ContributorsSharon A. Swencki, MD, FACEP, Jessica Shackman, MD, and Geoffrey Froehlich, DO, wrote ”Liver Disease.” Dr. Swencki is an attending physician at MedStar Harbor Hospital and MedStar Union Memorial Hospital in Baltimore, Maryland. Dr. Shackman and Dr. Froehlich are emergency medicine residents at Georgetown University Hospital/Washington Hospital Center in Washington, DC.

Daniel A. Handel, MD, MPH, FACEP, reviewed “Liver Disease.” Dr. Handel is chief medical officer and an associate professor of medicine and pediatrics in the Division of Emergency Medicine at the Medical University of South Carolina in Charleston.

Quynh Le, MD, and Kristin M. Drogell, MD, wrote ”Hyponatremia.” Dr. Le is an emergency medicine resident at Akron General Medical Center, in Akron, Ohio. Dr. Drogell is a staff physician at Akron General.

Michael S. Beeson, MD, MBA, FACEP, reviewed “Hyponatremia.” Dr. Beeson is program director for the Department of Emergency Medicine at Akron General in Akron, Ohio, and professor of clinical emergency medicine at Northeastern Ohio Universities College of Medicine in Rootstown.

Lynn Roppolo, MD, FACEP, reviewed the questions for these lessons. Dr. Roppolo is an associate professor of emergency medicine and associate emergency medicine residency director at the University of Texas Southwestern Medical Center in Dallas.

Louis G. Graff IV, MD, FACEP, is editor-in-chief of Critical Decisions. Dr. Graff is professor of traumatology and emergency medicine at the University of Connecticut School of Medicine in Farmington, Connecticut.Contributor Disclosures. In accordance with the ACCME Standards for Commercial Support and policy of the American College of Emergency Physicians, all individuals with control over CME content (including but not limited to staff, planners, reviewers, and authors) must disclose whether or not they have any relevant financial relationship(s) to learners prior to the start of the activity. These individuals have indicated that they have a relationship which, in the context of their involvement in the CME activity, could be perceived by some as a real or apparent conflict of interest (eg, ownership of stock, grants, honoraria, or consulting fees), but these individuals do not consider that it will influence the CME activity. Sharon E. Mace, MD, FACEP; Baxter Healthcare, consulting fees, fees for non-CME services, and contracted research; Gebauer Company, contracted research; Halozyme, consulting fees. Joshua S. Broder, MD, FACEP; GlaxoSmithKline; his wife is employed by GlaxoSmithKline as a research organic chemist. All remaining individuals with control over CME content have no significant financial interests or relationships to disclose.

Method of Participation. This educational activity consists of two lessons with a posttest, evaluation questions, and a pretest; it should take approximately 5 hours to complete. To complete this educational activity as designed, the participant should, in order, take the pretest (posted online following the previous month’s posttest), review the learning objectives, read the lessons as published in the print or online version, and then complete the online posttest and evaluation questions. Release date November 1, 2015. Expiration date October 31, 2018.

Accreditation Statement. The American College of Emergency Physicians is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American College of Emergency Physicians designates this enduring material for a maximum of 5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Each issue of Critical Decisions in Emergency Medicine is approved by ACEP for 5 ACEP Category I credits. Approved by the AOA for 5 Category 2-B credits. A minimum score of 75% is required.

Commercial Support. There was no commercial support for this CME activity.

Target Audience. This educational activity has been developed for emergency physicians.

Volume 29 • Number 11

In This IssueLesson 21 Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 2

With presentations that span the clinical spectrum – from mild symptoms that mimic viral gastroenteritis to critical encephalopathy and variceal bleeding – patients with acute and chronic liver diseases are common in the emergency department. It is imperative for clinicians to understand the pathophysiology, etiology, and management strategies of these often dangerous diseases, and know how to recognize and treat them expeditiously.

Lesson 22 Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 13 Hyponatremia is encountered frequently in the emergency department, and effective management of the disorder depends on the symptomatic presentation, acuity, and underlying cause of each particular case. The distinction between acute versus chronic, benign versus severe, and causality guide the differential diagnosis, workup, and treatment. Emergency providers must understand when and how to correct sodium levels in these patients to avoid significant morbidity and even death.

■ Also in This Issue• The LLSA

Literature Review page 11

• The Critical ECG page 12

• The Critical Image page 20

• CME Questions page 22

• The Drug Box page 24

■ Next Month• Approaches to

Abdominal Pain

• Pediatric Fever and Serious Bacterial Illness

November

2015

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Lesson 21Liver Disease

Sharon A. Swencki, MD, FACEP; Jessica Shackman, MD; and Geoffrey Froehlich, DO

■ ObjectivesOn completion of this lesson, you should be able to:

1. Identify the clinical signs of acute and chronic liver diseases.

2. Describe the management of acetaminophen overdose.

3. Identify liver diseases associated with pregnancy.

4. Describe the management of acute hepatic failure.

5. Explain the management strategies for common complications of cirrhosis.

■ From the EM Model

2.0 Abdominal and Gastrointestinal Disorders 2.3 Liver

Patients with liver disease present to the emergency department on a

daily basis with symptoms that vary widely in severity and presentation. Infections, toxins, and pregnancy-related disorders are among the most common causes of acute liver disease; while patients with chronic liver disease frequently seek emergency treatment for complications of cirrhosis. Diagnosing these conditions can be challenging, so it is important for the emergency physician to understand the pathophysiology and etiology of their many culprits and be adept at managing both acute and chronic cases.

Case Presentations■ Case One

A 28-year-old man presents with nausea, vomiting, mild abdominal pain, and jaundice. He admits to using intravenous drugs for the past 6 months, but denies a history of hepatitis. Vital signs are blood pressure 110/72, pulse rate 115, respiratory rate 22, and temperature 38.4°C (101.2°F). Sclera are icteric, and mucous membranes are dry. The patient’s lungs are clear, and his heart sounds are tachycardic but regular. The abdomen is soft with mild right upper-quadrant tenderness. Hepatomegaly is present with palpable firm liver edges.

Laboratory tests reveal mild dehydration. Alanine aminotrans ferase (ALT) and aspartate amino trans ferase (AST) levels are more than 1,000 IU/L, and the serum total bilirubin concentration is elevated at 6.4 mg/dL.

■ Case TwoA 35-year-old pregnant woman with

a 33-week twin gestation presents with dizziness and abdominal pain. She

reports acute epigastric pain, nausea, and vomiting that started about 2 hours ago. The patient’s pregnancy had been going well until recently, when she began experiencing headaches and swelling in her hands and face.

A physical examination reveals a gravid patient who is pale and diaphoretic; she is in obvious pain. Vital signs are blood pressure 75/46, pulse rate 136, respiratory rate 28, and temperature 37.2°C (99°F). The head and neck examination is unremarkable. The woman’s lungs are clear, and her heart is tachycardic. The abdomen is gravid with palpable fundus well above the umbilicus, and is somewhat rigid and extremely tender.

Laboratory abnormalities include a platelet count of 68,000, AST concentration of 870 IU/L, ALT concentration of 300 IU/L, bilirubin level of 18 mg/dL, INR of 2.6, and proteinuria. A bedside sonogram reveals free fluid in the abdomen and two fetuses with heart rates of 113 and 105 beats/min.

■ Case ThreeA 51-year-old man presents with a

24-hour history of acute mental status change. He is accompanied by his daughter, who states that he began vomiting yesterday and then became disoriented. He has become increasingly agitated, confused, and aggressive. The patient has a history of hepatitis C and sometimes takes lactulose for inattention, trouble sleeping, and disorientation.

In the emergency department, he is diaphoretic and yelling and grabbing at the air. Vital signs are blood pressure 147/99, pulse rate 109, respiratory rate 20, and temperature 36.4°C (97.5°F). Sclera are anicteric, and mucous membranes are moist. The neck is supple, lungs are clear, and heart sounds

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• What clinical findings should raise suspicion for acute viral hepatitis, and how should these infections be managed?

• What role do vaccines play in the treatment of viral hepatitis?

• What other infectious causes of acute liver inflammation should be included in the differential diagnosis?

• What medications are the most common culprits in drug-induced liver failure, and what antidotes should be employed?

• What special considerations should be made for pregnant patients with suspected liver disease?

• What therapies should be started immediately in patients with acute liver failure?

• What are the most common complications of chronic liver disease, and how should they be managed?

• How should coagulopathy be approached in patients with chronic liver disease?

• How should liver patients post-transplant be managed in the emergency department?

Critical Decisions

are tachycardic. The abdomen is soft but distended, with a positive fluid wave. There are notably engorged superficial vessels on the abdomen. A rectal examination shows heme-negative brown stool. The patient is alert, but does not follow commands. He is moving all four extremities, and asterixis is present.

A complete blood count reveals a hematocrit of 38.8% and a platelet count of 90,000. Electrolyte studies are notable for the following concen tra-tions: sodium 135 mEq/L; potassium 5.2 mEq/L; chloride 109 mEq/L; Co2 16 mEq/L; BUN 42 mg/dL; and creatinine 2.2 mg/dL. Liver function tests show only minor abnormalities. The blood ammonia level is 162 mcg/dL.

Acute Liver DiseaseAcute liver disease can result from

infection, metabolic disturbances, toxic injury, or hepatic perfusion abnormalities – all of which lead to inflammation or injury with hepatocyte necrosis and potential scarring in the liver. The clinical spectrum of disease ranges from asymptomatic infections to acute liver failure.

CRITICAL DECISIONWhat clinical findings should raise suspicion for acute viral hepatitis, and how should these infections be managed?

Most patients with viral hepatitis present during the symptomatic phase of illness. Common initial complaints

that should raise suspicion for acute liver disease include right upper-quadrant pain, fatigue, anorexia, aversion to strong odors, and dark urine or pale stools. A history of travel, consumption of undercooked foods, IV drug use, sexual contacts, and exposure to another person with viral hepatitis are important risk factors that should be assessed. The physical examination might reveal jaundice or a firm, enlarged liver with palpable margins. Dehydration also might be present secondary to nausea and vomiting.1

When viral hepatitis is suspected, laboratory studies (including a full set of liver function tests) should be requested, along with a coagulation profile, alkaline phosphatase, creatinine, electrolytes, and fractionated serum bilirubin.2 Elevated conjugated or direct bilirubin will be predominant in viral hepatitis. The alkaline phosphatase can be as high as twice normal levels; aminotransferases might be 10 to 20 times the upper limit of normal.3

The mainstay of emergency department management of acute viral hepatitis is supportive care, including intravenous rehydration and treatment of nausea and pain. Signs and symptoms that should raise concerns for more severe disease include altered mental status, hypoglycemia, severe hyperbilirubinemia, renal insufficiency, and prolonged coagulation tests. Hospital admission should be

considered in patients with any of these ominous indicators of acute liver failure.1

Serologic tests for viral antibodies should be requested if there is a clinical suspicion for acute viral hepatitis. Although the results usually do not affect emergency department management, they will aid inpatient or follow-up care. Ammonia levels may be elevated as well, and should be assessed in any patient with altered mental status in the setting of presumed acute hepatitis.1

Admission GuidelinesMost patients with viral hepatitis

do not require hospital admission. Patients with clinical and laboratory indicators of acute liver failure should be admitted to the ICU.3 For those who are discharged home, a primary care physician should be enlisted to provide additional monitoring, education, follow up of hepatitis serologic tests, and any necessary treatment.

CRITICAL DECISIONWhat role do vaccines play in the treatment of viral hepatitis?

Hepatitis A, B, and D are considered vaccine-preventable diseases. The hepatitis A (HAV) vaccine should be administered to any patient diagnosed with HAV who has not already been immunized, preferably within 14 days of exposure. Along with the first dose of the

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vaccine, a single intramuscular injection of HAV immunoglobulin is preferred in children older than 1 year, adults older than 40, and immunocompromised patients.3

The hepatitis B (HBV) vaccine is protective against both HBV and hepatitis D (HDV). In patients with known exposure to HBV and no history of vaccination, both HBV immunoglobulin and the first dose of HBV vaccine should be given within 2 weeks of exposure, preferably within the first 24 to 48 hours, as spontaneous recovery occurs in 95% of acute HBV cases. Routine antiviral therapy is of unlikely benefit; however, infection in immunocompromised individuals may respond to antiviral therapy with lamivudine.4,5

There is no vaccine or immunoglobulin that is effective against hepatitis C (HCV). Early initiation of interferon-based monotherapy should be considered in patients with acute HCV, although this therapy does not need to be initiated in the emergency department.3 Most recent studies demonstrate that early treatment (within the first 4 weeks of diagnosis) can improve the prognosis and prevent chronic infection.10 Immunoglobulin, vaccines, and antiviral agents are not recommended for postexposure prophylaxis in patients exposed to HCV.7

CRITICAL DECISIONWhat other infectious causes of acute liver inflammation should be included in the differential diagnosis?

