, lateral, and odontoid; or five views, three views plus obliques) has been the imaging study of choice for such patients. Unfortunately, however, cervical spine radiographs have severe limitations in identifying spinal injury. In a large retrospective review, Woodring and Lee,³ found that the standard three-view cervical spine series failed to demonstrate 61% of all fractures and 36% of all subluxation and dislocations. Similarly, in a prospective study of 1,006 patients with 72 injuries, Diaz et al,⁴ found a 52.3% missed fracture rate when five-view radiographs were used to identify cervical spine injury. In addition, radiographic evaluation of elderly patients was found to be even more challenging in identifying cervical spine injury due to age-related degenerative changes.

Given the abovementioned limitations associated with radiographic imaging, CT scan of the cervical spine has become the imaging study of choice in moderate-to-severe risk patients with blunt cervical spine trauma. This modality has been shown to have a higher sensitivity and specificity for evaluating cervical spine injury compared to plain X-ray films, with CT detecting 97% to 100% of cervical spine fractures.⁵

In addition to demonstrating a higher sensitivity, CT also has the advantage of speed—especially when the patient is undergoing other CT studies (eg, head, abdomen, pelvis). While some clinicians criticize the higher cost of CT versus plain films, CT has been shown to decrease institutional costs (when settlement costs are taken into account) due to the reduction of the incidence of paralysis resulting from false-negative imaging studies.⁶

Forgotten Tourniquet

The patient’s vital signs were: blood pressure, 138/82 mm Hg; heart rate, 102 beats/minute; respiratory rate, 18 breaths/minute; temperature 98.6˚F. Oxygen saturation was 99% on room air.

The patient appeared uncomfortable overall. The physical examination was remarkable only for mild left-sided costovertebral angle tenderness. Her abdomen was soft, nontender, and without guarding or rebound.

The EP ordered the placement of an intravenous (IV) line, through which the patient was administered normal saline and morphine and promethazine, respectively, for pain and nausea. A complete blood count, basic metabolic panel, urinalysis, and urine pregnancy test were ordered. All of the laboratory bloodwork results were normal, and the urine pregnancy test was negative. The urinalysis was remarkable for 50 to 100 red blood cells.

A noncontrast CT scan of the abdomen and pelvis revealed a 3-mm ureteral stone on the left side. When the patient returned from radiology services, her pain was significantly decreased and she felt much improved. She was diagnosed with a kidney stone and discharged home with an analgesic and a strainer, along with instructions to follow-up with urology services. The patient was in the ED for a total of 5 hours.

The plaintiff sued the EP and hospital, claiming that the tourniquet used to start the IV line and draw blood was never removed, which in turn caused nerve damage resulting in reflex sympathetic dystrophy and complex regional pain syndrome. The defense denied all of these allegations, and the ED personnel testified that the tourniquet was removed as soon as the IV was established. The defense cited the plaintiff’s medical records, which contained documentation that the tourniquet had been removed. The defense further argued that if the tourniquet had been left on as the patient alleged, she would have experienced obvious physical signs, such as swelling, redness, infiltration of fluids, pain, and numbness. A defense verdict was returned.

Discussion

It is very tempting to simply dismiss this case as absurd, with nothing to be learned from it. It does defy common sense that no one would have noticed the tourniquet or, at the very least, that the patient would not have spoken up about it during her stay in the ED. While the jury clearly came to the correct conclusion,  it does highlight a real problem: forgotten tourniquets.

According to the Pennsylvania Patient Safety Advisory (PPSA), there were 125 reports of tourniquets being left on patients in Pennsylvania healthcare facilities in 1 year alone.¹ In 5% of these cases, the tourniquet was discovered within a half hour of application. In approximately 66% of cases, the tourniquet was left on for up to 2 hours, and the remaining were left in place for 2 to 18 hours.

Few locations within the hospital are without risk for this type of accident. The PPSA further noted that approximately 30% of retained tourniquets occurred on medical/surgical units, 14% in the ED, and 14% on inpatient and ambulatory surgical services departments. Approximately 19% were discovered when patients were transferred from one department to another.¹

In the analysis of these incidents, contributing factors to forgotten tourniquets included staff failing to follow proper procedures, inadequate staff proficiency, and staff distractions and/or interruptions.¹ In addition, some patients appeared to be at increased risk of having a retained tourniquet than others. Sixty percent of 125 patients with a forgotten tourniquet were aged 70 years or older, whereas some patients were younger than age 2 years.¹ Not surprisingly, patients who were unable to verbally communicate (eg, patients who were intubated, under anesthesia, had expressive aphasia, severe dementia), were at the highest risk.

