A 68-year-old woman presented to the emergency department with altered mental status. On the morning prior to admission, she was fully alert and oriented. Over the course of the day, she became more confused and somnolent, and by the evening, she was unarousable to voice. She had not fallen and had no head trauma.

Altered mental status may arise from metabolic (eg, hyponatremia), infectious (eg, urinary tract infection), structural (eg, subdural hematoma), or toxin-related (eg, adverse medication effect) processes. Any of these categories of encephalopathy can develop gradually over the course of a day.

One year prior, the patient was admitted for a similar episode of altered mental status. Asterixis and elevated transaminases prompted an abdominal ultrasound, which revealed a nodular liver and ascites. Paracentesis revealed a high serum-ascites albumin gradient. The diagnosis of cirrhosis was made based on these findings. Testing for viral hepatitis, autoimmune hepatitis, hemochromatosis, and Wilson’s disease were negative. Although steatosis was not detected on ultrasound, nonalcoholic fatty liver disease (NAFLD) was suspected based on the patient’s risk factors of hypertension and type 2 diabetes mellitus. She had four additional presentations of altered mental status with asterixis; each episode resolved with lactulose.

Other medical history included end-stage renal disease (ESRD) requiring hemodialysis. Her medications were labetalol, amlodipine, insulin, propranolol, lactulose, and rifaximin. She was originally from China and moved to the United States 10 years earlier. Given concerns about her ability to consistently take medications, she had moved to a long-term facility. She did not use alcohol, tobacco, or illicit substances.

The normalization of the patient’s mental status after lactulose treatment, especially in the context of recurrent episodes, is characteristic of hepatic encephalopathy, in which ammonia and other substances bypass hepatic metabolism and impair cerebral function. Hepatic encephalopathy is the most common cause of lactulose-responsive encephalopathy, and may recur in the setting of infection or nonadherence with lactulose and rifaximin. Other causes of lactulose-responsive encephalopathy include hyperammonemia caused by urease-producing bacterial infection (eg, Proteus), valproic acid toxicity, and urea cycle abnormalities.

Other causes of confusion with a self-limited course should be considered for the current episode. A postictal state is possible, but convulsions were not reported. The patient is at risk of hypoglycemia from insulin use and impaired gluconeogenesis due to cirrhosis and ESRD, but low blood sugar would have likely been detected at the time of hospitalization. Finally, she might have experienced episodic encephalopathy from ingestion of unreported medications or toxins, whose effects may have resolved with abstinence during hospitalization.

The patient’s temperature was 37.8°C, pulse 73 beats/minute, blood pressure 133/69 mmHg, respiratory rate 12 breaths/minute, and oxygen saturation 98% on ambient air. Her body mass index (BMI) was 19 kg/m². She was somnolent but was moving all four extremities spontaneously. Her pupils were symmetric and reactive. There was no facial asymmetry. Biceps and patellar reflexes were 2+ bilaterally. Babinski sign was absent bilaterally. The patient could not cooperate with the assessment for asterixis. Her sclerae were anicteric. The jugular venous pressure was estimated at 13 cm of water. Her heart was regular with no murmurs. Her lungs were clear. She had a distended, nontender abdomen with caput medusae. She had symmetric pitting edema in her lower extremities up to the shins.

The elevated jugular venous pressure, lower extremity edema, and distended abdomen suggest volume overload. Jugular venous distention with clear lungs is characteristic of right ventricular failure from pulmonary hypertension, right ventricular myocardial infarction, tricuspid regurgitation, or constrictive pericarditis. However, chronic biventricular heart failure often presents in this manner and is more common than the aforementioned conditions. ESRD and cirrhosis may be contributing to the hypervolemia.

Although Asian patients may exhibit metabolic syndrome and NAFLD at a lower BMI than non-Asians, her BMI is uncharacteristically low for NAFLD, especially given the increased weight expected from volume overload. There are no signs of infection to account for worsening of hepatic encephalopathy.

Laboratory tests demonstrated a white blood cell count of 4400/µL with a normal differential, hemoglobin of 10.3 g/dL, and platelet count of 108,000 per cubic millimeter. Mean corpuscular volume was 103 fL. Basic metabolic panel was normal with the exception of blood urea nitrogen of 46 mg/dL and a creatinine of 6.4 mg/dL. Aspartate aminotransferase was 34 units/L, alanine aminotransferase 34 units/L, alkaline phosphatase 289 units/L (normal, 31-95), gamma-glutamyl transferase 104 units (GGT, normal, 12-43), total bilirubin 0.8 mg/dL, and albumin 2.5 g/dL (normal, 3.5-4.5). Pro-brain natriuretic peptide was 1429 pg/mL (normal, <100). The international normalized ratio (INR) was 1.0. Urinalysis showed trace proteinuria. The chest x-ray was normal. A noncontrast computed tomography (CT) of the head demonstrated no intracranial pathology. An abdominal ultrasound revealed a normal-sized nodular liver, a nonocclusive portal vein thrombus (PVT), splenomegaly (15 cm in length), and trace ascites. There was no biliary dilation, hepatic steatosis, or hepatic mass.

The evolving data set presents a mixed picture about the state of the liver. The distended abdominal wall veins, thrombocytopenia, and splenomegaly are commonly observed in advanced cirrhosis, but these findings reflect the associated portal hypertension and not the liver disease itself. The normal bilirubin and INR suggest preserved liver function and decrease the likelihood of cirrhosis being responsible for the portal hypertension. However, the elevated alkaline phosphatase and GGT levels suggest an infiltrative liver disease, such as lymphoma, sarcoidosis, or amyloidosis.

Furthermore, while a nodular liver on imaging is consistent with cirrhosis, no steatosis was noted to support the presumed diagnosis of NAFLD. One explanation for this discrepancy is that fatty infiltration may be absent when NAFLD-associated cirrhosis develops. In summary, there is evidence of liver disease, and there is evidence of portal hypertension, but there is no evidence of liver parenchymal failure. The key features of the latter – spider angiomata, palmar erythema, hyperbilirubinemia, and coagulopathy – are absent.

Noncirrhotic portal hypertension (NCPH) is an alternative explanation for the patient’s findings. NCPH is an elevation in the portal venous system pressure that arises from intrahepatic (but noncirrhotic) disease or from extrahepatic disease. Hepatic schistosomiasis is an example of intrahepatic but noncirrhotic portal hypertension. PVT that arises on account of a hypercoagulable condition (eg, abdominal malignancy, pancreatitis, or myeloproliferative disorders) is a prototype of extrahepatic NCPH. At this point, it is impossible to know if the PVT is a complication of NCPH or a cause of NCPH. PVT as a complication of cirrhosis is less likely.

An abdominal CT scan would better assess the hepatic parenchyma and exclude abdominal malignancies such as pancreatic adenocarcinoma. An echocardiogram is indicated to evaluate the cause of the elevated jugular venous pressure. A liver biopsy and measurement of portal venous pressure would help distinguish between cirrhotic and noncirrhotic portal hypertension.