In addition to hepatitis viruses, there are a variety of infectious agents that can cause acute liver inflammation, including the herpes simplex virus, cytomegalovirus, varicella-zoster virus, Coxsackie virus, and Epstein-Barr virus. Although unlikely to cause clinically significant hepatitis in an otherwise healthy patient, they can be a source of severe illness in the immunocompromised host.2

Liver abscesses can be

pyogenic, fungal, or amebic, and most commonly are found in immunocompromised patients and those with underlying malignancies. Biliary tract disease is the most common source of pyogenic abscesses, which usually are due to gram-negative rods (most commonly, Escherichia coli and Klebsiella pneumoniae).8

Patients often present with signs and symptoms of systemic toxicity. Entamoeba histolytica causes amebic liver abscesses, the most common extrahepatic manifestation of amebiasis. Fungal abscesses, primarily due to Candida albicans, often occur in patients with prolonged antibiotic exposure, hematologic malignancy, solid-organ transplant, or other immunodeficiency.8 Fitz-Hugh-Curtis syndrome is an uncommon perihepatic complication of pelvic inflammatory disease caused by Neisseria gonorrhoeae or Chlamydia trachomatis. Liver function tests typically are normal; therefore, the diagnosis frequently is made when a CT scan reveals perihepatic inflammation.2

CRITICAL DECISIONWhat medications are the most common culprits in drug-induced liver failure, and what antidotes should be employed?

Innumerable substances can cause acute liver failure, including prescription and over-the-counter pharmaceuticals, herbal remedies, and illicit drugs. The most common offending agents are antituberculosis drugs, antibiotics (eg, amoxicillin/clavulanate, trimethoprim-sulfamethoxazole, and nitrofurantoin), halothane, antiepileptics, nonsteroidal anti-inflammatory drugs, and acetaminophen.9

Acetaminophen hepatotoxicity is the most common cause of acute liver failure in the US and many other western countries, accounting for up to 42% of cases.10 Acetaminophen is a dose-dependent toxin.11 Therapeutic doses are defined as less than 4 grams per day for adults and less than 75 mg/kg for children. For single-dose

ingestions, drug levels are measured in relation to time of ingestion, and the concentrations are applied to the Rumack-Matthew nomogram to assess for toxicity. Levels should be measured at least 4 hours after acute ingestion; serial measurements up to 12 hours after ingestion might be warranted to fully exclude significant overdose with extended release preparations.

Serum acetaminophen levels above 150 mg/L at 4 hours are considered toxic. The United Kingdom, however, recently decreased its treatment threshold to 100 mg/L at the 4-hour mark.10 Chronic or staggered acetaminophen ingestions cannot be applied to this nomogram, and should be considered for treatment regardless of initial drug levels.10

Acetaminophen is metabolized in the liver by three mechanisms. The main pathways of metabolization are glucuronidation and sulfation, the end products of which are nontoxic substances excreted by the kidneys. The third metabolic pathway is represented by the cytochrome P-450 system. The end product of this pathway is N-acetyl-p-benzoquinoneimine (NAPQI), which binds to hepatic proteins and causes necrosis. The antidote to NAPQI is the naturally occurring substance glutathione, which is quickly depleted with toxic doses of acetaminophen, leading to hepatic necrosis.11 Due to baseline-depleted glutathione reserves and upregulation of the cytochrome P-450 system, patients with malnutrition, chronic alcohol use, fasting, and chronic liver disease are at an increased risk of hepatotoxicity from acetaminophen overdose.10,11

N-acetylcysteine therapy is the antidote for acetaminophen overdose; it is most effective when given within 8 to 10 hours after ingestion, but its beneficial effects can be extended.11 If there is any possibility a patient was exposed to a toxic level of the drug, the emergency physician should initiate treatment – either oral (loading dose 140 mg/kg, then 70 mg/kg every 4 hours for a total of

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17 doses over 3 days) or intravenous (loading dose 150 mg/kg, then 50 mg/kg for 4 hours, then 100 mg/kg over the next 16 hours).11 Treatment can be stopped if further evaluation reveals the patient was not exposed to a toxic amount of the drug.

Treatment for hepatotoxicity secondary to nonacetaminophen drug use requires cessation of the offending agent and supportive care.9

CRITICAL DECISIONWhat special considerations should be made for pregnant patients with suspected liver disease?

Although many of the previously discussed liver disorders can occur in pregnancy, there are several that specifically affect pregnant women. Given their significant clinical and laboratory overlap, these diseases often present a diagnostic dilemma.

Hyperemesis GravidarumAlthough not specific to the

liver, this disease frequently causes elevated aminotransferases, with AST/ALT levels often >200 IU/L. Total bilirubin and alkaline phosphatase levels may be elevated (up to twice the normal level), and jaundice might be evident.12

The condition occurs in the first trimester in approximately 0.3 to 1% of pregnancies, and often is accompanied by persistent nausea and vomiting that can lead to malnutrition and dehydration. Although the exact cause is unknown, risk factors include prior episodes of hyperemesis, mulitparity, molar pregnancy, multiple gestations, high body mass index, and pre-existing diabetes.12 Treatment consists of supportive care with fluids, and pharmacologic treatment with H1-receptor blockers, vitamin B6, and antiemetic agents.12

HELLP SyndromeA potentially life-threatening

complication of pregnancy, hemolysis elevated liver enzymes, low platelets (HELLP) syndrome is a multisystem disorder with or without preeclampsia. The prevalence is estimated at 6 in 1,000 deliveries.

Risk factors include advanced maternal age, Caucasian race, and multiparity.13 The pathogenesis is not clear, but the disorder may be related to abnormalities with the placenta.14

Patients often present with symptoms that mimic a nonspecific viral illness, most commonly abdominal pain (right upper-quadrant and epigastric), nausea, vomiting, and malaise. Headache and jaundice are less common.14 Hypertension and proteinuria are present in approximately 85% of cases. Although HELLP most frequently occurs in the third trimester, up to 30% of cases are postpartum, usually arising within 48 hours of delivery.16

Laboratory evaluation may reveal thrombocytopenia, elevated LDH (suggesting hemolysis), and elevated transaminases. Significant overlap exists between HELLP syndrome and acute fatty liver of pregnancy (AFLP); however, hypertension is more common in cases of HELLP, whereas AFLP often is associated with other signs of severe liver failure and renal dysfunction.13 Treatment is aimed at maternal stabilization and control of blood pressure. Consultation with obstetrics or a maternal-fetal specialist should be performed to determine the timing of fetal delivery, as this is the only definitive treatment.14

Acute Fatty Liver of Pregnancy AFLP is found in approximately 1

in 7,000 to 1 in 20,000 pregnancies during the third trimester.15 Although rare, the disorder is more common in first and multiple-gestation pregnancies. The pathophysiology involves microvesicular fatty infiltration of hepatocytes. Patients generally present with nonspecific complaints of abdominal pain, nausea, vomiting, malaise, anorexia, and jaundice (similar to viral hepatitis), and have true hepatic dysfunction with concomitant signs of preeclampsia and HELLP.15

Laboratory abnormalities can include elevated WBC count, transaminases (usually <500 IU/L), alkaline phosphatase, bilirubin, BUN, creatinine, and PTT and INR.

Thrombocytopenia and evidence of hemolysis also may be present.15 There is significant overlap between AFLP and HELLP syndrome, and it can be difficult to clinically distinguish these two conditions. However, evidence of hepatic insufficiency (eg, hypoglycemia, coagulopathy, and encephalopathy) more often is seen in cases of AFLP.12 Liver biopsy is diagnostic, but not routinely performed. Imaging (ie, ultrasound or CT) primarily is used to rule out other diagnoses such as hematoma, hepatic infarct, or gall bladder disease.15

If left untreated, AFLP can progress to acute liver failure, renal failure, pancreatitis, uncontrollable hemorrhage, disseminated intravascular coagulation, and death. Treatment is directed at maternal resuscitation and prompt delivery of the fetus, regardless of gestational age. Clinical recovery typically occurs within several days of delivery, although laboratory abnormalities may persist.15

Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) occurs in the second and third trimesters and is the most common liver disease in pregnant women (1.0% to 1.5%).16 Although the pathogenesis is unknown, the disease is thought to be related to elevated serum estrogen levels, as estrogen levels reach a peak in the third trimester. ICP also is more common in multiple gestation pregnancies, which are associated with higher levels of circulating estrogen.16

The acute presentation of ICP is characterized by pruritus of the palms and soles (often worse at night), along with elevated serum bile acids, alkaline phosphatase, and bilirubin. Transaminase levels can be markedly elevated (>1000 unit/L). Abdominal pain and jaundice are uncommon.16

Although ICP is a relatively benign maternal disease, it is associated with serious fetal complications, including an elevated risk of preterm delivery, meconium passage, fetal distress, and

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intrauterine demise. The mechanism is thought to be related to the toxicity of bile acids on fetal cardiac myocytes and vasoconstrictive effects on chorionic veins.17 Maternal treatment with ursodeoxycholic acid has been shown to relieve symptoms, reduce serum bile acid levels, and prolong gestation.16 However, emergency department management should be focused on differentiating ICP from other acute and infectious causes of liver disease; obstetrics should be consulted for further management. Delivery of the fetus is the only definitive treatment.17

CRITICAL DECISIONWhat therapies should be started immediately in patients with acute liver failure?

Acute liver failure is marked by the onset of hepatic encephalopathy and coagulopathy within a short time period in previously healthy individuals.18,19 This relatively rare but serious disease process is diagnosed in an estimated 2,000 US patients each year, and leads to multiorgan dysfunction with neurologic, renal, pulmonary, and hemodynamic sequelae.19

Acute liver failure commonly is divided into subgroups of hyperacute (<7 days), acute (1 to 4 weeks), and subacute (>5 weeks), based on the onset of encephalopathy after the appearance of jaundice.20 The highest survival rates are in patients with hyperacute disease, while those with subacute disease have the poorest prognosis.18,20

Specific targeted therapy exists for only a handful of conditions that cause acute liver failure (eg, N-acetylcysteine for acetaminophen overdose, penicillin or silibinin for Amanita muscaria mushroom poisoning, and delivery of the fetus for pregnancy-related liver disorders). For the remainder of these patients, supportive care is the mainstay of treatment. This includes volume expansion, correction of acid/base status and electrolytes, monitoring for infection with routine cultures, maintaining normothermia and normoglycemia, avoiding fluid

overload, controlling systemic hypertension, correcting hypoxia, controlling fever, avoiding nephrotoxic medications, and rapidly diagnosing and treating infection.18

Patients with acute liver failure are at high risk for fungal and bacterial infections (up to 80%).20 Worsening of hepatic encephalopathy or decreasing renal function might be the only sign of infection. Surveillance for infectious complications with chest radiographs and periodic cultures of urine, sputum, and blood are warranted, and prophylactic antibiotics often are administered.19,20

Chronic Liver DiseaseChronic diseases of the liver are the

12th leading cause of death in the US The most common causes of cirrhosis are viral hepatitis and alcoholic liver disease, which generally is viewed as a continuum – a description that may not truly reflect pathophysiology. Most heavy drinkers have increased fatty infiltration of hepatocytes (called steatosis), which can directly lead to cirrhosis that can be reversed with abstinence.

Many with steatosis will develop alcoholic hepatitis, an inflammatory process that leads to hepatocellular necrosis. This sometimes manifests as mild jaundice, ascites, hepatomegaly, or generalized malaise, but often is asymptomatic. The ratio of AST:ALT frequently is 2:1 or greater with both values less than 300 IU/mL, often with associated elevations in gamma-glutamyltransferase (GGT).21 The development of alcoholic hepatitis will accelerate the path toward cirrhosis.

Of those chronically infected with hepatitis B, 20% to 30% will go on to develop complications such as cirrhosis and hepatocellular carcinoma. While HBV largely is an asymptomatic process, patients can suffer from acute flares of the disease, leading to rapidly progressive acute-on-chronic liver failure signified by rapid elevations of ALT.22

Between 2.7 and 3.9 million Americans currently live with HCV. Given the high percentage of chronic

infection, the emergency department care of these patients largely centers on chronic complications.23

Regardless of underlying etiology, the final pathways that lead to cirrhosis are identical – hepatocellular death leads to the replacement of parenchymal tissue with fibrotic scar tissue surrounding nodules of regenerative tissue. This results in decreased hepatocellular function and the disruption of blood flow, leading to the development of portal hypertension.21

CRITICAL DECISIONWhat are the most common complications of chronic liver disease, and how should they be managed?