In a review of recovery room incidents, Salman and Asfar² identified two cases of forgotten tourniquets out of approximately 7,000 patients. Potential strategies to avoid this mistake include: (1) only documenting procedures after they have been completed (eg, tourniquet removal); (2) double-checking that the tourniquet has been removed prior to leaving patient bedside; and (3) the use of extra-long tourniquets so the ends are more clearly visible.

The patient’s physical examination was unremarkable. His vital signs were normal, and there was no obvious external evidence of trauma. The posterior cervical spine was tender to palpation in the midline, but no step-off signs were appreciated. The neurological examination, including strength and sensation in all four extremities, was normal.

Since the patient’s only complaint was neck pain and his physical examination and history were otherwise normal, the emergency physician (EP) ordered radiographs of the cervical spine. The imaging studies were interpreted as showing advanced degenerative changes but no fractures, and the patient was prescribed an analgesic and discharged home.

When the patient woke up the next morning, he was unable to move his extremities, and returned to the same ED via EMS. He was placed in a cervical collar and found to have flaccid extremities on examination. A computed tomography (CT) scan of the cervical spine revealed a transverse fracture through the C6 vertebra. Radiology services also reviewed the cervical spine X-rays from the previous day, noting the presence of fracture.

The patient was taken to the operating room by neurosurgery services but remained paralyzed postoperatively. He never recovered from his injury and died 6 months later. His family sued the EP and the hospital for missed diagnosis of cervical spine fracture at the first ED presentation and the resulting paralysis. The case was settled for $1.3 million prior to trial.

Discussion

The evaluation of suspected cervical spine injury secondary to blunt trauma is a frequent and important skill practiced by EPs. Motor vehicle accidents are the most common cause of spinal cord injury in the United States (42%), followed by falls (27%), acts of violence (15%), and sports-related injuries (8%).¹ A review by Sekon and Fehlings² showed that 55% of all spinal injuries involve the cervical spine. Interestingly, the majority of cervical spine injuries occur at the upper or lower ends of the cervical spine; C2 vertebral fractures account for 33%, while C6 and C7 vertebral fractures account for approximately 50%.¹

There are two commonly used criteria to clinically clear the cervical spine (ie, no imaging studies necessary) in blunt-trauma patients. The first is the National Emergency X-Radiography Use Study (NEXUS), which has a sensitivity of 99.6% of identifying cervical spine fractures.¹ According to the NEXUS criteria, no imaging studies are required if: (1) there is no midline cervical spine tenderness; (2) there are no focal neurological deficits; (3) the patient exhibits a normal level of alertness; (4) the patient is not intoxicated; and (5) there is no distracting injury.¹

The other set of criteria used to clear the cervical spine is the Canadian Cervical Spine Rule. In these criteria, a patient is considered at very low risk for cervical spine fracture in the following cases: (1) the patient is fully alert with a Glasgow Coma scale of 15; (2) the patient has no high-risk factors (ie, age >65 years, dangerous mechanism of injury, fall greater than five stairs, axial load to the head, high-speed vehicular crash, bicycle or motorcycle crash, or the presence of paresthesias in the extremities); (3) the patient has low-risk factors (eg, simple vehicle crash, sitting position in the ED, ambulatory at any time, delayed onset of neck pain, and the absence of midline cervical tenderness); and (4) the patient can actively rotate his or her neck 45 degrees to the left and to the right. The Canadian group found the above criteria to have 100% sensitivity for predicting the absence of cervical spine injury.¹

The patient in this case failed both sets of criteria (ie, presence of cervical spine tenderness and age >65 years) and therefore required imaging. Historically, cervical spine X-ray (three views, anteroposterior, lateral, and odontoid; or five views, three views plus obliques) has been the imaging study of choice for such patients. Unfortunately, however, cervical spine radiographs have severe limitations in identifying spinal injury. In a large retrospective review, Woodring and Lee,³ found that the standard three-view cervical spine series failed to demonstrate 61% of all fractures and 36% of all subluxation and dislocations. Similarly, in a prospective study of 1,006 patients with 72 injuries, Diaz et al,⁴ found a 52.3% missed fracture rate when five-view radiographs were used to identify cervical spine injury. In addition, radiographic evaluation of elderly patients was found to be even more challenging in identifying cervical spine injury due to age-related degenerative changes.