Hepatitis A, B, and C serologies were negative as were antinuclear and antimitochondrial antibodies. Ferritin and ceruloplasmin levels were normal. A CT scan of the abdomen with contrast demonstrated a nodular liver contour, splenomegaly, and a nonocclusive PVT (Figure 1). A transthoracic echocardiogram showed normal biventricular systolic function and size, normal diastolic function, a pulmonary artery systolic pressure of 57 mmHg (normal, < 25), moderate tricuspid regurgitation, and no pericardial effusion or thickening. The patient’s confusion and somnolence resolved after two days of lactulose therapy. She denied the use of other medications, supplements, or herbs.

Schistosomiasis is the most common cause of NCPH worldwide. Parasite eggs trapped within the terminal portal venules cause inflammation, leading to fibrosis and intrahepatic portal hypertension. The liver becomes nodular on account of these changes, but the overall hepatic function is typically preserved. Portal hypertension, variceal bleeding, and pulmonary hypertension are common complications. The latter can arise from portosystemic shunting, which leads to embolization of schistosome eggs into the pulmonary circulation, where a granulomatous reaction ensues.

A percutaneous liver biopsy showed granulomatous inflammation and dilated portal venules consistent with increased resistance to venous inflow (Figure 2). There was no sinusoidal congestion to indicate impaired hepatic venous outflow. Mild sinusoidal and portal fibrosis and increased iron in Kupffer cells were noted. There was no evidence of cirrhosis or steatohepatitis. Stains for acid-fast bacilli and fungi were negative. 16S rDNA (a test assessing for bacterial DNA) and Mycobacterium tuberculosis polymerase chain reactions were negative. The biopsy confirmed the diagnosis of noncirrhotic portal hypertension.

Infections, such as brucellosis, Q fever, and tuberculosis, are common causes of granulomatous hepatitis in the developing world. Tuberculosis is prevalent in China, but the test results do not support tuberculosis as a unifying diagnosis.

Schistosomiasis accounts for the major clinical features (portal and pulmonary hypertension and preserved liver function) and hepatic pathology (ie, portal venous fibrosis with granulomatous inflammation) in this case and is prevalent in China, where the patient emigrated from. The biopsy specimen should be re-examined for schistosome eggs and serologic tests for schistosomiasis pursued.

Antibodies to human immunodeficiency virus, Brucella, Bartonella quintana, Bartonella henselae, Coxiella burnetii, Francisella tularensis, and Histoplasma were negative. Cryptococcal antigen and rapid plasma reagin were negative. IgG antibodies to Schistosoma were 0.21 units (normal, < 0.19 units). Based on the patient’s epidemiology, biopsy findings, and serology results, hepatic schistosomiasis was diagnosed. Praziquantel was prescribed. She continues to receive daily lactulose and rifaximin and has not had any episodes of encephalopathy in the year after discharge.

Portal hypertension arises when there is resistance to flow in the portal venous system. It is defined as a pressure gradient greater than 5 mmHg between the portal vein and the intra-abdominal portion of the inferior vena cava.¹ Clinicians are familiar with the manifestations of portal hypertension – portosystemic shunting leading to encephalopathy and variceal hemorrhage, ascites, and splenomegaly with thrombocytopenia – because of their close association with cirrhosis. In developed countries, cirrhosis accounts for over 90% of cases of portal hypertension.¹ In the remaining 10%, conditions such as portal vein thrombosis primarily affect the portal vasculature and increase resistance to portal blood flow while leaving hepatic synthetic function relatively spared (Figure 3). Therefore, cirrhosis cannot be inferred with certainty from signs of portal hypertension alone.

Liver biopsy is the gold standard for the diagnosis of cirrhosis, but this method is increasingly being replaced by noninvasive assessments of liver fibrosis, including imaging and scoring systems.² Clinicians often infer cirrhosis from the combination of a known cause of liver injury, abnormal liver biochemical tests, evidence of liver dysfunction, and signs of portal hypertension.³ However, when signs of portal hypertension are present, but liver dysfunction cannot be established on physical exam (eg, palmar erythema, spider nevi, gynecomastia, and testicular atrophy) or laboratory testing (eg, low albumin, elevated INR, and elevated bilirubin), noncirrhotic causes of portal hypertension should be considered. In this case, the biopsy showed vascular changes that suggested impaired venous inflow without bridging fibrosis, which pointed to NCPH.

NCPH is categorized based on the location of resistance to blood flow: prehepatic (eg, portal vein thrombosis), intrahepatic (eg, schistosomiasis), and posthepatic (eg, right-sided heart failure).¹ In our patient, the dilated portal venules (inflow) in the presence of normal hepatic vein outflow suggested an increased intrahepatic resistance to blood flow. This finding excluded a causal role of the portal vein thrombosis and prompted testing for schistosomiasis.

Schistosomiasis affects more than 200 million people worldwide and is prevalent in Sub-Saharan Africa, South America, Egypt, China, and Southeast Asia.^4,5 Transmission occurs in fresh water, where the infectious form of the parasite is released from snails.^4,6 Schistosome worms are not found in the United States, but as a result of immigration and travel, more than 400,000 people in the United States are estimated to be infected.⁵

Chronic schistosomiasis develops from the host’s granulomatous reaction to schistosome eggs whose location (depending on the species) leads to genitourinary, intestinal, hepatic, or rarely, neurologic disease.⁶ Hepatic schistosomiasis arises when eggs released in the portal venous system lodge in small portal venules and cause granulomatous inflammation, periportal fibrosis, and microvascular obstruction.⁶ The resultant portal hypertension develops insidiously, but the architecture and synthetic function of the liver is maintained until the very late stages of disease.^6,7 Pulmonary hypertension can arise from the embolization of eggs to the pulmonary arterioles via portosystemic collaterals.

The demonstration of eggs in stool is the gold standard for the diagnosis of hepatic schistosomiasis, which is most commonly caused by Schistosoma mansoni and S. japonicum.⁷ Serologic assays provide evidence of infection or exposure but may cross-react with other helminths. Liver biopsy may reveal characteristic histopathologic findings, including granulomatous inflammation, distorted vasculature, and the deposition of collagen deposits in the periportal space, leading to “pipestem fibrosis.”^8,9 If eggs cannot be detected on stool or histology, then serology, secondary histologic changes, and sometimes PCR are used to diagnose hepatic schistosomiasis. In our patient, the epidemiology, Schistosoma antibody titer, pulmonary hypertension, and liver biopsy with granulomatous inflammation, periportal fibrosis, and intrahepatic portal venule dilation were diagnostic of hepatic schistosomiasis.

The recurrent episodes of confusion which resolved with lactulose therapy were suggestive of hepatic encephalopathy, which results from shunting and accumulation of neurotoxic substances that would otherwise undergo hepatic metabolism.¹⁰ Clinicians are most familiar with hepatic encephalopathy in cirrhosis, where multiple liver functions – synthesis, excretion, metabolism, and circulation – simultaneously fail. NCPH represents a scenario where only the circulation is impaired, but this is sufficient to cause the portosystemic shunting that leads to encephalopathy. Our patient’s recurrent hepatic encephalopathy, despite adherence to lactulose and rifaximin and its resolution after praziquantel treatment, underscores the importance of addressing the underlying cause of portosystemic shunting.Associating portal hypertension with cirrhosis is efficient and accurate in many cases. However, when specific manifestations of cirrhosis are lacking, clinicians must decouple this association and pursue an alternative explanation for portal hypertension. The presence of some intrahepatic pathology (from schistosomiasis) but no cirrhosis made this case a particularly tough egg to crack.