Many patients are asymptomatic during the period of compensated cirrhosis, and might only be diagnosed by their history and abnormal labora tory findings (eg, increased bilirubin and prothrombin time, elevated INR, and decreased albumin and platelets). These patients should be referred for further workup if discovered de novo in the emergency department.24

AscitesAscites is the most frequent

complication in cirrhosis (experienced by roughly 60% of patients within 10 years of receiving the diagnosis), and indicates an increased risk of death. In patients without an established diagnosis of cirrhosis, however, laboratory studies, imaging, and ascitic fluid sampling should be used to rule out extrahepatic causes such as right heart failure, malignancy, pancreatic disease, tuberculosis, and renal pathology.

The pathophysiology of ascites in patients with cirrhosis is complex and not well understood. The arterial vasodilation theory (the most recent and accepted hypothesis) suggests that portal hypertension leads to a higher splanchnic blood volume and increased production of nitric oxide, resulting in splanchnic and arterial vasodilatation. This decreases the effective circulating

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blood volume; the kidneys – sensing a relative malperfusion – activate the renin-angiotensin-aldosterone system, resulting in increased sodium and water retention. This further dilutes an already-reduced albumin concentration. The increased splanchnic hydrostatic pressure subsequently overwhelms the oncotic pressure, allowing transudative fluid to leak into the peritoneum.25

Medical therapy should be guided by salt restriction, loop diuretic therapy, aldosterone antagonists such as spironolactone, and oral midodrine. Avoid NSAIDs to reduce renal sodium retention, and beta-blockers and ACE inhibitors to prevent arterial hypotension. Up to 10% of patients will have refractory ascites despite maximal medical therapy; in such cases, serial paracentesis can be used to relieve associated pain and shortness of breath (4 to 6 liters of fluid can be safely removed without complication).

In patients who undergo large-volume paracentesis (>6 liters), administration of albumin is recommended to prevent paracentesis-induced circulatory dysfunction (PICD), a worsening of renal function, and a rapid reaccumulation of ascites. Despite the frequent comorbid coagulopathy and thrombocytopenia in patients with ascites, the prophylactic transfusion of blood products is discouraged.25,26

Patients who become refractory to medical therapy should be referred for a procedure such as transjugular intrahepatic portosystemic shunt (TIPS), peritoneovenous shunt, or liver transplantation, as 6-month mortality in these patients is as high as 20%.25

Spontaneous Bacterial PeritonitisSpontaneous bacterial peritonitis

(SBP) is a feared complication of the development of ascites that carries a mortality rate of 20% per episode. Patients often present with localizing abdominal symptoms (eg, pain, tenderness, nausea, vomiting), signs of systemic inflammation (eg, fever, leukocytosis, tachycardia, tachypnea,

shock), or other symptoms such as worsening encephalopathy, renal failure, or acute liver decompensation.25 A significant percentage of patients (10% to 40%) can be asymptomatic, so all fluid removed by paracentesis should be analyzed. The incidence of SBP in hospitalized patients with ascites approaches 30%; diagnostic paracentesis should be performed on all such patients, regardless of the admitting diagnosis.26

If SBP is suspected, a cell count and culture of the peritoneal fluid should be obtained. Patients with a peritoneal fluid polymorphonuclear leukocyte (PMN) count greater than 250 cells/mm3 are at risk of SBP and should receive antibiotic treatment. Antibiotics also should be initiated for any patient in whom signs or symptoms of SBP exist, regardless of peritoneal fluid PMN count.

When positive, cultures can help confirm the diagnosis, but it is important to note that they may be negative in as many as 60% of patients. While unlikely to be encountered in the emergency department, patients with positive cultures of peritoneal fluid and a negative PMN count should undergo a repeat paracentesis. These patients should be treated if they show signs of infection pending the second culture, and consideration should be given to secondary sources of bacteria.26

In patients for whom a secondary source of peritonitis is suspected, imaging with CT should be obtained in addition to peritoneal cell counts. Other testing of the peritoneal fluid for protein, glucose, LDH, CEA, and alkaline phosphatase has been suggested to distinguish primary from secondary peritonitis, but no clear consensus exists.26

While the exact mechanism of bacterial entry into peritoneal fluid is not fully understood, 95% of SBP is attributed to E. coli, gram-positive Streptococcus, or the Enterococcus species. Antibiotic coverage should reflect this. Third-generation cephalosporins are the first-line treatment choice (of note, cefotaxime

Pearls

• The mainstay of treatment for both acute and chronic liver disease is general supportive care.

• Unstable gravid women with pregnancy-related liver diseases require delivery of the fetus as soon as possible.

• Maintain a high level of suspicion for systemic infection in patients with acute liver failure.

• All patients with variceal bleeding should be given antibiotics, which reduce mortality.

Pitfalls

• Failing to initiate treatment for acetaminophen toxicity in cases of unconfirmed overdose.

• Using abnormal ammonia levels to diagnose hepatic encephalopathy. This diagnosis must be made clinically; however, normal ammonia levels are useful in ruling out HE.

• Using fresh-frozen plasma to normalize INR as a bleeding prophylaxis. INR is not useful in this regard and will lead to increased transfusion of products and a higher risk of adverse events.

• Failing to assess and adjust medication dosages in patients with cirrhosis. Due to an impairment of metabolism in both activation or degradation of medications, clinical effects can be significantly altered in these patients.

Critical Decisions in Emergency Medicine

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has good accumulation in ascitic fluid). Other antibiotics such as amoxicillin/clavulanate or fluoroquinolones are viable alternatives.

Treatment in patients with a sus-pected nosocomial source or a recent exposure to beta-lactam antibiotics should be guided by personal or insti-tutional antibiograms.26 Albumin also should be added to the treatment reg-imen at 1.5 g/kg in patients with SBP and creatinine >1 mg/dL, blood urea nitrogen >30 mg/dL, or total bilirubin >4 mg/dL. Treatment with albumin outside of these parameters is contro-versial. Any patient with a previous ep-isode of SBP should receive prophylaxis with norfloxacin or trimethoprim/sul-famethoxazole, and should be referred for liver transplant.26

Hepatorenal SyndromeHepatorenal syndrome is defined

as deterioration of renal function that occurs in patients with advanced liver disease. It may occur spontaneously or after an infectious process such as SBP. Decreased effective arterial blood volume due to splanchnic vasodilation, often combined with impaired cardiac function, leads to an increase in the renin-angiotensin-aldosterone system (RAAS), increased renal artery vasoconstriction, and decreased renal perfusion.25 Other causes of renal failure must be excluded, including parenchymal renal disease, hypovolemia from excess diuresis, shock, or nephrotoxins. Patients should be screened for sepsis with blood, urine, and ascitic fluid cultures. Urinalysis should be performed to assess for hematuria or proteinuria, and a renal ultrasound should be obtained.

Patients with hepatorenal syndrome, especially those with rapidly deteriorating renal function, might be best managed in an intensive care unit, where hemodynamic parameters and fluid balance can be closely monitored. Patients should be treated with a combination of albumin and vasoconstrictors such as norepinephrine or midodrine and octreotide. Terlipressin, a vasopressin analogue, is a first-line treatment in

Europe, but remains unavailable in the US. Consideration should be given to renal replacement therapy, and patients should be given an expedited referral for liver transplantation.26

Hyponatremia Hyponatremia, a frequent

complication of cirrhosis, shares its pathogenesis with other cirrhotic complications described in previous sections. The activation of the RAAS axis leads to an increase in ADH secretion, as do baroreceptors in the carotid sinus and left ventricle, which sense a decreased effective blood volume. This excess ADH causes increased free water reabsorption and decreased free water excretion, leading to a dilutional hyponatremia.27

The body – particularly the brain – is able to compensate fairly well to chronic changes in sodium concentration, and many patients are asymptomatic. Vague symptoms such as imbalance, fatigue, nausea, and confusion are common. Acute drops in serum sodium can occur with changes in renal perfusion from processes such as medication noncompliance or infection, as well as the ingestion of large amounts of hypotonic fluids and binge drinking. This can lead to cerebral edema, coma, and seizures.27

Consistent with other causes of hyponatremia, the acuity of the drop in sodium levels should match the speed at which levels are corrected, with rapid corrections reserved for severe acute hyponatremia and severe neurologic symptoms. Therapy generally is instituted with a threshold of 130 mEq/L, and free-water restriction to less than 1 to 1.5 L/day. Small studies have shown a benefit in albumin infusion. The use of antagonists of the V2 receptor in the kidney (vaptans) have shown some promise in improving hyponatremia and decreasing ascites. No mortality benefit has been demonstrated, however, and the treatment is not currently recommended.27

Hepatic Encephalopathy Hepatic encephalopathy (HE)

is defined by the American and European Associations for the Study of Liver Disease (AASLD and EASL) as “brain dysfunction caused by liver insufficiency and/or portosystemic shunting; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma.” Encephalopathy is staged from minimal impairment (recognized only with psychometric or neuropsychological testing) to stage IV (comatose). Grades II-IV, which are referred to as overt hepatic encephalopathy (OHE), represent decompensated cirrhosis. An estimated 30% to 40% of patients with cirrhosis will experience HE, with 20% to 80% having minimal impairment, and 5% to 25% experiencing OHE within 5 years of diagnosis.28

The pathogenesis of HE is complex and not well understood. Theories center on the altered metabolism of neurotoxic substances, and growing evidence points to disturbances in astrocyte function, cellular swelling, and disruption of the blood-brain barrier. Ammonia is one of the chief substances implicated in this process, but blood ammonia levels are neither diagnostic nor prognostic. A normal ammonia level, however, should prompt a search for alternate causes of altered mental status.

Acute decompensations can be triggered by a number of processes, including (but not limited to) gastrointestinal bleeding (especially variceal bleeding), infection, medication effects, constipation, dietary changes, or worsening of hepatic or renal function. Because there is no definitive test for HE in the emergency department, it is important to maintain a broad differential, with particular consideration given to electrolyte abnormalities such as hyponatremia, hypoglycemia, ketoacidosis, infection, medication or intoxicant effects, or intracranial events such as stroke or hemorrhage.28

Treatment should be initiated for any patient with OHE. Management

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of the airway and identification and control of the precipitating factor should be the primary focus; these strategies may be effective in up to 90% of patients. The first-line therapy for HE is nonabsorbable disaccharides, including lactulose. Antibiotics such as rifaximin also can be added. These treatments may be given via a nasogastric tube in patients who are at risk for aspiration.28

Variceal BleedingVariceal bleeding can be dramatic;

unfortunately, the development of upper gastrointestinal tract varices is quite common in patients with liver disease. The prevalence of esophageal varices is 30% to 70% in patients with cirrhosis, and generally is correlated with the severity of liver disease. Thirty percent of patients will have bleeding within the first year of this diagnosis.29

Prevention of variceal bleeding is done with endoscopic band ligation or sclerotherapy, as well as treatment with nonselective beta-blockers such as nadolol, propranolol, or carvedilol, which appear to decrease rates of hemorrhage but do not reduce the mortality risk of varices.29

The treatment of acute bleeding from varices should start with resuscitation with blood products; intubation should be considered to decrease the risk of blood aspiration. A restrictive transfusion strategy targeting a hemoglobin concentration of 7 g/dL versus 9 g/dL has been shown to decrease rebleeding and reduce mortality in patients with milder cirrhosis. No mortality benefit has been found in patients with severe cirrhosis, due in part to decreased portal pressures and a reduction in adverse transfusion-associated events.30 The early transfusion of platelets or plasma should be considered, although no clear evidence exists to indicate their routine use.

Octreotide is the first-line treatment in the US, but terlipressin is the drug of choice when available. Patients should be treated endoscopically with banding or sclerotherapy as soon as

possible, and should be considered for TIPS if this is unsuccessful.29 In patients with severe bleeding, balloon tamponade with a Sengstaken-Blakemore, Minnesota, or similar tube should only be attempted when endoscopy or TIPS are not available.29

All patients with variceal bleeding should be treated with antibiotics (eg, oral norfloxacin, IV ciprofloxacin, or IV ceftriaxone), which can decrease rebleeding, reduce bacterial translocation and SBP, and improve survival.29 Although commonly used in the emergency department management of upper gastrointestinal hemorrhage, proton pump inhibitors are not recommended in the treatment of variceal bleeding.

Medication TherapyA substantial number of medications

require liver processing for activation, metabolism, and excretion, or may be bound to albumin or other proteins that are synthesized in the liver. By some accounts, nearly 50% of all medications have the potential to cause varying degrees of liver injury.31 A discussion of the many changes in liver disease pharmacokinetics is beyond the scope of this article, but it is important to exercise caution and be deliberate when prescribing medications for a patient with cirrhosis. Reference materials and pharmacists should be consulted liberally to ensure patient safety.

CRITICAL DECISIONHow should coagulopathy be approached in patients with chronic liver disease?