Given the abovementioned limitations associated with radiographic imaging, CT scan of the cervical spine has become the imaging study of choice in moderate-to-severe risk patients with blunt cervical spine trauma. This modality has been shown to have a higher sensitivity and specificity for evaluating cervical spine injury compared to plain X-ray films, with CT detecting 97% to 100% of cervical spine fractures.⁵

In addition to demonstrating a higher sensitivity, CT also has the advantage of speed—especially when the patient is undergoing other CT studies (eg, head, abdomen, pelvis). While some clinicians criticize the higher cost of CT versus plain films, CT has been shown to decrease institutional costs (when settlement costs are taken into account) due to the reduction of the incidence of paralysis resulting from false-negative imaging studies.⁶

Forgotten Tourniquet

The patient’s vital signs were: blood pressure, 138/82 mm Hg; heart rate, 102 beats/minute; respiratory rate, 18 breaths/minute; temperature 98.6˚F. Oxygen saturation was 99% on room air.

The patient appeared uncomfortable overall. The physical examination was remarkable only for mild left-sided costovertebral angle tenderness. Her abdomen was soft, nontender, and without guarding or rebound.

The EP ordered the placement of an intravenous (IV) line, through which the patient was administered normal saline and morphine and promethazine, respectively, for pain and nausea. A complete blood count, basic metabolic panel, urinalysis, and urine pregnancy test were ordered. All of the laboratory bloodwork results were normal, and the urine pregnancy test was negative. The urinalysis was remarkable for 50 to 100 red blood cells.

A noncontrast CT scan of the abdomen and pelvis revealed a 3-mm ureteral stone on the left side. When the patient returned from radiology services, her pain was significantly decreased and she felt much improved. She was diagnosed with a kidney stone and discharged home with an analgesic and a strainer, along with instructions to follow-up with urology services. The patient was in the ED for a total of 5 hours.

The plaintiff sued the EP and hospital, claiming that the tourniquet used to start the IV line and draw blood was never removed, which in turn caused nerve damage resulting in reflex sympathetic dystrophy and complex regional pain syndrome. The defense denied all of these allegations, and the ED personnel testified that the tourniquet was removed as soon as the IV was established. The defense cited the plaintiff’s medical records, which contained documentation that the tourniquet had been removed. The defense further argued that if the tourniquet had been left on as the patient alleged, she would have experienced obvious physical signs, such as swelling, redness, infiltration of fluids, pain, and numbness. A defense verdict was returned.

Discussion

It is very tempting to simply dismiss this case as absurd, with nothing to be learned from it. It does defy common sense that no one would have noticed the tourniquet or, at the very least, that the patient would not have spoken up about it during her stay in the ED. While the jury clearly came to the correct conclusion,  it does highlight a real problem: forgotten tourniquets.

According to the Pennsylvania Patient Safety Advisory (PPSA), there were 125 reports of tourniquets being left on patients in Pennsylvania healthcare facilities in 1 year alone.¹ In 5% of these cases, the tourniquet was discovered within a half hour of application. In approximately 66% of cases, the tourniquet was left on for up to 2 hours, and the remaining were left in place for 2 to 18 hours.

Few locations within the hospital are without risk for this type of accident. The PPSA further noted that approximately 30% of retained tourniquets occurred on medical/surgical units, 14% in the ED, and 14% on inpatient and ambulatory surgical services departments. Approximately 19% were discovered when patients were transferred from one department to another.¹

In the analysis of these incidents, contributing factors to forgotten tourniquets included staff failing to follow proper procedures, inadequate staff proficiency, and staff distractions and/or interruptions.¹ In addition, some patients appeared to be at increased risk of having a retained tourniquet than others. Sixty percent of 125 patients with a forgotten tourniquet were aged 70 years or older, whereas some patients were younger than age 2 years.¹ Not surprisingly, patients who were unable to verbally communicate (eg, patients who were intubated, under anesthesia, had expressive aphasia, severe dementia), were at the highest risk.