Teaching Points

• In the developed world, 90% of portal hypertension is due to cirrhosis. Hepatic schistosomiasis is the most common cause of NCPH worldwide.
• Chronic schistosomiasis affects the gastrointestinal, hepatic, and genitourinary systems and causes significant global morbidity and mortality.
• Visualization of schistosome eggs is the diagnostic gold standard. Indirect testing such as schistosoma antibodies and secondary histologic changes may be required for the diagnosis in patients with a low burden of eggs.

Disclosures

Dr. Geha has no disclosures. Dr. Dhaliwal reports receiving honoraria from ISMIE Mutual Insurance Company and Physicians’ Reciprocal Insurers. Dr. Peters’ spouse is employed by Hoffman-La Roche. Dr. Manesh is supported by the Jeremiah A. Barondess Fellowship in the Clinical Transaction of the New York Academy of Medicine, in collaboration with the Accreditation Council for Graduate Medical Education (ACGME).

A 68-year-old woman presented to the emergency department with altered mental status. On the morning prior to admission, she was fully alert and oriented. Over the course of the day, she became more confused and somnolent, and by the evening, she was unarousable to voice. She had not fallen and had no head trauma.

Altered mental status may arise from metabolic (eg, hyponatremia), infectious (eg, urinary tract infection), structural (eg, subdural hematoma), or toxin-related (eg, adverse medication effect) processes. Any of these categories of encephalopathy can develop gradually over the course of a day.

One year prior, the patient was admitted for a similar episode of altered mental status. Asterixis and elevated transaminases prompted an abdominal ultrasound, which revealed a nodular liver and ascites. Paracentesis revealed a high serum-ascites albumin gradient. The diagnosis of cirrhosis was made based on these findings. Testing for viral hepatitis, autoimmune hepatitis, hemochromatosis, and Wilson’s disease were negative. Although steatosis was not detected on ultrasound, nonalcoholic fatty liver disease (NAFLD) was suspected based on the patient’s risk factors of hypertension and type 2 diabetes mellitus. She had four additional presentations of altered mental status with asterixis; each episode resolved with lactulose.

Other medical history included end-stage renal disease (ESRD) requiring hemodialysis. Her medications were labetalol, amlodipine, insulin, propranolol, lactulose, and rifaximin. She was originally from China and moved to the United States 10 years earlier. Given concerns about her ability to consistently take medications, she had moved to a long-term facility. She did not use alcohol, tobacco, or illicit substances.

The normalization of the patient’s mental status after lactulose treatment, especially in the context of recurrent episodes, is characteristic of hepatic encephalopathy, in which ammonia and other substances bypass hepatic metabolism and impair cerebral function. Hepatic encephalopathy is the most common cause of lactulose-responsive encephalopathy, and may recur in the setting of infection or nonadherence with lactulose and rifaximin. Other causes of lactulose-responsive encephalopathy include hyperammonemia caused by urease-producing bacterial infection (eg, Proteus), valproic acid toxicity, and urea cycle abnormalities.

Other causes of confusion with a self-limited course should be considered for the current episode. A postictal state is possible, but convulsions were not reported. The patient is at risk of hypoglycemia from insulin use and impaired gluconeogenesis due to cirrhosis and ESRD, but low blood sugar would have likely been detected at the time of hospitalization. Finally, she might have experienced episodic encephalopathy from ingestion of unreported medications or toxins, whose effects may have resolved with abstinence during hospitalization.

The patient’s temperature was 37.8°C, pulse 73 beats/minute, blood pressure 133/69 mmHg, respiratory rate 12 breaths/minute, and oxygen saturation 98% on ambient air. Her body mass index (BMI) was 19 kg/m². She was somnolent but was moving all four extremities spontaneously. Her pupils were symmetric and reactive. There was no facial asymmetry. Biceps and patellar reflexes were 2+ bilaterally. Babinski sign was absent bilaterally. The patient could not cooperate with the assessment for asterixis. Her sclerae were anicteric. The jugular venous pressure was estimated at 13 cm of water. Her heart was regular with no murmurs. Her lungs were clear. She had a distended, nontender abdomen with caput medusae. She had symmetric pitting edema in her lower extremities up to the shins.

The elevated jugular venous pressure, lower extremity edema, and distended abdomen suggest volume overload. Jugular venous distention with clear lungs is characteristic of right ventricular failure from pulmonary hypertension, right ventricular myocardial infarction, tricuspid regurgitation, or constrictive pericarditis. However, chronic biventricular heart failure often presents in this manner and is more common than the aforementioned conditions. ESRD and cirrhosis may be contributing to the hypervolemia.

Although Asian patients may exhibit metabolic syndrome and NAFLD at a lower BMI than non-Asians, her BMI is uncharacteristically low for NAFLD, especially given the increased weight expected from volume overload. There are no signs of infection to account for worsening of hepatic encephalopathy.

Laboratory tests demonstrated a white blood cell count of 4400/µL with a normal differential, hemoglobin of 10.3 g/dL, and platelet count of 108,000 per cubic millimeter. Mean corpuscular volume was 103 fL. Basic metabolic panel was normal with the exception of blood urea nitrogen of 46 mg/dL and a creatinine of 6.4 mg/dL. Aspartate aminotransferase was 34 units/L, alanine aminotransferase 34 units/L, alkaline phosphatase 289 units/L (normal, 31-95), gamma-glutamyl transferase 104 units (GGT, normal, 12-43), total bilirubin 0.8 mg/dL, and albumin 2.5 g/dL (normal, 3.5-4.5). Pro-brain natriuretic peptide was 1429 pg/mL (normal, <100). The international normalized ratio (INR) was 1.0. Urinalysis showed trace proteinuria. The chest x-ray was normal. A noncontrast computed tomography (CT) of the head demonstrated no intracranial pathology. An abdominal ultrasound revealed a normal-sized nodular liver, a nonocclusive portal vein thrombus (PVT), splenomegaly (15 cm in length), and trace ascites. There was no biliary dilation, hepatic steatosis, or hepatic mass.

The evolving data set presents a mixed picture about the state of the liver. The distended abdominal wall veins, thrombocytopenia, and splenomegaly are commonly observed in advanced cirrhosis, but these findings reflect the associated portal hypertension and not the liver disease itself. The normal bilirubin and INR suggest preserved liver function and decrease the likelihood of cirrhosis being responsible for the portal hypertension. However, the elevated alkaline phosphatase and GGT levels suggest an infiltrative liver disease, such as lymphoma, sarcoidosis, or amyloidosis.

Furthermore, while a nodular liver on imaging is consistent with cirrhosis, no steatosis was noted to support the presumed diagnosis of NAFLD. One explanation for this discrepancy is that fatty infiltration may be absent when NAFLD-associated cirrhosis develops. In summary, there is evidence of liver disease, and there is evidence of portal hypertension, but there is no evidence of liver parenchymal failure. The key features of the latter – spider angiomata, palmar erythema, hyperbilirubinemia, and coagulopathy – are absent.