Synthetic function of the hepato cytes is impaired in chronic liver disease. There are proteins produced by the liver that possess both procoagu lant and anticoagulant factors, potentially altering the clotting hemostasis. It was long assumed that the increased international normalized ratio (INR) seen in chronic liver disease shifted this balance in favor of coagulopathy. However, there is growing evidence that this assumption may not always be true.32 This balance is extremely brittle, however, and subtle upsets of the tenuous equilibrium can push

a patient toward coagulopathy or hypercoagulability. Additionally, with the frequent comor bidity of decreased platelet counts, assessment of bleeding risk in cirrhotic patients can be exceedingly difficult.

Current laboratory tests, particularly INR, unfortunately do not predict the risk of bleeding in patients with cirrhosis, and INR and platelet counts should not be used alone to determine the risk of bleeding from a procedure.32 Given these limitations, plasma should be used judiciously. Using an INR-guided strategy to determine the amounts of FFP transfused may lead to an increased risk of adverse transfusion-associated reactions. In patients with variceal bleeds, using INR to guide the transfusion of plasma can have the additional undue effect of raising portal pressure.

There is growing evidence that an increased INR does not preclude the development of venous thromboembo-lism (VTE) in patients with cirrhosis, and that patients with chronic liver disease may be at a higher risk of VTE. While research is incomplete and no formal guidelines exist, many experts encourage pharmacological prophylaxis in patients lacking a clear contraindi-cation, especially those with additional risk factors.32

CRITICAL DECISIONHow should liver patients post-transplant be managed in the emergency department?

Liver transplantation ultimately becomes necessary in many patients with chronic liver disease. Patients should be referred early to transplant centers when disease complications begin to manifest.

Despite extensive outpatient sup-port, post-transplant patients visit the emergency department 0.75 to 2 times per year on average. The most common presenting symptoms include gastroin-testinal complaints (eg, abdominal pain, vomiting, and diarrhea) and infectious symptoms (eg, fever, skin and soft tissue infections), reflecting the immunosup-pressive regimens these patients are undergoing. As time from transplant

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increases, injuries and musculoskele-tal complaints frequently arise, likely a response to the neurotoxic and osteopenic effects of these medications. Admission rates have been reported as high as 70%, demonstrating the increased risk of serious disease and fear of decompensation in this patient population.33

Case Resolutions■ Case One

The young IV drug user was given antiemetic agents. He was able to tolerate oral hydration and was discharged home. Serology test results were positive for both hepatitis B surface antigen (HBsAg) and anti-hepatitis B core IgM (anti-HBc), revealing an acute viral infection. A hepatitis B surface antibody (anti-HBs) test was negative, indicating no prior HBV exposure (vaccine or infection). Concurrent infection with HAV or HCV also was ruled out with negative antibody testing.

■ Case TwoA diagnosis of hepatic rupture was

considered in the pregnant woman with HELLP because of her severe pain, acute abdominal findings, hypotension, and free fluid on abdominal ultrasound. She underwent immediate emergency caesarean section and packing of the liver. Her postoperative course was complicated by disseminated intravascular coagulation and renal failure; however, she was discharged home following a long hospitalization. After an unevent ful course in the neonatal ICU, both babies were discharged in good condition.

■ Case ThreeThe disoriented middle-aged man

was admitted to the hospital. Lactulose was given via a nasogastric tube, and he was hydrated with IV fluids and treated prophylactically with antibiotics. Diagnostic para centesis showed no evidence of spontaneous bacterial peritonitis. The patient’s mental status improved, and he signed out against medical advice.

Summary Acute liver disease arises from

hepatic injury caused by infections, toxins, and other metabolic or perfusion abnormalities. Infectious hepatitis viruses – specifically HAV, HBV, and HCV – are the most common infectious causes of liver disease. Toxin-induced acute liver injury can result from many different medications; however, acetaminophen toxicity is one of the most common causes of acute liver disease. Overdose is treated with N-acetylcysteine, both orally and intravenously. Several pregnancy-specific liver diseases exist and must be quickly recognized to ensure positive outcomes for both mother and fetus. In cases of acute liver failure, care is mostly supportive and often requires intensive care-level monitoring.

Cirrhosis of the liver most commonly is the result of chronic alcohol use and viral hepatitis (specifically HBV and HCV). Emergency physicians often are called upon to manage the complications of chronic liver disease, including ascites, SBP, variceal bleeds, hepatorenal syndrome, hyponatremia, coagulopathy, and encephalopathy. While managing these patients revolves around general supportive care, a thorough understanding of related complications and their causes can help guide targeted therapies.

References1. Buggs AM. Viral hepatitis treatment and management.

Medscape Drugs and Diseases [online resource]. Dronen SC, ed. Updated Dec 2014. Available at: http://emedicine.medscape.com/article/775507-treatment#aw2aab6b6b3. Accessed April 12, 2015.

2. O’Mara SR, Gebreyes K. Chapter 83. Hepatic Disorders, Jaundice, and Hepatic Failure. In: Tintinalli JE, Stapczynski J, Ma O, Cline DM, Cydulka RK, Meckler GD, T. eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7e. New York, NY: McGraw-Hill; 2011. Available at: http://accessmedicine.mhmedical.com/content.aspx?bookid=348&Sectionid=40381550. Accessed April 9, 2015.

3. Karmal SM, Fouly AE, Kamel RR, Hockenjos B, et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology. 2006;130(3):632-638.

4. Umar M, Khan AG, Abbas Z, Arora S, et al. Diagnosis, management, and prevention of Hepatitis C. World Gastroenterology Organization Practice Guidelines. April 2013. [online resource]. Accessed April 10, 2015.

5. Tillmann HL, Zachou K, Dalekos GN. Management of severe acute to fulminant hepatits B: to treat or not to treat or when to treat? Liver Int. 2012;32(4):544-553.

6. Wiegand J, Buggisch P, Boecher W, et al. Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study. Hepatology. 2006;43(2):250-256.

7. Centers for Disease Control and Prevention: Viral

Hepatitis. Available at: http://www.cdc.gov/hepatitis. Updated September 2014. Accessed March 25, 2015.

8. Peralta R. Liver abscess. Medscape Drugs and Diseases [online resource]. Geibel J, ed. Updated April 2014. Available at: http://emedicine.medscape.com/article/188802-overview#a0199. Accessed April 12, 2015.

9. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52(6):2065-2076.

10. Lancaster EM, Hiatt JR, Zarrinpar A. Acetaminophen hepatotoxicity: an updated review. Arch Toxicol. 2015;89(2):193-199.

11. Bunchorntavakul C, Reddy KR. Acetaminophen-related hepatotoxicity. Clin Liver Dis. 2013;17(4):587-607.

12. Sasaki KJ. Liver disease and pregnancy. Medscape Drugs and Diseases [online resource]. Isaacs, C, ed. Updated May 2014. Available at: http://emedicine.medscape.com/article/188143-overview#aw2aab6b3. Accessed April 15, 2015.

13. Sibai BM. HELPP syndrome. In UpToDate, Lockwood CJ, Lindor KD (Eds). UpToDate, Waltham, MA. Last updated Jan 2015. Accessed April 15, 2015.

14. Pan C, Perumalswami PV. Pregnancy related liver diseases. Clin Liver Dis. 2011;15(1):199-208.

15. Bacq Y, Lee RH. Acute fatty liver of pregnancy. In UpToDate, Lindor KD, Lockwood, CJ, Travis AC (Eds). UpToDate, Waltham, MA. Accessed April 15, 2015.

16. Lindor KD, Lee RH. Intrehepatic cholestasis of pregnancy. In UpToDate, Lockwood CJ, Chopra S (Eds). UpToDate, Waltham A. Accessed April 15, 2015.

17. Brouwers L, Koster MP, Page-Christiaens GC, et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acids. Am J Obstet Gynecol. 2015;212(1):100.e1-100.e7.

18. Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013;369(26):2525-2534. doi: 10.1056/NEJMra1208937.

19. Polson J, Lee WM; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology. 2005;41(5):1179-1197.

20. Singanayagam A, Bernal W. Update on acute liver failure. Curr Opin Crit Care. 2015;21(2):134-141.

21. O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Am J Gastroenterol. 2010;105(1):14-32.

22. Jindal A, Kumar M, Sarin SK. Management of acute hepatitis B and reactivation of hepatitis B. Liver Int. 2013;33 Suppl 1:164-175.

23. Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. N Engl J Med. 2013;368(20):1859-1861.

24. Marsano LS, Mendez C, Hill D, et al. Diagnosis and treatment of alcoholic liver disease and its complications. Alcohol Res Health. 2003;27(3):247-256.

25. Moore CM, Van Thiel DH. Cirrhotic ascites review: Pathophysiology, diagnosis and management. World J Hepatol. 2013;5(5):251-263.

26. Runyon B. Management of adult patients with ascites due to cirrhosis: update 2012. American Association for the Study of Liver Diseases. [accessed online]. 2013. Available at: http://www.aasld.org/sites/default/files/guideline_documents/adultascitesenhanced.pdf. Accessed May 5, 2015.

27. Gianotti RJ, Cardenas A. (2014). Hyponatraemia and cirrhosis. Gastroenterol Rep (Oxf).2014;2(1):21-26.

28. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2): 715-735.

29. World Gastroenterology Organisation (WGO). Esophageal varices. World Gastroenterology Organisation Global Guidelines [online text]. 2014. Available at http://www.worldgastroenterology.org/assets/export/userfiles/2014_FINAL_ESOPHAGEAL-VARICES.pdf. Accessed May 5, 2015.

30. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11-21.

31. Amarapurkar DN. Prescribing medications in patients with decompensated liver cirrhosis. Int J Hepatol. 2011;2011:519-526.

32. Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol. 2013;11(9):1064-1074.

33. Turtay MG, Oguzturk H, Aydin C, et al. A descriptive analysis of 188 liver transplant patient visits to an emergency department. Eur Rev Med Pharmacol Sci. 2012;16 Suppl 1: 3-7.

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Colchicine traditionally has been recommended as the first-line treatment for recurrent

pericarditis. The referenced study, conducted in Italy from 2005 to 2010, was designed to examine the medication’s role in the treatment of acute cases.

The 240 patients in the multicenter, double-blind trial were randomized to receive either colchicine (.5 mg twice a day for 3 months) or placebo. Both groups, which were demographically and clinically similar, received concurrent anti-inflammatory medication (aspirin or ibuprofen).

Patients over the age of 18 with new-onset pericarditis were invited to enroll. The diagnosis was made using at least two of the following criteria: chest pain typical of pericarditis, a friction rub, suggestive electrocardiographic findings, or a new pericardial effusion. The diagnosis of recurrent pericarditis required a symptom-free interval of 6 weeks; otherwise, patients were diagnosed with incessant pericarditis. Remission was defined as a full resolution of symptoms, as well as electro- and echocardiographic signs of disease.

Patients were followed for almost 2 years with frequent follow-up visits, during which investigators collected laboratory data, an electrocardiogram, and an echocardiogram. No patients were lost to follow up, and adherence was over 95%.

The primary outcome was incessant or recurrent pericarditis, which occurred less frequently in the colchicine group versus the placebo group (16.7% versus 37.5%, p <.001), with a relative risk reduction in the colchicine subset of .56 (95% confidence interval .3 to .72). The colchicine group also demonstrated a statistically significant decrease in symptoms at 72 hours (19.2 % versus 40.0%, p = 0.001), the number of recurrences per patient (.21 versus .52, p = 0.001), and hospitalization

related to pericarditis (5.0% versus 14.2%, p = 0.02). The medication also improved the rate of remission within 1 week of treatment (85.0% versus 58.3%, p <0.001). The overall number of adverse events was similar in the two study groups. Diarrhea was the most common side effect, which occurred in less than 10% of patients.

In summary, this is the first study to investigate the role of colchicine in the treatment of acute pericarditis. This research suggests that the drug can reduce the rate of recurrent or incessant pericarditis, as well as the duration of symptoms and hospitalization associated with the diagnosis. Furthermore, these effects were seen without a loading dose, which often is associated with the unpleasant gastrointestinal side effects of the medication. There was no significant increase in adverse events or side effects in the patients treated with colchicine.

The LLSA Literature Review“The LLSA Literature Review” summarizes articles from ABEM’s 2016 Lifelong Learning and Self-Assessment Reading List. These articles are available online in the ACEP LLSA Resource Center (www.acep.org/llsa) and on the ABEM website.

A Randomized Trial of Colchicine for Acute PericarditisReviewed by Katie E. Golden, MD, Brigham and Women’s Hospital, Boston, Massachussets

Imazio M, Brucato A, Cemin R, et al; ICAP Investigators. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013;369(16):1522-1528.