In a review of recovery room incidents, Salman and Asfar² identified two cases of forgotten tourniquets out of approximately 7,000 patients. Potential strategies to avoid this mistake include: (1) only documenting procedures after they have been completed (eg, tourniquet removal); (2) double-checking that the tourniquet has been removed prior to leaving patient bedside; and (3) the use of extra-long tourniquets so the ends are more clearly visible.

The patient’s physical examination was unremarkable. His vital signs were normal, and there was no obvious external evidence of trauma. The posterior cervical spine was tender to palpation in the midline, but no step-off signs were appreciated. The neurological examination, including strength and sensation in all four extremities, was normal.

Since the patient’s only complaint was neck pain and his physical examination and history were otherwise normal, the emergency physician (EP) ordered radiographs of the cervical spine. The imaging studies were interpreted as showing advanced degenerative changes but no fractures, and the patient was prescribed an analgesic and discharged home.

When the patient woke up the next morning, he was unable to move his extremities, and returned to the same ED via EMS. He was placed in a cervical collar and found to have flaccid extremities on examination. A computed tomography (CT) scan of the cervical spine revealed a transverse fracture through the C6 vertebra. Radiology services also reviewed the cervical spine X-rays from the previous day, noting the presence of fracture.

The patient was taken to the operating room by neurosurgery services but remained paralyzed postoperatively. He never recovered from his injury and died 6 months later. His family sued the EP and the hospital for missed diagnosis of cervical spine fracture at the first ED presentation and the resulting paralysis. The case was settled for $1.3 million prior to trial.

Discussion

The evaluation of suspected cervical spine injury secondary to blunt trauma is a frequent and important skill practiced by EPs. Motor vehicle accidents are the most common cause of spinal cord injury in the United States (42%), followed by falls (27%), acts of violence (15%), and sports-related injuries (8%).¹ A review by Sekon and Fehlings² showed that 55% of all spinal injuries involve the cervical spine. Interestingly, the majority of cervical spine injuries occur at the upper or lower ends of the cervical spine; C2 vertebral fractures account for 33%, while C6 and C7 vertebral fractures account for approximately 50%.¹

There are two commonly used criteria to clinically clear the cervical spine (ie, no imaging studies necessary) in blunt-trauma patients. The first is the National Emergency X-Radiography Use Study (NEXUS), which has a sensitivity of 99.6% of identifying cervical spine fractures.¹ According to the NEXUS criteria, no imaging studies are required if: (1) there is no midline cervical spine tenderness; (2) there are no focal neurological deficits; (3) the patient exhibits a normal level of alertness; (4) the patient is not intoxicated; and (5) there is no distracting injury.¹

The other set of criteria used to clear the cervical spine is the Canadian Cervical Spine Rule. In these criteria, a patient is considered at very low risk for cervical spine fracture in the following cases: (1) the patient is fully alert with a Glasgow Coma scale of 15; (2) the patient has no high-risk factors (ie, age >65 years, dangerous mechanism of injury, fall greater than five stairs, axial load to the head, high-speed vehicular crash, bicycle or motorcycle crash, or the presence of paresthesias in the extremities); (3) the patient has low-risk factors (eg, simple vehicle crash, sitting position in the ED, ambulatory at any time, delayed onset of neck pain, and the absence of midline cervical tenderness); and (4) the patient can actively rotate his or her neck 45 degrees to the left and to the right. The Canadian group found the above criteria to have 100% sensitivity for predicting the absence of cervical spine injury.¹

The patient in this case failed both sets of criteria (ie, presence of cervical spine tenderness and age >65 years) and therefore required imaging. Historically, cervical spine X-ray (three views, anteroposterior, lateral, and odontoid; or five views, three views plus obliques) has been the imaging study of choice for such patients. Unfortunately, however, cervical spine radiographs have severe limitations in identifying spinal injury. In a large retrospective review, Woodring and Lee,³ found that the standard three-view cervical spine series failed to demonstrate 61% of all fractures and 36% of all subluxation and dislocations. Similarly, in a prospective study of 1,006 patients with 72 injuries, Diaz et al,⁴ found a 52.3% missed fracture rate when five-view radiographs were used to identify cervical spine injury. In addition, radiographic evaluation of elderly patients was found to be even more challenging in identifying cervical spine injury due to age-related degenerative changes.