Noncirrhotic portal hypertension (NCPH) is an alternative explanation for the patient’s findings. NCPH is an elevation in the portal venous system pressure that arises from intrahepatic (but noncirrhotic) disease or from extrahepatic disease. Hepatic schistosomiasis is an example of intrahepatic but noncirrhotic portal hypertension. PVT that arises on account of a hypercoagulable condition (eg, abdominal malignancy, pancreatitis, or myeloproliferative disorders) is a prototype of extrahepatic NCPH. At this point, it is impossible to know if the PVT is a complication of NCPH or a cause of NCPH. PVT as a complication of cirrhosis is less likely.

An abdominal CT scan would better assess the hepatic parenchyma and exclude abdominal malignancies such as pancreatic adenocarcinoma. An echocardiogram is indicated to evaluate the cause of the elevated jugular venous pressure. A liver biopsy and measurement of portal venous pressure would help distinguish between cirrhotic and noncirrhotic portal hypertension.

Hepatitis A, B, and C serologies were negative as were antinuclear and antimitochondrial antibodies. Ferritin and ceruloplasmin levels were normal. A CT scan of the abdomen with contrast demonstrated a nodular liver contour, splenomegaly, and a nonocclusive PVT (Figure 1). A transthoracic echocardiogram showed normal biventricular systolic function and size, normal diastolic function, a pulmonary artery systolic pressure of 57 mmHg (normal, < 25), moderate tricuspid regurgitation, and no pericardial effusion or thickening. The patient’s confusion and somnolence resolved after two days of lactulose therapy. She denied the use of other medications, supplements, or herbs.

Schistosomiasis is the most common cause of NCPH worldwide. Parasite eggs trapped within the terminal portal venules cause inflammation, leading to fibrosis and intrahepatic portal hypertension. The liver becomes nodular on account of these changes, but the overall hepatic function is typically preserved. Portal hypertension, variceal bleeding, and pulmonary hypertension are common complications. The latter can arise from portosystemic shunting, which leads to embolization of schistosome eggs into the pulmonary circulation, where a granulomatous reaction ensues.

A percutaneous liver biopsy showed granulomatous inflammation and dilated portal venules consistent with increased resistance to venous inflow (Figure 2). There was no sinusoidal congestion to indicate impaired hepatic venous outflow. Mild sinusoidal and portal fibrosis and increased iron in Kupffer cells were noted. There was no evidence of cirrhosis or steatohepatitis. Stains for acid-fast bacilli and fungi were negative. 16S rDNA (a test assessing for bacterial DNA) and Mycobacterium tuberculosis polymerase chain reactions were negative. The biopsy confirmed the diagnosis of noncirrhotic portal hypertension.

Infections, such as brucellosis, Q fever, and tuberculosis, are common causes of granulomatous hepatitis in the developing world. Tuberculosis is prevalent in China, but the test results do not support tuberculosis as a unifying diagnosis.

Schistosomiasis accounts for the major clinical features (portal and pulmonary hypertension and preserved liver function) and hepatic pathology (ie, portal venous fibrosis with granulomatous inflammation) in this case and is prevalent in China, where the patient emigrated from. The biopsy specimen should be re-examined for schistosome eggs and serologic tests for schistosomiasis pursued.

Antibodies to human immunodeficiency virus, Brucella, Bartonella quintana, Bartonella henselae, Coxiella burnetii, Francisella tularensis, and Histoplasma were negative. Cryptococcal antigen and rapid plasma reagin were negative. IgG antibodies to Schistosoma were 0.21 units (normal, < 0.19 units). Based on the patient’s epidemiology, biopsy findings, and serology results, hepatic schistosomiasis was diagnosed. Praziquantel was prescribed. She continues to receive daily lactulose and rifaximin and has not had any episodes of encephalopathy in the year after discharge.

Portal hypertension arises when there is resistance to flow in the portal venous system. It is defined as a pressure gradient greater than 5 mmHg between the portal vein and the intra-abdominal portion of the inferior vena cava.¹ Clinicians are familiar with the manifestations of portal hypertension – portosystemic shunting leading to encephalopathy and variceal hemorrhage, ascites, and splenomegaly with thrombocytopenia – because of their close association with cirrhosis. In developed countries, cirrhosis accounts for over 90% of cases of portal hypertension.¹ In the remaining 10%, conditions such as portal vein thrombosis primarily affect the portal vasculature and increase resistance to portal blood flow while leaving hepatic synthetic function relatively spared (Figure 3). Therefore, cirrhosis cannot be inferred with certainty from signs of portal hypertension alone.

Liver biopsy is the gold standard for the diagnosis of cirrhosis, but this method is increasingly being replaced by noninvasive assessments of liver fibrosis, including imaging and scoring systems.² Clinicians often infer cirrhosis from the combination of a known cause of liver injury, abnormal liver biochemical tests, evidence of liver dysfunction, and signs of portal hypertension.³ However, when signs of portal hypertension are present, but liver dysfunction cannot be established on physical exam (eg, palmar erythema, spider nevi, gynecomastia, and testicular atrophy) or laboratory testing (eg, low albumin, elevated INR, and elevated bilirubin), noncirrhotic causes of portal hypertension should be considered. In this case, the biopsy showed vascular changes that suggested impaired venous inflow without bridging fibrosis, which pointed to NCPH.

NCPH is categorized based on the location of resistance to blood flow: prehepatic (eg, portal vein thrombosis), intrahepatic (eg, schistosomiasis), and posthepatic (eg, right-sided heart failure).¹ In our patient, the dilated portal venules (inflow) in the presence of normal hepatic vein outflow suggested an increased intrahepatic resistance to blood flow. This finding excluded a causal role of the portal vein thrombosis and prompted testing for schistosomiasis.

Schistosomiasis affects more than 200 million people worldwide and is prevalent in Sub-Saharan Africa, South America, Egypt, China, and Southeast Asia.^4,5 Transmission occurs in fresh water, where the infectious form of the parasite is released from snails.^4,6 Schistosome worms are not found in the United States, but as a result of immigration and travel, more than 400,000 people in the United States are estimated to be infected.⁵

Chronic schistosomiasis develops from the host’s granulomatous reaction to schistosome eggs whose location (depending on the species) leads to genitourinary, intestinal, hepatic, or rarely, neurologic disease.⁶ Hepatic schistosomiasis arises when eggs released in the portal venous system lodge in small portal venules and cause granulomatous inflammation, periportal fibrosis, and microvascular obstruction.⁶ The resultant portal hypertension develops insidiously, but the architecture and synthetic function of the liver is maintained until the very late stages of disease.^6,7 Pulmonary hypertension can arise from the embolization of eggs to the pulmonary arterioles via portosystemic collaterals.

The demonstration of eggs in stool is the gold standard for the diagnosis of hepatic schistosomiasis, which is most commonly caused by Schistosoma mansoni and S. japonicum.⁷ Serologic assays provide evidence of infection or exposure but may cross-react with other helminths. Liver biopsy may reveal characteristic histopathologic findings, including granulomatous inflammation, distorted vasculature, and the deposition of collagen deposits in the periportal space, leading to “pipestem fibrosis.”^8,9 If eggs cannot be detected on stool or histology, then serology, secondary histologic changes, and sometimes PCR are used to diagnose hepatic schistosomiasis. In our patient, the epidemiology, Schistosoma antibody titer, pulmonary hypertension, and liver biopsy with granulomatous inflammation, periportal fibrosis, and intrahepatic portal venule dilation were diagnostic of hepatic schistosomiasis.