Article 4

Key Points• Colchicine historically has been

recommended for the treatment of chronic pericarditis. This is the first prospective trial to study the drug in acute pericarditis.

• Colchicine was shown to reduce rates of both recurrent and incessant pericarditis as compared to placebo. It also reduced the length of symptoms, number of recurrences, and hospitalization associated with pericarditis.

• These results were seen with low-dose colchicine without a loading dose. This regimen may help reduce the rate of diarrhea, the drug’s most common adverse side effect.

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The Critical ECGA 21-year-old woman with chest pain.

Ectopic atrial rhythm, rate 97, acute pericarditis. Ectopic atrial rhythm is diagnosed because of inverted P waves in lead III, which excludes the sinus node as the origin of the P waves. The PR interval is normal, excluding an AV junctional rhythm. Diffuse ST-segment elevation is noted. Causes of diffuse ST-segment elevation include large acute MI, acute pericarditis, benign early repolarization, coronary vasospasm, and LVH. Very subtle PR-segment depression is present in several leads (I, II, V4-V6), suggesting acute pericarditis. Additionally, PR-segment elevation is present in lead aVR, and is most suggestive of pericarditis among the various entities in the differential diagnosis.

Feature Editor: Amal Mattu, MD, FACEP. From: Mattu A, Brady W. ECGs for the Emergency Physician 2. London: BMJ Publishing; 2008:11,23. Reprinted with permission.

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Lesson 22

Hyponatremia

Quynh Le, MD and Kristin M. Drogell, MD

■ ObjectivesOn completion of this lesson, you should be able to:

1. Identify and assess patients with hyponatremia.

2. Order and interpret appropriate laboratory studies for assessing hyponatremia.

3. Classify different types of hyponatremia.

4. Describe the signs of acute severe hyponatremia that require emergent treatment.

5. Administer appropriate treatments based on current guidelines.

6. Monitor and control correction to minimize risk.

■ From the EM Model

5.0 Endocrine, Metabolic, and Nutritional Disorders 5.3 Fluid and Electrolyte Disturbances

Approximately 20% of total body weight is comprised of

extracellular fluid (ECF), the majority of which is sodium with an average concentration of 140 mEq/L. Changes to sodium levels can have a substantial impact on a patient’s fluid shift and volumes. Rigid cavities such as the skull are ill equipped to accommodate such fluctuations, which can result in potential damage to the brain.1

Hyponatremia, the most common electrolyte abnormality in hospitalized patients (affecting 15% to 30%), can have a significant impact on morbidity and mortality.1-3 The risk of death increases to 30% in even mild cases, and these patients are hospitalized longer than those who are isonatremic.

Despite the startling statistics, this diagnosis often is neglected by clinicians.3 Its signs and symptoms can be subtle and easily overlooked in patients presenting with vague complaints. Even “asymptomatic” patients can be vulnerable to serious underlying complications.4

On the other hand, symptoms of severe acute hyponatremia may be more overt. The relationship between sodium and water is a balancing act; sudden changes in osmolality, fluid content, and cerebral space restrictions can cause serious neurological sequelae unless quickly identified and reversed.

The rapid deterioration of a patient’s neurological function can be muddled by a practitioner’s fear of potential treatment complications, however, further delaying the initiation of decisive care. Emergency physicians must understand how to identify, categorize, and risk stratify cases of hyponatremia, and be adept at managing these vulnerable patients.

Case Presentations■ Case One

A 20-year-old previously healthy woman is brought to the emergency department after being found unconscious by her roommates. After drinking several alcoholic beverages at home last night, the patient attended a crowded rave party. Her friends report that she took two tabs of Ectasy (3,4-methylenedioxy-methamphetamine [MDMA]) during the rave, but say that she was diligent about drinking water. The patient seemed agitated after the group returned home, but they attributed her behavior to the drug. She was found unresponsive this afternoon.

EMS reports that the patient was hypotensive, tachycardic, and lethargic when they arrived. She was given 1 liter of normal saline (NS) in the ambulance. Initial vitals are blood pressure 88/48 mm Hg, pulse rate 126, respiratory rate 34, temperature 35.0º C (95ºF), and oxygen saturation 80% on a nonrebreather mask. Her pupils are dilated and sluggish. Chest auscultation reveals diffuse crackles bilaterally, distal extremities are cool and cyanotic, and there are no signs of edema.

The patient is intubated, placed on mechanical ventilation, and started on 1 liter of warmed intravenous fluids. She continued to be hypotensive. An additional 2-liter NS bolus is given, and she is placed on a dopamine drip. A Foley catheter is placed, which results in a total urine output of approximately 2 liters.

Initial diagnostic findings are Na 116 mEq/L, Cl 87 mEq/L, Hco

3

16 mEq/L, BUN 18 mg/dL, creatinine 1.0 mg/dL, glucose 110 mg/dL,

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• What critical signs and symptoms should raise suspicion for hyponatremia?

• What are the most common and serious causes of hyponatremia?

• What are the primary markers of hyponatremia, and how is it classified?

Critical Decisions

calcium 9.0 mg/dL, pH 7.14, Pco2 39 mm Hg, and Po2 99 mm Hg. The patient has a serum osmolality of 245 mOsm/kg, urine specific gravity of 1.015, WBC 17,500 cells/mm3, Hg 13.1 g/dL, and platelet count of 289,000 cells/mm3. A chest radiograph reveals bilateral pleural edema, and a head CT shows cerebral edema.

■ Case TwoA 25-year-old man with a history of

paranoid schizophrenia is brought to the emergency department following 4 to 5 witnessed “full body” seizures, which lasted approximately 5 minutes with a brief pause in between. On arrival, the patient is somnolent, moaning to painful stimuli, and moving all extremities.

Initial vital signs are blood pressure 108/83 mm Hg, pulse 110, respiratory rate 30, temperature 36.9ºC (98.2ºF), and oxygen saturation 88%. An examination reveals a laceration to the left margin of the patient’s tongue, grade II/VI systolic murmur, hypoactive symmetrical reflexes, and absence of Babinski reflexes bilaterally. There are no signs of trauma, respira-tory distress, arrhythmia, cyanosis, or edema. He is compliant with his medications (chlorpromazine and imipramine). The patient is placed on 5 liters O2 via nasal cannula.

Initial diagnostic findings are Na 116 mEq/L, potassium 4.9 mEq/L, chloride 88 mEq/L, carbon dioxide 20 mEq/L, BUN 9 mg/dL, creatinine 1.0 mg/dL, and glucose 105 mg/dL. The patient’s serum osmolality is 231 mOsm/kg H2O, urine osmolality is 79 mOsm/kg H2O, and urine sodium is 24 mEq/L. The results of a head CT are normal.

■ Case ThreeA 24-year-old woman presents

with abdominal pain, nausea, and vomiting. She is restless with a headache, and she reports two episodes of non-bloody nonbilious vomiting at home. The patient presented with similar symptoms yesterday and was diagnosed with acute appendicitis. She was admitted for a laparoscopic appendectomy and received a 5% dextrose infusion pre- and postoperatively. There were no surgical complications and she was discharged home this morning.

On examination, she appears uncomfortable and confused. She is mildly tachypneic, has mild rales in both lung bases, and mild tenderness over the incisions, which are dry and intact. Mucous membranes are moist, and she has no signs of edema. There are no other notable physical findings.

She is placed on 2 liters nasal cannula, given a 1-liter NS bolus, 4 mg ondansetron hydrochloride, and 4 mg of morphine. A chest radiograph shows mild pulmonary vascular congestion and edema. Initial diagnostic findings are Na 119 mEq/L, serum osmolality 249 mOsm/kg, and urine osmolality 210 mOsm/kg.

CRITICAL DECISIONWhat critical signs and symptoms should raise suspicion for hyponatremia?

Patients generally present with neurological complaints, which are triggered as the brain attempts to prevent cerebral edema by managing the fluid shifts caused by hyponatremia. As with most systems, the severity

of symptoms and a patient’s ability to compensate are related to the rate of change. Some patients are asymptomatic, while others present with seizures that progress to coma and death. More often, patients present with ambiguous complaints such as headache, nausea and vomiting, restlessness, anorexia, malaise, myalgia, minor gait disturbances, poor memory and/or confusion.1,4,5

Most patients begin to show overt neurological symptoms such as obtun-dation and seizure when serum sodium levels fall below 120 mEq/L. Symptoms are secondary to intracerebral osmotic fluid shifts and cerebral edema, espe-cially if this shift is acute or subacute (<48 hours). Increased intracranial pressures can progress to hypoxia, respiratory arrest, and noncardiac pul-monary edema. Eventually, the patient develops seizures, which can progress to coma and ultimately death. Hypona-tremic seizures are self-limited and will stop with correction of hyponatremia; however, they may be refractory to anti-convulsants.1,6

Brief PathophysiologySodium levels are determined

in the context of water, particularly extracellular fluid (the primary solvent of sodium). Sodium regulation occurs through two primary systems: consumption and excretion via thirst regulation and antidiuretic hormone (ADH) respectively. In general, hyponatremia results from the kidney’s inability to balance water excretion and retention with oral intake and serum sodium levels. Nonosmotic causes are associated with poor arterial circulation, such as in cases of congestive heart failure.

• How should patients be risk stratified and monitored in the emergency department?

• What are the most effective treatments for hyponatremia?

• What guidelines should be followed when correcting sodium levels?

• What special considerations are of importance?

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CRITICAL DECISIONWhat are the most common and serious causes of hyponatremia?1. Rapid consumption of low-solute

fluids (eg, drinking water in response to vomiting and diarrhea, and psychogenic polydipsia)

2. Exercise-associated loss of sodium through sweating and excessive water retention

3. Renal excretion of sodium induced by diuretics, particularly thiazides

4. Cerebral salt wasting following neurological insult

5. Syndrome of inappropriate antidiuretic hormone (SIADH) secondary to malignancies, neurological injury, or medications. The continued secretion or action of ADH despite normal or increased plasma volume results in impaired water excretion.

6. Mineralocorticoid deficiency, leading to renal sodium wasting or poor ADH suppression

7. Hypothyroidism (very rare)8. Renal failure (may be related to

acute injury, chronic disease, or nephrotic syndrome)

9. Congestive heart failure10. Liver disease (cirrhosis)11. Multiple medications (Table 1)

CRITICAL DECISIONWhat are the primary markers of hyponatremia, and how is it classified?

Hyponatremia, which is defined as serum sodium less than 135 mEq/L, can develop acutely (<48 hours) or chronically (weeks to months). Sodium concentrations between 130 and 135 mEq/L are classified as mild. Moderate hyponatremia is defined as concentration between 125 and 129 mEq/L, and severe hyponatremia is classified as a concentration less than 125 mEq/L.4,6,7

When fluid regulation systems function properly, plasma osmolality is maintained at 275 to 295 mOsm/L, and sodium levels range from 135 to 145 mEq/L.8 Pseudohyponatremia occurs when sodium levels are normal or high, but are measured as artificially

low – a complication that arises when sodium is displaced from the serum by other solutes, including glucose or proteins. In such cases, the osmolar gap is increased and the patient will be asymptomatic for hyponatremia; no treatment is required. Hypertonic hyponatremia, which occurs in severely hyperglycemic patients, is a common presentation.1,4,7

True hyponatremia is marked by a low plasma osmolality (<280 mOsm/L) and low sodium levels.1,4,7 It results from the kidney’s inability to excrete water in sufficient proportion to serum sodium. The major pathophysiology of the disorder is divided into three categories according to effective intravascular volume: hypovolemic, isovolemic (euvolemic), and hyper-volemic.

As previously mentioned, urine electrolytes are helpful in determining disease pathophysiology and guiding treatment. For example, urine sodium levels can help the provider distinguish between impaired free water excretion secondary to SIADH versus increased free water intake from primary polydipsia. The values will change in response to treatment, confounding the differentials; it is optimal to obtain them before administering fluids or medications.