Given the abovementioned limitations associated with radiographic imaging, CT scan of the cervical spine has become the imaging study of choice in moderate-to-severe risk patients with blunt cervical spine trauma. This modality has been shown to have a higher sensitivity and specificity for evaluating cervical spine injury compared to plain X-ray films, with CT detecting 97% to 100% of cervical spine fractures.⁵

In addition to demonstrating a higher sensitivity, CT also has the advantage of speed—especially when the patient is undergoing other CT studies (eg, head, abdomen, pelvis). While some clinicians criticize the higher cost of CT versus plain films, CT has been shown to decrease institutional costs (when settlement costs are taken into account) due to the reduction of the incidence of paralysis resulting from false-negative imaging studies.⁶

Forgotten Tourniquet

The patient’s vital signs were: blood pressure, 138/82 mm Hg; heart rate, 102 beats/minute; respiratory rate, 18 breaths/minute; temperature 98.6˚F. Oxygen saturation was 99% on room air.

The patient appeared uncomfortable overall. The physical examination was remarkable only for mild left-sided costovertebral angle tenderness. Her abdomen was soft, nontender, and without guarding or rebound.

The EP ordered the placement of an intravenous (IV) line, through which the patient was administered normal saline and morphine and promethazine, respectively, for pain and nausea. A complete blood count, basic metabolic panel, urinalysis, and urine pregnancy test were ordered. All of the laboratory bloodwork results were normal, and the urine pregnancy test was negative. The urinalysis was remarkable for 50 to 100 red blood cells.

A noncontrast CT scan of the abdomen and pelvis revealed a 3-mm ureteral stone on the left side. When the patient returned from radiology services, her pain was significantly decreased and she felt much improved. She was diagnosed with a kidney stone and discharged home with an analgesic and a strainer, along with instructions to follow-up with urology services. The patient was in the ED for a total of 5 hours.

The plaintiff sued the EP and hospital, claiming that the tourniquet used to start the IV line and draw blood was never removed, which in turn caused nerve damage resulting in reflex sympathetic dystrophy and complex regional pain syndrome. The defense denied all of these allegations, and the ED personnel testified that the tourniquet was removed as soon as the IV was established. The defense cited the plaintiff’s medical records, which contained documentation that the tourniquet had been removed. The defense further argued that if the tourniquet had been left on as the patient alleged, she would have experienced obvious physical signs, such as swelling, redness, infiltration of fluids, pain, and numbness. A defense verdict was returned.

Discussion

It is very tempting to simply dismiss this case as absurd, with nothing to be learned from it. It does defy common sense that no one would have noticed the tourniquet or, at the very least, that the patient would not have spoken up about it during her stay in the ED. While the jury clearly came to the correct conclusion,  it does highlight a real problem: forgotten tourniquets.

According to the Pennsylvania Patient Safety Advisory (PPSA), there were 125 reports of tourniquets being left on patients in Pennsylvania healthcare facilities in 1 year alone.¹ In 5% of these cases, the tourniquet was discovered within a half hour of application. In approximately 66% of cases, the tourniquet was left on for up to 2 hours, and the remaining were left in place for 2 to 18 hours.

Few locations within the hospital are without risk for this type of accident. The PPSA further noted that approximately 30% of retained tourniquets occurred on medical/surgical units, 14% in the ED, and 14% on inpatient and ambulatory surgical services departments. Approximately 19% were discovered when patients were transferred from one department to another.¹

In the analysis of these incidents, contributing factors to forgotten tourniquets included staff failing to follow proper procedures, inadequate staff proficiency, and staff distractions and/or interruptions.¹ In addition, some patients appeared to be at increased risk of having a retained tourniquet than others. Sixty percent of 125 patients with a forgotten tourniquet were aged 70 years or older, whereas some patients were younger than age 2 years.¹ Not surprisingly, patients who were unable to verbally communicate (eg, patients who were intubated, under anesthesia, had expressive aphasia, severe dementia), were at the highest risk.

In a review of recovery room incidents, Salman and Asfar² identified two cases of forgotten tourniquets out of approximately 7,000 patients. Potential strategies to avoid this mistake include: (1) only documenting procedures after they have been completed (eg, tourniquet removal); (2) double-checking that the tourniquet has been removed prior to leaving patient bedside; and (3) the use of extra-long tourniquets so the ends are more clearly visible.