The recurrent episodes of confusion which resolved with lactulose therapy were suggestive of hepatic encephalopathy, which results from shunting and accumulation of neurotoxic substances that would otherwise undergo hepatic metabolism.¹⁰ Clinicians are most familiar with hepatic encephalopathy in cirrhosis, where multiple liver functions – synthesis, excretion, metabolism, and circulation – simultaneously fail. NCPH represents a scenario where only the circulation is impaired, but this is sufficient to cause the portosystemic shunting that leads to encephalopathy. Our patient’s recurrent hepatic encephalopathy, despite adherence to lactulose and rifaximin and its resolution after praziquantel treatment, underscores the importance of addressing the underlying cause of portosystemic shunting.Associating portal hypertension with cirrhosis is efficient and accurate in many cases. However, when specific manifestations of cirrhosis are lacking, clinicians must decouple this association and pursue an alternative explanation for portal hypertension. The presence of some intrahepatic pathology (from schistosomiasis) but no cirrhosis made this case a particularly tough egg to crack.

Teaching Points

• In the developed world, 90% of portal hypertension is due to cirrhosis. Hepatic schistosomiasis is the most common cause of NCPH worldwide.
• Chronic schistosomiasis affects the gastrointestinal, hepatic, and genitourinary systems and causes significant global morbidity and mortality.
• Visualization of schistosome eggs is the diagnostic gold standard. Indirect testing such as schistosoma antibodies and secondary histologic changes may be required for the diagnosis in patients with a low burden of eggs.

Disclosures

Dr. Geha has no disclosures. Dr. Dhaliwal reports receiving honoraria from ISMIE Mutual Insurance Company and Physicians’ Reciprocal Insurers. Dr. Peters’ spouse is employed by Hoffman-La Roche. Dr. Manesh is supported by the Jeremiah A. Barondess Fellowship in the Clinical Transaction of the New York Academy of Medicine, in collaboration with the Accreditation Council for Graduate Medical Education (ACGME).

A 68-year-old woman presented to the emergency department with altered mental status. On the morning prior to admission, she was fully alert and oriented. Over the course of the day, she became more confused and somnolent, and by the evening, she was unarousable to voice. She had not fallen and had no head trauma.

Altered mental status may arise from metabolic (eg, hyponatremia), infectious (eg, urinary tract infection), structural (eg, subdural hematoma), or toxin-related (eg, adverse medication effect) processes. Any of these categories of encephalopathy can develop gradually over the course of a day.

One year prior, the patient was admitted for a similar episode of altered mental status. Asterixis and elevated transaminases prompted an abdominal ultrasound, which revealed a nodular liver and ascites. Paracentesis revealed a high serum-ascites albumin gradient. The diagnosis of cirrhosis was made based on these findings. Testing for viral hepatitis, autoimmune hepatitis, hemochromatosis, and Wilson’s disease were negative. Although steatosis was not detected on ultrasound, nonalcoholic fatty liver disease (NAFLD) was suspected based on the patient’s risk factors of hypertension and type 2 diabetes mellitus. She had four additional presentations of altered mental status with asterixis; each episode resolved with lactulose.

Other medical history included end-stage renal disease (ESRD) requiring hemodialysis. Her medications were labetalol, amlodipine, insulin, propranolol, lactulose, and rifaximin. She was originally from China and moved to the United States 10 years earlier. Given concerns about her ability to consistently take medications, she had moved to a long-term facility. She did not use alcohol, tobacco, or illicit substances.

The normalization of the patient’s mental status after lactulose treatment, especially in the context of recurrent episodes, is characteristic of hepatic encephalopathy, in which ammonia and other substances bypass hepatic metabolism and impair cerebral function. Hepatic encephalopathy is the most common cause of lactulose-responsive encephalopathy, and may recur in the setting of infection or nonadherence with lactulose and rifaximin. Other causes of lactulose-responsive encephalopathy include hyperammonemia caused by urease-producing bacterial infection (eg, Proteus), valproic acid toxicity, and urea cycle abnormalities.

Other causes of confusion with a self-limited course should be considered for the current episode. A postictal state is possible, but convulsions were not reported. The patient is at risk of hypoglycemia from insulin use and impaired gluconeogenesis due to cirrhosis and ESRD, but low blood sugar would have likely been detected at the time of hospitalization. Finally, she might have experienced episodic encephalopathy from ingestion of unreported medications or toxins, whose effects may have resolved with abstinence during hospitalization.

The patient’s temperature was 37.8°C, pulse 73 beats/minute, blood pressure 133/69 mmHg, respiratory rate 12 breaths/minute, and oxygen saturation 98% on ambient air. Her body mass index (BMI) was 19 kg/m². She was somnolent but was moving all four extremities spontaneously. Her pupils were symmetric and reactive. There was no facial asymmetry. Biceps and patellar reflexes were 2+ bilaterally. Babinski sign was absent bilaterally. The patient could not cooperate with the assessment for asterixis. Her sclerae were anicteric. The jugular venous pressure was estimated at 13 cm of water. Her heart was regular with no murmurs. Her lungs were clear. She had a distended, nontender abdomen with caput medusae. She had symmetric pitting edema in her lower extremities up to the shins.

The elevated jugular venous pressure, lower extremity edema, and distended abdomen suggest volume overload. Jugular venous distention with clear lungs is characteristic of right ventricular failure from pulmonary hypertension, right ventricular myocardial infarction, tricuspid regurgitation, or constrictive pericarditis. However, chronic biventricular heart failure often presents in this manner and is more common than the aforementioned conditions. ESRD and cirrhosis may be contributing to the hypervolemia.

Although Asian patients may exhibit metabolic syndrome and NAFLD at a lower BMI than non-Asians, her BMI is uncharacteristically low for NAFLD, especially given the increased weight expected from volume overload. There are no signs of infection to account for worsening of hepatic encephalopathy.

Laboratory tests demonstrated a white blood cell count of 4400/µL with a normal differential, hemoglobin of 10.3 g/dL, and platelet count of 108,000 per cubic millimeter. Mean corpuscular volume was 103 fL. Basic metabolic panel was normal with the exception of blood urea nitrogen of 46 mg/dL and a creatinine of 6.4 mg/dL. Aspartate aminotransferase was 34 units/L, alanine aminotransferase 34 units/L, alkaline phosphatase 289 units/L (normal, 31-95), gamma-glutamyl transferase 104 units (GGT, normal, 12-43), total bilirubin 0.8 mg/dL, and albumin 2.5 g/dL (normal, 3.5-4.5). Pro-brain natriuretic peptide was 1429 pg/mL (normal, <100). The international normalized ratio (INR) was 1.0. Urinalysis showed trace proteinuria. The chest x-ray was normal. A noncontrast computed tomography (CT) of the head demonstrated no intracranial pathology. An abdominal ultrasound revealed a normal-sized nodular liver, a nonocclusive portal vein thrombus (PVT), splenomegaly (15 cm in length), and trace ascites. There was no biliary dilation, hepatic steatosis, or hepatic mass.