Patients with neurologic symptoms and signs of possible hyponatremia require a careful history and physical examination to determine the time of onset (acute versus chronic) and volume status. In such cases, laboratory studies should include measurements of plasma osmolality, urine osmolality, and urine sodium concentration.1,4,5,7,9

Hypovolemic HyponatremiaHypovolemic hyponatremia occurs

with loss of total body water (TBW) and sodium. These patients usually have a history and presentation consistent with dehydration. The cause may be renal (eg, diuretics, salt-wasting neuropathy, adrenal insufficiency) or extrarenal, as in cases of excessive fluid loss (eg, vomiting, diarrhea, sweating, burns, third-spacing).1,4,7,10

Euvolemic HyponatremiaIn patients with euvolemic

hyponatremia, the total body water is increased, while the total body sodium level remains normal. There may be a slight decrease in intravascular volume, but these patients do not exhibit signs of dehydration. Euvolemic hyponatremia most commonly is seen in patients with disorders related to syndrome of inappropriate ADH release, excess water, or salt wasting.1,4,7,10

SIADH-related diseases result in water retention, which can be secondary to increased secretion (eg, pulmonary carcinoma, medications), central nervous system disease that results in poor regulation, or a combination of both. Reset osmostat is a condition in which the kidney retains its ability to appropriately concentrate and dilute urine, but the threshold for ADH secretion is reset. This can result in either hypo- or hypernatremia. Adrenal insufficiency and hypothyroidism result in salt-wasting conditions.1,4,10 Despite their low plasma osmolalities, patients with SIADH experience thirst and have a daily fluid intake similar to that of healthy patients.2

Beer-drinker potomania, psychogenic polydipsia, and medications that cause dry mouth result in an increased intake of low-solute fluids. Some solute is required to excrete free water by the kidney, but if intake is too low, daily maximal urine excretion is limited.2

Hypervolemic HyponatremiaHypervolemic hyponatremia

usually is secondary to chronic conditions associated with fluid retention and increased ECF volume (eg, congestive heart failure, cirrhosis, and nephrotic syndrome). The kidneys sense a low effective circulating volume, which can cause sodium and water retention and a disproportionately elevated total body water in comparison to body sodium and symptomatic volume overload. Urine sodium usually is lower than 20 mEq/L, except in patients taking

Critical Decisions in Emergency Medicine

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diuretics (such as in cases of thiazide-induced hyponatremia).1,4

CRITICAL DECISIONSHow should patients be risk stratified and monitored in the emergency department?

Brain herniation is seen almost exclusively in patients with acute hyponatremia. Osmality changes that exceed the brain’s ability to adapt result in cerebral edema; therefore, the faster the onset of hyponatremia, the higher the risk of herniation. This complication is most common postoperatively (particularly in premenopausal females), and in patients with self-induced water intoxication secondary to endurance exercise, psychiatric disease, and a history of drug abuse (especially Ecstasy).

In such cases, rapid correction may stop symptoms and prevent brain herniation. Fortunately, acutely swollen cells tolerate rapid correction well, and the risk of iatrogenesis secondary to rapid treatment is lower in acute presentations.1,5,6 Osmotic demyelination syndrome is unlikely to occur in patients who have been hyponatremic for less than 24 hours or in whom serum sodium is ≥120 mEq/L without other comorbid factors.6

In chronic hyponatremia, brain cells exchange other solutes for sodium, allowing adaptation and a decreased rate of cell water accumulation.6 Cerebral edema is milder and occurs more slowly. Patients have modest symptoms and almost never die of herniation.1 Chronic presentations are best treated with slower correction and

management of underlying illnesses. A longer duration and lower serum sodium levels correlate with a higher risk of injury from overcorrection. If the patient is not expressing overt symptoms (eg, seizure) and there is doubt regarding acuity, it is safer to consider hyponatremia as chronic.1,6

Several formulas are used to calculate the rate, strength, and volume of saline infusions, but they carry a risk of underestimating the rise of sodium. Saline infusion with hypovolemic hyponatremia has the highest risk of overcorrection. Additionally, formulas assume a closed system, but active input and output can affect serum levels.6 Patients should be closely monitored, and sodium levels should be checked every 2 to 4 hours during the acute phase. Regular reassessment, consideration of other causes, and timely adjustments will reduce the risk of iatrogenesis. This is particularly important when treating hyponatremia, which carries a serious risk of cerebral edema and osmotic demyelination syndrome.6

CRITICAL DECISIONWhat are the most effective treatments for hyponatremia?

The treatment approaches for hyponatremia can be confusing for many clinicians, and great care must be taken to avoid the catastrophic consequences of misuse. On initial discovery of hyponatremia, it is essential to determine the timeline of presentation, and a detailed history and laboratory studies should be obtained to determine the underlying

cause. These factors will guide the therapeutic approach and level of aggressiveness. Water restriction, saline (hypertonic and normal) with or without furosemide are the mainstays of treatment. Patients with overt acute hyponatremia are treated with hypertonic saline, whereas those with hypovolemia first should be treated with normal saline.

Hypovolemic HyponatremiaThe treatment of hypovolemic

hyponatremia entails restoring the extracellular fluid volume (ECF) with isotonic fluid resuscitation. The most common and recommended therapy is infusion with normal saline (0.9% sodium chloride), which replaces both salt and water. It is crucial to assess the patient’s volume and sodium status regularly during treatment. Hyponatremia may remain after hypovolemia is resolved if the patient’s condition has a secondary cause.

Continued treatment with NS with-out reassessing serum sodium levels can result in worsening hyponatre-mia, as demonstrated in cases of renal failure, Ecstasy use, and increased ADH release secondary to dehydration. Cautious volume replacement may help when hypovolemia is unclear.4,7,10

Euvolemic HyponatremiaUrine sodium and urine osmality

will help distinguish between disorders associated with SIADH and those associated with excess water. In patients with SIADH, the urine is inappropriately concentrated (>100 mOsm/kg H

2O), and the urine

sodium usually is greater than 20 mEq/L. In cases of excess water intake, diluted urine osmolality is less than 100 mOsm/L.1,4,7,10

SIADH is a diagnosis of exclusion as it assumes normal renal, thyroid, and adrenal function. Some causes of SIADH (eg, malignant disease or intracranial pathology) might be irreversible. In such cases, fluid restriction, increased salt intake, and vasopressin-receptor antagonists can be used in inpatient or outpatient settings, depending on other

TABLE 1. Medications and Mechanism of Hyponatremia12

Effect Drug ClassesAffect sodium and water hemostasis

All diuretics (loop, potassium sparing, particularly thiazides), trimethoprim/sulfamethoxazole

Increase ADH secretion Psychotropic drugs (SSRIs, antipsychotics), antiepileptic agents (carbamazepine), opiates, cancer agents

Increase distal tubule sensitivity to ADH

Carbamazepine, cyclophosphamide, NSAIDs

Reset the osmostat Venlafaxine, carbamazepine

Induce pseudohyponatremia IVIG, mannitol

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FIGURE 1. Overview of Approach to Diagnosis, Evaluation and Treatment of Hyponatremia

comorbidities. Offending drugs should be discontinued. Of note, intravenous administration of 0.9% normal sodium usually worsens hyponatremia by causing a net fluid shift into the intravascular space.1,2,7

The urge to drink in psychogenic polydipsia can be excessive; patients often are compelled to drink from any available source, including the toilet. Such patients require medical management, close monitoring, and psychological therapy (eg, psychosocial rehabilitation and behavioral interventions).11

Hypervolemic HyponatremiaWater restriction to 1 to 1.5 L/day

and a low-salt diet may be adequate in managing hypervolemic hypona-tremia. Loop diuretics can help promote salt and water excretion, and a potassium-sparing diuretic can help prevent hypokalemia and improve edema. Vasopressin-receptor antagonists are becoming more common in the treatment of hyponatremia associated with congestive heart failure, cirrhosis, and SIADH.2 Treatment can be optimized with slow correction in consultation with cardiology, hepatology, and nephrology to address underlying causes of disease.6

CRITICAL DECISIONWhat guidelines should be followed when correcting sodium levels?

The rapid correction of hypona-tremia appears to cause iatrogenic brain damage, most concerning of which is osmotic demyelination syndrome (ODS). The rate of sodium correction should be no faster than 0.5 mEq/hr, or no more than a total of 12 mEq/day. In light of case reports of neurologic complications despite “safe” correction rates, some experts advocate reducing the daily maximum to 6 mEq/day. For patients without risk factors for ODS, a correction limit of 10 to 12 mEq/L over 24 hours, or 18 mEq/L over 48 hours, may be appropriate.1,4,7,10

Factors that increase the risk of developing ODS with the correction of chronic hyponatremia include a

serum sodium concentration ≤105 mEq/L, hypokalemia, alcoholism, malnutrition, and advanced liver disease. A goal of increasing the serum sodium by 4 to 6 mEq/L per day is advised to avoid complications. Careful monitoring and interventions to prevent and reverse overcorrection are recommended for patients with serum sodium ≤120 mEq/L. Serum sodium levels should be obtained every 4 to 6 hours, and urine output should be monitored until serum sodium levels are ≥125 mEq/L.1

Acute HyponatremiaIn severe cases of symptomatic

hyponatremia, an intravenous bolus of 3% hypertonic saline over 10 minutes is recommended. For the average patient, this should acutely raise serum sodium levels by 2 to 3 mEq/L. The dose can be repeated twice if symptoms persist; however, the third dose should be limited to patients with a known acute onset of less than 48 hours. It also is important to obtain a serum sodium level prior to giving a third dose to prevent overcorrection.

Treatment is aimed at correcting acute cerebral edema and associated

neurological symptoms. In patients with intact ADH regulation (eg, those with self-induced water intoxication), sodium levels will correct sponta-neously with fluid restriction; correc tion to normal values is unnecessary. A 4 to 6 mEq/L increase or correction to 125 mEq/L serum sodium is sufficient to treat cerebral edema and reverse clinical signs of hyponatremia such as headache and seizures.1,2 Response is confirmed by the excretion of a large volume of dilute urine despite water restriction. Patients with milder symptoms or a less acute onset (<48 hours) may benefit from a slower correction (100 mL of 3% hypertonic saline over 60 minutes, or 0.5 to 2 mL/kg/hr). If there is uncertainty regarding the timing of onset, correct according to the limits for chronic hyponatremia.1,6

CRITICAL DECISIONWhat special considerations are of importance?

Several deaths have been attributed to the use of MDMA (ie, Ecstasy or Molly), a street drug that can precipitate severe hyponatremia and water intoxication. Its presentation

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may be confounded by the stimulant effects of MDMA, resulting in tachycardia. Use caution in patients without other signs of hypovolemia; do not reflexively give normal saline, which can worsen hyponatremia and cause rapid decline.1,4-6

Approximately 4.4% of postopera-tive patients develop hyponatremia within 1 week of surgery, triggering nonosmotic stimuli for ADH release, including subclinical volume deple tion, pain, nausea, stress, comorbidities, and administration of hypotonic fluids.2 The patient’s history (particularly comorbid disease and medications) and urine osmolality and urine sodium levels will help differentiate between renal and extrarenal causes.1,4-7

ADH levels are universally elevated from baseline in the postoperative period. Postoperative levels in menstruating females are up to 40 times higher than in postmenopausal women. Young women are at particular risk from neurological damage caused by hyponatremic encephalopathy. Due to differences in hormonal regulation and secretion in response to surgical stimuli, the relative risk in females is 30 times greater than in males.9

Complications often are the result of self-correction during the course of treatment. Patients with hyponatremia caused by volume depletion, cortisol deficiency, and medications such as desmopressin or thiazide diuretics are particularly at risk. Once these factors are corrected with fluids, steroids, or medication cessation, the stimulus for ADH secretion is lost, causing the pa-tient to excrete dilute urine (which can increase serum sodium by 2 mEq/L/hr). It is best to aim for correction goals below the limit.

Although the method has not been validated, relowering serum sodium to prevent ODS appears to be well tolerated in the event of rapid overcorrection. Preliminary research points to the administration of 2 to 4 µg of desmopressin and 3 mL/kg infusions of 5% dextrose in water over 1 hour, with repeated infusions until sodium levels reach the patient’s subtherapeutic limit.1

Vasopressin-receptor antagonists (vaptans, including conivaptan, tolvaptan, and lixivaptan) recently were introduced for the treatment of hyponatremia. They work by selectively increasing renal excretion of solute free water. Conivaptan is FDA approved for euvolemic and hypervolemic hyponatremia in hospitalized patients. Generally, the medication is indicated for the treatment of chronic hypovolemia; it should not be used for severe symptomatic hyponatremia.2,10

Case Resolutions■ Case One

The young partygoer was treated with 20 mL of 3% hypertonic saline, and her sodium levels improved. Repeat laboratory studies showed a sodium level of 120 mEq/L, pH 7.25, Pco2 40 mm Hg, and Po2 60 mm Hg.

Nephrology was consulted, and the patient was given 2 liters of NS and 40 mg furosemide before being trans-ferred to the ICU. After a second bolus of NS, the patient’s serum sodium decreased to 118 mEq/L; she then was given 225 mL of 3% hypertonic saline and 60 g of mannitol. Repeat sodium after infusion was 125 mEq/L, and (due to her low urine output) further IV fluids (500 mL/hr) were administered.

Approximately 2 hours later, the patient seized; a code blue was called and she expired. She had been inappropriately managed with too much normal and hypertonic saline.

■ Case TwoThe schizophrenic man was

deter mined to be suffering from self-induced water intoxication secondary to psychogenic polydipsia. He was treated with NS at a maintenance rate and placed on an inpatient water restriction of 500 mL per day.