The evolving data set presents a mixed picture about the state of the liver. The distended abdominal wall veins, thrombocytopenia, and splenomegaly are commonly observed in advanced cirrhosis, but these findings reflect the associated portal hypertension and not the liver disease itself. The normal bilirubin and INR suggest preserved liver function and decrease the likelihood of cirrhosis being responsible for the portal hypertension. However, the elevated alkaline phosphatase and GGT levels suggest an infiltrative liver disease, such as lymphoma, sarcoidosis, or amyloidosis.

Furthermore, while a nodular liver on imaging is consistent with cirrhosis, no steatosis was noted to support the presumed diagnosis of NAFLD. One explanation for this discrepancy is that fatty infiltration may be absent when NAFLD-associated cirrhosis develops. In summary, there is evidence of liver disease, and there is evidence of portal hypertension, but there is no evidence of liver parenchymal failure. The key features of the latter – spider angiomata, palmar erythema, hyperbilirubinemia, and coagulopathy – are absent.

Noncirrhotic portal hypertension (NCPH) is an alternative explanation for the patient’s findings. NCPH is an elevation in the portal venous system pressure that arises from intrahepatic (but noncirrhotic) disease or from extrahepatic disease. Hepatic schistosomiasis is an example of intrahepatic but noncirrhotic portal hypertension. PVT that arises on account of a hypercoagulable condition (eg, abdominal malignancy, pancreatitis, or myeloproliferative disorders) is a prototype of extrahepatic NCPH. At this point, it is impossible to know if the PVT is a complication of NCPH or a cause of NCPH. PVT as a complication of cirrhosis is less likely.

An abdominal CT scan would better assess the hepatic parenchyma and exclude abdominal malignancies such as pancreatic adenocarcinoma. An echocardiogram is indicated to evaluate the cause of the elevated jugular venous pressure. A liver biopsy and measurement of portal venous pressure would help distinguish between cirrhotic and noncirrhotic portal hypertension.

Hepatitis A, B, and C serologies were negative as were antinuclear and antimitochondrial antibodies. Ferritin and ceruloplasmin levels were normal. A CT scan of the abdomen with contrast demonstrated a nodular liver contour, splenomegaly, and a nonocclusive PVT (Figure 1). A transthoracic echocardiogram showed normal biventricular systolic function and size, normal diastolic function, a pulmonary artery systolic pressure of 57 mmHg (normal, < 25), moderate tricuspid regurgitation, and no pericardial effusion or thickening. The patient’s confusion and somnolence resolved after two days of lactulose therapy. She denied the use of other medications, supplements, or herbs.

Schistosomiasis is the most common cause of NCPH worldwide. Parasite eggs trapped within the terminal portal venules cause inflammation, leading to fibrosis and intrahepatic portal hypertension. The liver becomes nodular on account of these changes, but the overall hepatic function is typically preserved. Portal hypertension, variceal bleeding, and pulmonary hypertension are common complications. The latter can arise from portosystemic shunting, which leads to embolization of schistosome eggs into the pulmonary circulation, where a granulomatous reaction ensues.

A percutaneous liver biopsy showed granulomatous inflammation and dilated portal venules consistent with increased resistance to venous inflow (Figure 2). There was no sinusoidal congestion to indicate impaired hepatic venous outflow. Mild sinusoidal and portal fibrosis and increased iron in Kupffer cells were noted. There was no evidence of cirrhosis or steatohepatitis. Stains for acid-fast bacilli and fungi were negative. 16S rDNA (a test assessing for bacterial DNA) and Mycobacterium tuberculosis polymerase chain reactions were negative. The biopsy confirmed the diagnosis of noncirrhotic portal hypertension.

Infections, such as brucellosis, Q fever, and tuberculosis, are common causes of granulomatous hepatitis in the developing world. Tuberculosis is prevalent in China, but the test results do not support tuberculosis as a unifying diagnosis.

Schistosomiasis accounts for the major clinical features (portal and pulmonary hypertension and preserved liver function) and hepatic pathology (ie, portal venous fibrosis with granulomatous inflammation) in this case and is prevalent in China, where the patient emigrated from. The biopsy specimen should be re-examined for schistosome eggs and serologic tests for schistosomiasis pursued.

Antibodies to human immunodeficiency virus, Brucella, Bartonella quintana, Bartonella henselae, Coxiella burnetii, Francisella tularensis, and Histoplasma were negative. Cryptococcal antigen and rapid plasma reagin were negative. IgG antibodies to Schistosoma were 0.21 units (normal, < 0.19 units). Based on the patient’s epidemiology, biopsy findings, and serology results, hepatic schistosomiasis was diagnosed. Praziquantel was prescribed. She continues to receive daily lactulose and rifaximin and has not had any episodes of encephalopathy in the year after discharge.

Portal hypertension arises when there is resistance to flow in the portal venous system. It is defined as a pressure gradient greater than 5 mmHg between the portal vein and the intra-abdominal portion of the inferior vena cava.¹ Clinicians are familiar with the manifestations of portal hypertension – portosystemic shunting leading to encephalopathy and variceal hemorrhage, ascites, and splenomegaly with thrombocytopenia – because of their close association with cirrhosis. In developed countries, cirrhosis accounts for over 90% of cases of portal hypertension.¹ In the remaining 10%, conditions such as portal vein thrombosis primarily affect the portal vasculature and increase resistance to portal blood flow while leaving hepatic synthetic function relatively spared (Figure 3). Therefore, cirrhosis cannot be inferred with certainty from signs of portal hypertension alone.

Liver biopsy is the gold standard for the diagnosis of cirrhosis, but this method is increasingly being replaced by noninvasive assessments of liver fibrosis, including imaging and scoring systems.² Clinicians often infer cirrhosis from the combination of a known cause of liver injury, abnormal liver biochemical tests, evidence of liver dysfunction, and signs of portal hypertension.³ However, when signs of portal hypertension are present, but liver dysfunction cannot be established on physical exam (eg, palmar erythema, spider nevi, gynecomastia, and testicular atrophy) or laboratory testing (eg, low albumin, elevated INR, and elevated bilirubin), noncirrhotic causes of portal hypertension should be considered. In this case, the biopsy showed vascular changes that suggested impaired venous inflow without bridging fibrosis, which pointed to NCPH.

NCPH is categorized based on the location of resistance to blood flow: prehepatic (eg, portal vein thrombosis), intrahepatic (eg, schistosomiasis), and posthepatic (eg, right-sided heart failure).¹ In our patient, the dilated portal venules (inflow) in the presence of normal hepatic vein outflow suggested an increased intrahepatic resistance to blood flow. This finding excluded a causal role of the portal vein thrombosis and prompted testing for schistosomiasis.

Schistosomiasis affects more than 200 million people worldwide and is prevalent in Sub-Saharan Africa, South America, Egypt, China, and Southeast Asia.^4,5 Transmission occurs in fresh water, where the infectious form of the parasite is released from snails.^4,6 Schistosome worms are not found in the United States, but as a result of immigration and travel, more than 400,000 people in the United States are estimated to be infected.⁵

Chronic schistosomiasis develops from the host’s granulomatous reaction to schistosome eggs whose location (depending on the species) leads to genitourinary, intestinal, hepatic, or rarely, neurologic disease.⁶ Hepatic schistosomiasis arises when eggs released in the portal venous system lodge in small portal venules and cause granulomatous inflammation, periportal fibrosis, and microvascular obstruction.⁶ The resultant portal hypertension develops insidiously, but the architecture and synthetic function of the liver is maintained until the very late stages of disease.^6,7 Pulmonary hypertension can arise from the embolization of eggs to the pulmonary arterioles via portosystemic collaterals.

The demonstration of eggs in stool is the gold standard for the diagnosis of hepatic schistosomiasis, which is most commonly caused by Schistosoma mansoni and S. japonicum.⁷ Serologic assays provide evidence of infection or exposure but may cross-react with other helminths. Liver biopsy may reveal characteristic histopathologic findings, including granulomatous inflammation, distorted vasculature, and the deposition of collagen deposits in the periportal space, leading to “pipestem fibrosis.”^8,9 If eggs cannot be detected on stool or histology, then serology, secondary histologic changes, and sometimes PCR are used to diagnose hepatic schistosomiasis. In our patient, the epidemiology, Schistosoma antibody titer, pulmonary hypertension, and liver biopsy with granulomatous inflammation, periportal fibrosis, and intrahepatic portal venule dilation were diagnostic of hepatic schistosomiasis.

The recurrent episodes of confusion which resolved with lactulose therapy were suggestive of hepatic encephalopathy, which results from shunting and accumulation of neurotoxic substances that would otherwise undergo hepatic metabolism.¹⁰ Clinicians are most familiar with hepatic encephalopathy in cirrhosis, where multiple liver functions – synthesis, excretion, metabolism, and circulation – simultaneously fail. NCPH represents a scenario where only the circulation is impaired, but this is sufficient to cause the portosystemic shunting that leads to encephalopathy. Our patient’s recurrent hepatic encephalopathy, despite adherence to lactulose and rifaximin and its resolution after praziquantel treatment, underscores the importance of addressing the underlying cause of portosystemic shunting.Associating portal hypertension with cirrhosis is efficient and accurate in many cases. However, when specific manifestations of cirrhosis are lacking, clinicians must decouple this association and pursue an alternative explanation for portal hypertension. The presence of some intrahepatic pathology (from schistosomiasis) but no cirrhosis made this case a particularly tough egg to crack.

Teaching Points

• In the developed world, 90% of portal hypertension is due to cirrhosis. Hepatic schistosomiasis is the most common cause of NCPH worldwide.
• Chronic schistosomiasis affects the gastrointestinal, hepatic, and genitourinary systems and causes significant global morbidity and mortality.
• Visualization of schistosome eggs is the diagnostic gold standard. Indirect testing such as schistosoma antibodies and secondary histologic changes may be required for the diagnosis in patients with a low burden of eggs.

Disclosures

Dr. Geha has no disclosures. Dr. Dhaliwal reports receiving honoraria from ISMIE Mutual Insurance Company and Physicians’ Reciprocal Insurers. Dr. Peters’ spouse is employed by Hoffman-La Roche. Dr. Manesh is supported by the Jeremiah A. Barondess Fellowship in the Clinical Transaction of the New York Academy of Medicine, in collaboration with the Accreditation Council for Graduate Medical Education (ACGME).

For the last 35 years, Medicare’s prospective payment system has transformed reimbursement for hospital-based care of patients. This “revolutionary” system shifted payment from being retrospective—the government paid hospitals for what they did—to prospective—the government paid hospitals against a predetermined fee schedule based on a patient’s condition and other factors.¹ When the system started in 1983, the then-new payment system classified patients into 467 Diagnosis-Related Groups (DRGs). In those early days, Medicare paid hospitals “an average price for an average patient within the DRG.”² Not surprisingly, early critics were concerned that this average payment would disadvantage hospitals that cared for more complex patients, such as teaching hospitals; studies then demonstrated that theoretical concern.³ The Severity of Illness (SOI) index, which was developed in the 1980s, attempted to correct this problem by using SOI-stratified DRGs as a payment mechanism. By adding SOI to DRGs, the homogeneity of resource consumption in each group increased, resulting in more accurate comparisons about complexity, outcomes, resource utilization, and ultimately payment. Eventually, along with the risk of mortality, the SOI made its way into the All Patients Refined (APR) DRG system, which is more representative of non-Medicare populations and thus could be applied to children.

The ongoing challenge with SOI classification is that its 4-level categories (1-mild, 2-moderate, 3-severe, 4-extreme) is not comparable across DRGs; that is, a “moderate” patient in one DRG may be sicker and use more resources than an “extreme” patient in another DRG. For this reason, more than a decade ago, Medicare replaced the DRG/SOI approach with the Medicare Severity (MS)-DRG for Medicare payments to hospitals. The distinguishing feature of MS-DRGs is that they represent a complete relative scale; the relative weights are not categorical but can be lined up and payments assigned relative to the average Medicare patient. For example, a look at the 2015 tables shows that heart transplant has the highest relative weight and is the most expensive one, whereas false labor has the lowest relative weight and is the least expensive.⁴ Due to its exclusive intent for use on Medicare patients, the system could not be used for pediatrics. Interestingly, New York State developed a Service Intensity Weight (SIW) in 2009 by using 3 years of Medicaid and commercial payer data to create a relative scale for payment within the state.⁵

Thanks to Richardson, et al, in this issue of Journal of Hospital Medicine, pediatrics has its first relative weight system for hospitalized children across the United States.⁶ Similar to the MS-DRG system, those with the interest or need can line up the APR-DRGs into a relative scale and see that a normal newborn has a relative weight on their H-RISK scale of 0.18, while a heart transplant patient has a weight of 91.66. This is a welcome and much-needed addition to the world of pediatric health services and health service research. Stakeholders can use this system for comparative analyses, risk adjustment, resource utilization comparison, and payment. For those inclined, one can explore the comparisons of relative weights on different scales; for example, the ratio between simple pneumonia and heart transplant is 21 on the MS-DRG, 60 on the NY State SIW scale,⁷ and 187 on H-RISK. A generation of health service researchers and economists may find great satisfaction in elucidating why this relativity in relative scales exists!

There are limitations to all weighting and relative weighting systems. The H-RISK is based on DRG and SOI, which rely on accurate coding. In addition, as the authors note, iatrogenic complications are not differentiated from naturally occurring ones. Thus, a hospital may obtain a higher relative weight applied to a patient who did not enter the hospital as sick as the final score suggests. Researchers noted this problem from the start of the DRG/SOI journey, and all systems that rely on post hoc scoring based on coded diagnoses and activities, without differentiation of presence on admission, have this limitation.⁸ Furthermore, children’s hospitals have far more variable use of observation status than in Medicare, and many DRG analyses exclude observation-status patients.

Despite these limitations, this is an important first step for children’s hospitals to be better able to do comparative analyses and benchmarking with a true relative weight scale that is appropriate for use among hospitalized children.

Disclosure 

The author declares no conflicts of interest.