The patient’s urine output was 8000 mL over the next 24 hours, and his mental status gradually improved. He became more alert, communicative, and tolerated a normal diet. His repeat sodium after 24 hours was 125 mEq/L. After 72 hours, the patient returned

to baseline, and his electrolyte levels normalized (Na 135 mEq/L, K 4.5 mEq/L, Cl 103 mEq/L, HCO3 28 mEq/L, BUN 9 mg/dL). Serum osmolality was 275 mOsm/kG H

2O.

Prior to discharge, the patient and his family were instructed to monitor and limit his water consumption to 1.5 to 2 liters per day, and follow up with his psychiatrist.

■ Case ThreeThe confused, nauseated young

woman was diagnosed with postop-erative hyponatremia. Intravenous fluids were discontinued, and she was given an infusion of 3% hypertonic saline at a rate of 50 mL/hr. The patient was placed on NPO and admitted to the ICU, where her sodium level was checked every 4 hours. After 8 hours of treatment, the level improved to 125 mEq/L. She showed gradual improvement in mental status, becoming alert, oriented, and appropriate. Her headache and nausea improved significantly, and hypertonic saline was discontinued.

The patient produced 2.5 liters of urine during these 8 hours and was allowed to resume normal oral intake. Her sodium normalized at 136 mEq/L within 24 hours of initial presentation, and she was discharged home with a plan for surgical follow up.

SummaryHyponatremia is encountered

frequently in the emergency department, and effective management depends on the symptomatic presentation, acuity, and underlying cause of each particular case. Treatment generally consists of hypertonic saline, normal saline, and water restriction, in addition to treatments that address the underlying disease.

A patient’s volume status must be determined prior to starting therapy, as it can dictate the use and type of IV fluids or fluid restriction. The volume and sodium status can change during the course of treatment, so it is important to strictly monitor urine input and output; sodium levels should be checked every 2 hours.

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Hypovolemia should be addressed prior to or in conjunction with the treatment of hyponatremia, and sodium levels should be reassessed after a patient’s volume status has normalized. Prior to initiating therapy for suspected hyponatremia, plasma osmolality, urine osmolality, and urine sodium should be measured.

Unstable patients with severe symptoms (eg, seizure, coma, and focal neurological deficits) require emergent treatment with 100 mL of 3% hypertonic saline over 10 minutes. If the patient remains unstable, a second and even third dose can be initiated. However, sodium levels, other electrolytes, and volume status should be reevaluated prior to administering additional treatment.

Patients with milder symptoms or a less acute onset (<48 hours) should be treated with a slower correction of 100 mL of 3% hypertonic saline over 60 minutes, or at a rate of 0.5 to 2 mL/kg/hr. Severe hyponatremia (sodium <110 to <115 mEq/L) should be treated even in seemingly asymptomatic patients, as subtle signs may be missed.

Increasing sodium levels to 4 to 6 mEq/L or above 125 mEq/L should improve symptoms while lowering the risk of osmotic demyelination syndrome. The maximum rate of correction should be 0.5 mEq/L per hour with an upper limit of 12 mEq/L in 24 hours, and 18 mEq/L over 48 hours. The general target for correction should be 8 mEq/L per day, with 10 mEq/L tolerated and 12 mEq/L as the maximum.

Acutely ill patients (<48 hours) with severe presentations should be treated for hyponatremic encephalopathy, and steps should be taken to prevent the severe neurological consequences of cerebral edema such as brainstem herniation, which is not seen in chronic cases.

Patients with acute hyponatremia tolerate acute rapid reversal better than those with chronic hyponatremia, who present with less cerebral edema and milder symptoms for corresponding sodium levels. Rapid correction is particularly dangerous in this setting

of chronic hyponatremia. Correction should be performed in a controlled environment with close observation and frequent monitoring of sodium levels. Target correction rates for stable hyponatremia should be no faster than 6 to 8 mEq/L per day.

It is important to consider and address underlying causes. Once determined, additional therapy with desmopressin, diuretics, and vasopressin-receptor antagonists can be helpful. Remember that SIADH is a diagnosis of exclusion.

References1. Verbalis JG, Goldsmith SR, Greenberg A, et al.

Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1-S42.

2. Assadi F. Hyponatremia: a problem-solving approach to clinical cases. J Nephrol. 2012;25(4):473-480.

3. Nagler EV, Vanmassenhove J, van der Veer SN, et al. Diagnosis and treatment of hyponatremia: a systemic review of clinical practice guidelines and consensus statements. BMC Med. 2014,12:1. doi:10.1186/s12916-014-0231-1.

4. Harring TR, Deal NS, Kuo DC. Disorders of sodium and water balance. Emerg Med Clin North Am. 2014;32(2):379-401.

5. Kalantar-Zadeh K, Nguyen MK, Chang R, Kurtz I. Fatal hyponatremia in a young woman after ecstasy ingestion. Nat Clin Pract Neprol. 2006;2(5):283-288.

6. Tzamaloukas AH, Malhotra D, Rosen BH, et al. Principles of management of severe hyponatremia. J Am Heart Assoc. 2013;2(1):e005199.

7. Volkova NV, Simons RJ. Case studies in hyponatremia. Hospital Physician. 2003;10(part 1):1-17.

8. Hoom EJ. A fatal case of Ecstasy poisoning. Paediatr Child Health. 2001;6(7):491.

9. Moritz ML, Ayus JC. The pathophysiology and treatment of hyponatraemic encephalopathy: an update. Nephrol Dial Transplant. 2003;18(12):2486-2491.

10. Lee JJ, Kilonzo K, Nistico A, Yeates K. Management of hyponatremia. CMAJ. 2014;186(8):E281-E286. 11. Hutcheon D. Psychogenic Polydipsia (Excessive Fluid Seeking Behaviour). BC Psychologist. 2013; 15-16. Available at: http://www.apadivisions.org/division-31/publications/articles/british-columbia/psychogenic-polydipsia.pdf. Accessed May 6, 2015.

11. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis. 2008;52(1):144-153.

Pearls• The “rule of sixes” describes a safe strategy for the correction of

hyponatremia. “Six a day makes sense for safety; so six in six hours for severe symptoms and stop,” meaning a safe correction rate of 6 mEq/L over 6 hours for patients with severe symptoms.1

• Acutely symptomatic hyponatremia should be treated aggressively, starting with a bolus of 3% hypertonic saline at a dose of 2 mL/kg (maximum of 100 mL) over 10 minutes. This can be repeated twice.

• A serum sodium level above 125 should not cause altered mental status or seizures. Look for other possible causes.

• Consider adrenal insufficiency in patients with hypotension, hypo-glycemia, hyponatremia, and hyperkalemia.

• Correct and adjust for other electrolyte abnormalities. Repletion of hypokalemia also increases sodium levels.

• Artificially low serum sodium levels can occur in cases of hyper-glycemia, hyperlipidemia, and hyperproteinemia conditions such as multiple myeloma and macroglobulinemia.

Pitfalls• Delaying treatment of acute onset hypovolemia, or giving overly

aggressive treatment to chronically ill patients.

• Inadequately treating patients with acute severe symptomatic hyponatremia (eg, giving NS when hypertonic saline is warranted).

• Admitting symptomatic patients to a regular nursing floor where monitoring and neurological checks are inadequate.

• Treating seizures caused by hyponatremia with traditional anticonvulsants. Patients can remain in status epilepticus unless hyponatremia is diagnosed and reversed.

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The Critical Image

■ Case

A 65-year-old woman with diabetes and hypertension presents with painful urination and gross hematuria. She visited an urgent care center 5 days earlier when her symptoms first began, where she received intramuscular ceftri-axone and was prescribed ciprofloxacin for a urinary tract infection. After some initial improvement, she noted increased left flank pain and persistent hematuria, prompting her emergency department visit.

Vital signs are blood pressure 148/68, pulse rate 87, respiratory rate 18, temperature 36.9°C (98.4°F), and oxygen saturation 99%.

The patient’s examination is notable for left costovertebral angle and suprapubic tenderness. Her creatinine is 1.5 mg/dL, an increase from the baseline value of 0.9. Urinalysis shows >50 RBCs, 45 WBC, 3+ leukocyte esterase, positive nitrite, and 5-50 bacteria. A CT scan without contrast is ordered to assess for possible nephrolithiasis or ureterolithiasis.

Slice at the level of the kidneys. The left kidney demonstrates hydronephrosis with a dilated renal pelvis and calyces.

A calcification resembling a ureteral stone is seen, but

the “stone” actually lies outside of the left ureter,

which is enlarged and lies medial to the calcification.

Dilated renal pelvis

Dilated renal

calyces

Extra-ureteral calcification

Dilated left ureter

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Feature Editor: Joshua S. Broder, MD, FACEP. See also Diagnostic Imaging for the Emergency Physician and Critical Images in Emergency Medicine by Dr. Broder, available from the ACEP Bookstore, acep.org/bookstore.

Cases for the Critical Image are contributed by the residents and faculty of the Duke University Hospital Emergency Residency Program.

References1. Smith-Bindman R, Aubin C, Bailitz J, et al. Ultrasonography versus

computed tomography for suspected nephrolithiasis. N Engl J Med 2014;371:1100-1110.

An exophytic mass is seen in the pelvis, projecting into the lumen of the bladder and obstructing the left ureter.

Key Points• Noncontrast CT is highly sensitive for the presence of

hydronephrosis, hydroureter, and calcified renal or ureteral stones. However, extra-ureteral calcifications can be mistaken for ureteral stones without careful inspection. Small renal and bladder neoplasms may not be recognized on CT without intravenous contrast. Even with a large mass, as in this case, premature cessation of the image interpretation might occur if a reader mistakes the calcification for a ureteral stone.

• Concern about radiation exposure from CT has prompted a search for alternative imaging strategies. Recent evidence suggests that ultrasound may be used instead of CT as the initial imaging study for the emergency department evaluation of suspected renal colic.1 In older patients (in whom radiation risk of CT is negligible), and for any patient whose differential diagnosis includes malignancy, CT may remain the better study.

• Limited ultrasound of the kidneys could readily miss the diagnosis in this patient. Unilateral hydronephrosis could be recognized by ultrasound and might be incorrectly attributed to an obstructing ureteral stone. If sonographic inspection of the bladder were not performed, misdiagnosis could occur.

Case ResolutionCT with intravenous contrast identified additional retroperitoneal lymph nodes. The patient underwent cystoscopic resection of the mass, and pathology reports demonstrated a high-grade neuroendocrine carcinoma arising in a background of high-grade urothelial carcinoma. The patient required neoadjuvant chemotherapy.

Bladder Soft tissue mass projecting into

bladder

Critical Decisions in Emergency Medicine

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Qualified, paid subscribers to Critical Decisions in Emergency Medicine may receive CME certificates for up to 5 ACEP Category I credits, 5 AMA PRA Category 1 Credits™, and 5 AOA Category 2-B credits for answering the following questions. To receive your certificate, go to www.acep.org/newcriticaldecisionstesting and submit your answers online. On achieving a score of 75% or better, you will receive a printable CME certificate. You may submit the answers to these questions at any time within 3 years of the publication date. You will be given appropriate credit for all tests you complete and submit within this time. Answers to this month’s questions will be published in next month’s issue.

CME Questions

1. A 23-year-old intravenous drug user presents withnausea, vomiting, jaundice, and mild abdominal pain.You suspect viral hepatitis. Which of the following isan indication to admit the patient?A. ALT concentration higher than AST concentrationB. Elevated INRC. Elevation of AST, ALT, and serum bilirubinD. Mild dehydration on examination

2. A 41-year-old health care worker presents afteraccidentally sticking herself with a dirty needle. Shehas no history of a hepatitis vaccination. The sourcepatient was an intravenous drug user. What treatmentshould be given?A. HBV immunoglobulin and HBV vaccineB. HBV immunoglobulin onlyC. HCV immunoglobulin and vaccineD. No treatment is necessary

3. A 17-year-old boy presents at 6 p.m. He reportsingesting a handful of over-the-counter pain relieversapproximately 1 hour earlier. At what time should ablood sample be drawn to measure the acetaminophenlevel?A. 6 p.m.B. 8 p.m.C. 9 p.m.D. 10 p.m.

4. What is the treatment of choice for spontaneousbacterial peritonitis?A. AmoxacillinB. CefotaximeC. Oral ofloxacinD. Vancomycin

5. What percentage of patients with spontaneousbacterial peritonitis is asymptomatic?A. <10%B. 10% to 40%C. 40% to 60%D. >60%

6. A 35-year-old pregnant woman presents with itching.She has markedly elevated transaminases, but noabdominal pain or jaundice. Which disease is likely tobe the cause of her symptom?A. Acute fatty liver of pregnancyB. HELLP syndromeC. Infectious hepatitisD. Intrahepatic cholestasis of pregnancy

7. Hepatic insufficiency with hypoglycemia, coagulopathy, and encephalopathy is more common in which of the following pregnancy-related diseases?A. Acute fatty liver of pregnancyB. HELLP syndromeC. Hyperemesis gravidarumD. Intrahepatic cholestasis of pregnancy

8. Which of the following laboratory abnormalities is common in patients with alcoholic liver disease?A. Decreased mean corpuscular volumeB. Elevated platelet countC. Increased serum magnesium levelD. Ratio of AST:ALT>2

9. A 72-year-old man presents with an acute variceal bleed. Which treatment is shown to decrease the rate of rebleeding and mortality?A. Proton pump inhibitorsB. Transfusion to hemoglobin of 10g/dLC. Transfusion of platelets and plasmaD. Treatment with antibiotics such as norfloxacin,

ciprofloxacin, or ceftriaxone

10. In patients with a history suspicious for chronic liver disease, which laboratory abnormalities can indicate undiagnosed cirrhosis?A. Decreased bilirubin, decreased albumin, decreased

plateletsB. Elevated albumin, elevated PTT and INR, elevated plateletsC. Elevated bilirubin, decreased albumin, decreased plateletsD. Elevated PTT and INR, elevated platelets, elevated bilirubin

11. A 38-year-old Caucasian woman presents with confusion, headache, and mild dyspnea. She also complains of abdominal pain with nausea, vomiting, and diarrhea. The patient just completed the Boston marathon, during which she maintained a steady pace and consumed a small bottle of water at every mile station. What laboratory values can you expect to see in this case?A. Na 121 mEq/L, serum osmolality 254 mOsm/kg, urine

specific gravity 1.020, urine Na 9 mEq/LB. Na 140 mEq/L, serum osmolality 280 mOsm/kg, urine

specific gravity 1.020, urine Na 9 mEq/LC. Na 125 mEq/L, serum osmolality 280 mOsm/kg, urine

specific gravity 1.030, urine Na 12 mEq/LD. Na 125 mEq/L, serum osmolality 254 mOsm/kg, urine

specific gravity 1.020, urine Na 29 mEq/L

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Answer Key for October 2015, Volume 29, Number 10

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20B D B B B A C B C C C D B A C A B A B D

12. Which treatment is appropriate in a patient presenting with severe hyponatremia with seizures?A. 0.9% normal salineB. ½ normal salineC. 3% hypertonic salineD. Fluid restriction

13. A 66-year-old man presents with increasing shortness of breath, fatigue, orthopnea and increased edema in his lower extremities. His has a history of congestive heart failure and coronary artery bypass grafting. A examina tion reveals jugular venous extension, b/l pleural effusions, and cardiomegaly. The patient’s sodium level is 122 mEq/L, and his plasma osmolality is 260 mOsm/kg H2O. Which best describes his sodium disorder?A. Hypervolemic, hypo-osmotic hyponatremiaB. Hypervolemic, isosmotic hyponatremiaC. Hypovolemic, hypo-osmotic hyponatremiaD. Isovolemic, hypo-osmotic hyponatremia

14. What is the likely cause of the previous patient’s hyponatremia?A. Exacerbation of congestive heart failureB. Increased thirst drive secondary to use of diureticsC. Side effect of his medicationsD. Syndrome of inappropriate antidiuretic hormone secretion

15. A 35-year-old woman recently underwent an elective laparoscopic cholecystectomy. The patient experienced postoperative pain and severe nausea, which were treated with IV morphine, promethazine, and fluids. She gradually improved and was discharged home yesterday (postoperative day 2). She is accompanied by her husband, who reports that she is more confused and combative. Vital signs are within normal limits. Surgical incisions are clean, dry, and intact, and the abdomen is soft without peritoneal signs. She is noted to have brief apnea spells. Laboratory tests show a serum sodium level of 116, and a chest x-ray reveals pulmonary edema. What is the most likely cause of the patient’s pulmonary edema?A. Acute renal failureB. Adrenal insufficiencyC. Congestive heart failureD. Hyponatremic encephalopathy

16. What is the most effective treatment for the syndrome of inappropriate hormone secretion?A. 0.9% normal salineB. ½ normal salineC. 3% hypertonic salineD. Fluid restriction

17. A psychiatric patient presents with dizziness. She is given 2 liter boluses of normal saline while awaiting her lab results. Two hours later, her sodium level is measured at 120. The patient is reassessed and found to have stroke-like symptoms. What is the probable cause of her symptoms?A. Brainstem herniationB. Cerebral edemaC. HypoglycemiaD. Osmotic demyelination syndrome

18. A 50-year-old man was referred to the emergency department for an abnormally low sodium level found on a routine follow-up examination. The patient was discharged home with salt tablets, and has been compliant with his medications. Today, his sodium level is 126, and his urine sodium is 56 mEq/kg. The patient denies any neurological complaints. What is the probable cause of his hyponatremia?A. DiabetesB. HypoaldosteronismC. HypothyroidismD. Reset osmostat

19. A 55-year-old man presents with general malaise. His sodium level is 126, which is lower than his previous sodium of 133 (measured 1 year ago). The patient’s primary care physician added several medications to the man’s regimen 6 months ago, but he does not remember which prescriptions are new. Which medication most likely is contributing to his hyponatremia?A. AmlodipineB. ClopidogrelC. HydrochlorothiazideD. Rosuvastatin

20. A 29-year-old man with a history of schizophrenia presents to the emergency department. He was started on carbamazepine several months ago, and his family reports recent polyuria and frequent urination, and increased somnolence and confusion over the last 3 days. His glucose is normal, and his serum sodium level is 122 mEq/L. You suspect the hyponatremia is being caused by polydipsia, as opposed to a side effect from the carbamazepine. What further diagnostic measurements can help distinguish between the two?A. Carbamazepine levelsB. Orthostatic blood pressuresC. Urine drug screenD. Urine electrolytes

NONPROFIT

U.S. POSTAGE

P A I DDALLAS, TX

PERMIT NO. 1586

November 2015 • Volume 29 • Number 11Critical Decisions in Emergency Medicine is the official CME publication of the American College of Emergency Physicians. Additional volumes are available to keep emergency medicine professionals up-to-date on relevant clinical issues.

Editor-in-ChiefLouis G. Graff IV, MD, FACEP Professor of Traumatology and Emergency Medicine, Professor of Clinical Medicine, University of Connecticut School of Medicine; Farmington, CT

Editor-ElectMichael S. Beeson, MD, MBA, FACEP Program Director, Department of Emergency Medicine, Akron General, Akron, Ohio; Professor, Clinical Emergency Medicine, Northeastern Ohio Universities College of Medicine, Rootstown, OH

Section EditorsJ. Stephen Bohan, MS, MD, FACEP Executive Vice Chairman and Clinical Director, Department of Emergency Medicine, Brigham & Women’s Hospital; Instructor, Harvard Medical School, Boston, MAJoshua S. Broder, MD, FACEP Associate Clinical Professor of Surgery, Residency Program Director, Division of Emergency Medicine, Duke University Medical Center, Durham, NCAmal Mattu, MD, FACEP Professor and Vice Chair, Department of Emergency Medicine, Director, Faculty Development and Emergency Cardiology Fellowships, University of Maryland School of Medicine, Baltimore, MDLynn P. Roppolo, MD, FACEP Associate Emergency Medicine Residency Director, Associate Professor of Emergency Medicine, University of Texas Southwestern Medical Center, Dallas, TXSteven J. Warrington, MD Institutional Director of Simulation; Core Faculty, Emergency Medicine and General Surgery Residency Programs; Associate Medical Director for Emergency Department Education and Outreach, Kaweah Delta Medical Center, Visalia, CA

Associate EditorsWalter L. Green, MD, FACEP Assistant Emergency Medicine Program Director, Associate Professor of Emergency Medicine, University of Texas Southwestern Medical Center, Dallas, TXJohn C. Greenwood, MD Associate Professor of Clinical Emergency Medicine; Medical Director, ED Critical Care Resuscitation Unit, Department of Emergency Medicine, University of Pennsylvania, PhiladelphiaDaniel A. Handel, MD, MPH, FACEP Chief Medical Officer, Associate Professor of Medicine and Pediatrics, Division of Emergency Medicine, Medical University of South Carolina, Charleston, SCFrank LoVecchio, DO, MPH, FACEP Research Director, Maricopa Medical Center Emergency Medicine Program; Medical Director, Banner Poison Control Center, Phoenix, Arizona; Professor, Midwestern University/Arizona College of Osteopathic Medicine, Glendale, AZSharon E. Mace, MD, FACEP Associate Professor, Department of Emergency Medicine, Ohio State University School of Medicine; Faculty, MetroHealth Medical Center/Cleveland Clinic Foundation Emergency Medicine Residency Program; Director, Pediatric Education/Quality Improvement and Observation Unit, Cleveland Clinic Foundation, Cleveland, OHJennifer L. Martindale, MD Clinical Associate Professor, Department of Emergency Medicine, SUNY Downstate Medical Center, Brooklyn, NY Robert A. Rosen, MD, FACEP Medical Director, Culpeper Regional Hospital, Culpeper, Virginia; Associate Professor, Emergency Medicine, University of Virginia School of Medicine, Charlottesville, VAGeorge Sternbach, MD, FACEP Clinical Professor of Surgery (Emergency Medicine), Stanford University Medical Center, Stanford, CAKathleen Wittels, MD Instructor, Harvard Medical School, Boston, MA

Editorial StaffRachel Donihoo, Managing EditorJessica Hamilton, Educational Products AssistantLexi Schwartz, Subscriptions CoordinatorMarta Foster, Director, Educational ProductsCritical Decisions in Emergency Medicine is a trademark owned and published monthly by the American College of Emergency Physicians, PO Box 619911, Dallas, TX 75261-9911. Send address changes and comments to Critical Decisions in Emergency Medicine, PO Box 619911, Dallas, TX 75261-9911, or to cdem@acep.org; call toll-free 800-798-1822, or 972-550-0911.Copyright 2015 © by the American College of Emergency Physicians. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form or by any means, electronic or mechanical, including storage and retrieval systems, without permission in writing from the Publisher. Printed in the USA.The American College of Emergency Physicians (ACEP) makes every effort to ensure that contributors to its publications are knowledgeable subject matter experts. Readers are nevertheless advised that the statements and opinions expressed in this publication are provided as the contributors’ recommendations at the time of publication and should not be construed as official College policy. ACEP recognizes the complexity of emergency medicine and makes no representation that this publication serves as an authoritative resource for the prevention, diagnosis, treatment, or intervention for any medical condition, nor should it be the basis for the definition of, or standard of care that should be practiced by all health care providers at any particular time or place. Drugs are generally referred to by generic names. In some instances, brand names are added for easier recognition. Device manufacturer information is provided according to style conventions of the American Medical Association. ACEP received no commercial support for this publication. To the fullest extent permitted by law, and without limitation, ACEP expressly disclaims all liability for errors or omissions contained within this publication, and for damages of any kind or nature, arising out of use, reference to, reliance on, or performance of such information.

ISSN2325-0186(Print) ISSN2325-8365(Online)

Feature Editor: Steven Warrington, MD

The Drug BoxOphthalmic DiclofenacStephen Wolfe, DO, Kaweah Delta Healthcare District, Visalia, California

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) with antipyretic and analgesic effects. Ophthalmic diclofenac is a 0.1% preparation most commonly used in peri- and postophthalmic surgical patients, but the drug also can be used off-label to decrease pain and inflammation in patients with corneal abrasions (potentially reducing the need for sys-temic analgesics).

Mechanism of Action

Ophthalmic NSAID that inhibits ocular prostaglandins, resulting in decreased inflammation and decreased local pain stimulation

Indications Corneal abrasions, postoperative ophthalmic inflammation or pain, and prophylaxis against the development of cystoid macular edema (CME) after cataract surgery

Off-label: Some discussion on use in anterior uveitis/iritis and treat-ment of CME following cataract surgery

Dosing Corneal abrasion: 1 drop to affected eye 4 times per day, for no more than 2 weeks

Cataract surgery: 1 drop 4 times per day for 2 weeks, beginning 24 hours after surgery

Side Effects Temporary mild burning/stinging upon application, slowed corneal wound healing, keratitis, lacrimation, corneal deposits, corneal edema, conjunctivitis, corneal thinning or perforation, fever, chills, nausea, vomiting

Precautions Contraindications: Hypersensitivity to component of preparation, to other NSAIDs, or aspirin

Use caution in presence of concomitant ophthalmic corticosteroids and in patients with contact lenses or bleeding disorders.

Pregnancy: Category C

Lactation: Excretion in milk falls well below systemic levels and is not believed to be clinically significant.