For the last 35 years, Medicare’s prospective payment system has transformed reimbursement for hospital-based care of patients. This “revolutionary” system shifted payment from being retrospective—the government paid hospitals for what they did—to prospective—the government paid hospitals against a predetermined fee schedule based on a patient’s condition and other factors.¹ When the system started in 1983, the then-new payment system classified patients into 467 Diagnosis-Related Groups (DRGs). In those early days, Medicare paid hospitals “an average price for an average patient within the DRG.”² Not surprisingly, early critics were concerned that this average payment would disadvantage hospitals that cared for more complex patients, such as teaching hospitals; studies then demonstrated that theoretical concern.³ The Severity of Illness (SOI) index, which was developed in the 1980s, attempted to correct this problem by using SOI-stratified DRGs as a payment mechanism. By adding SOI to DRGs, the homogeneity of resource consumption in each group increased, resulting in more accurate comparisons about complexity, outcomes, resource utilization, and ultimately payment. Eventually, along with the risk of mortality, the SOI made its way into the All Patients Refined (APR) DRG system, which is more representative of non-Medicare populations and thus could be applied to children.

The ongoing challenge with SOI classification is that its 4-level categories (1-mild, 2-moderate, 3-severe, 4-extreme) is not comparable across DRGs; that is, a “moderate” patient in one DRG may be sicker and use more resources than an “extreme” patient in another DRG. For this reason, more than a decade ago, Medicare replaced the DRG/SOI approach with the Medicare Severity (MS)-DRG for Medicare payments to hospitals. The distinguishing feature of MS-DRGs is that they represent a complete relative scale; the relative weights are not categorical but can be lined up and payments assigned relative to the average Medicare patient. For example, a look at the 2015 tables shows that heart transplant has the highest relative weight and is the most expensive one, whereas false labor has the lowest relative weight and is the least expensive.⁴ Due to its exclusive intent for use on Medicare patients, the system could not be used for pediatrics. Interestingly, New York State developed a Service Intensity Weight (SIW) in 2009 by using 3 years of Medicaid and commercial payer data to create a relative scale for payment within the state.⁵

Thanks to Richardson, et al, in this issue of Journal of Hospital Medicine, pediatrics has its first relative weight system for hospitalized children across the United States.⁶ Similar to the MS-DRG system, those with the interest or need can line up the APR-DRGs into a relative scale and see that a normal newborn has a relative weight on their H-RISK scale of 0.18, while a heart transplant patient has a weight of 91.66. This is a welcome and much-needed addition to the world of pediatric health services and health service research. Stakeholders can use this system for comparative analyses, risk adjustment, resource utilization comparison, and payment. For those inclined, one can explore the comparisons of relative weights on different scales; for example, the ratio between simple pneumonia and heart transplant is 21 on the MS-DRG, 60 on the NY State SIW scale,⁷ and 187 on H-RISK. A generation of health service researchers and economists may find great satisfaction in elucidating why this relativity in relative scales exists!

There are limitations to all weighting and relative weighting systems. The H-RISK is based on DRG and SOI, which rely on accurate coding. In addition, as the authors note, iatrogenic complications are not differentiated from naturally occurring ones. Thus, a hospital may obtain a higher relative weight applied to a patient who did not enter the hospital as sick as the final score suggests. Researchers noted this problem from the start of the DRG/SOI journey, and all systems that rely on post hoc scoring based on coded diagnoses and activities, without differentiation of presence on admission, have this limitation.⁸ Furthermore, children’s hospitals have far more variable use of observation status than in Medicare, and many DRG analyses exclude observation-status patients.

Despite these limitations, this is an important first step for children’s hospitals to be better able to do comparative analyses and benchmarking with a true relative weight scale that is appropriate for use among hospitalized children.

Disclosure 

The author declares no conflicts of interest.

For the last 35 years, Medicare’s prospective payment system has transformed reimbursement for hospital-based care of patients. This “revolutionary” system shifted payment from being retrospective—the government paid hospitals for what they did—to prospective—the government paid hospitals against a predetermined fee schedule based on a patient’s condition and other factors.¹ When the system started in 1983, the then-new payment system classified patients into 467 Diagnosis-Related Groups (DRGs). In those early days, Medicare paid hospitals “an average price for an average patient within the DRG.”² Not surprisingly, early critics were concerned that this average payment would disadvantage hospitals that cared for more complex patients, such as teaching hospitals; studies then demonstrated that theoretical concern.³ The Severity of Illness (SOI) index, which was developed in the 1980s, attempted to correct this problem by using SOI-stratified DRGs as a payment mechanism. By adding SOI to DRGs, the homogeneity of resource consumption in each group increased, resulting in more accurate comparisons about complexity, outcomes, resource utilization, and ultimately payment. Eventually, along with the risk of mortality, the SOI made its way into the All Patients Refined (APR) DRG system, which is more representative of non-Medicare populations and thus could be applied to children.

The ongoing challenge with SOI classification is that its 4-level categories (1-mild, 2-moderate, 3-severe, 4-extreme) is not comparable across DRGs; that is, a “moderate” patient in one DRG may be sicker and use more resources than an “extreme” patient in another DRG. For this reason, more than a decade ago, Medicare replaced the DRG/SOI approach with the Medicare Severity (MS)-DRG for Medicare payments to hospitals. The distinguishing feature of MS-DRGs is that they represent a complete relative scale; the relative weights are not categorical but can be lined up and payments assigned relative to the average Medicare patient. For example, a look at the 2015 tables shows that heart transplant has the highest relative weight and is the most expensive one, whereas false labor has the lowest relative weight and is the least expensive.⁴ Due to its exclusive intent for use on Medicare patients, the system could not be used for pediatrics. Interestingly, New York State developed a Service Intensity Weight (SIW) in 2009 by using 3 years of Medicaid and commercial payer data to create a relative scale for payment within the state.⁵

Thanks to Richardson, et al, in this issue of Journal of Hospital Medicine, pediatrics has its first relative weight system for hospitalized children across the United States.⁶ Similar to the MS-DRG system, those with the interest or need can line up the APR-DRGs into a relative scale and see that a normal newborn has a relative weight on their H-RISK scale of 0.18, while a heart transplant patient has a weight of 91.66. This is a welcome and much-needed addition to the world of pediatric health services and health service research. Stakeholders can use this system for comparative analyses, risk adjustment, resource utilization comparison, and payment. For those inclined, one can explore the comparisons of relative weights on different scales; for example, the ratio between simple pneumonia and heart transplant is 21 on the MS-DRG, 60 on the NY State SIW scale,⁷ and 187 on H-RISK. A generation of health service researchers and economists may find great satisfaction in elucidating why this relativity in relative scales exists!

There are limitations to all weighting and relative weighting systems. The H-RISK is based on DRG and SOI, which rely on accurate coding. In addition, as the authors note, iatrogenic complications are not differentiated from naturally occurring ones. Thus, a hospital may obtain a higher relative weight applied to a patient who did not enter the hospital as sick as the final score suggests. Researchers noted this problem from the start of the DRG/SOI journey, and all systems that rely on post hoc scoring based on coded diagnoses and activities, without differentiation of presence on admission, have this limitation.⁸ Furthermore, children’s hospitals have far more variable use of observation status than in Medicare, and many DRG analyses exclude observation-status patients.

Despite these limitations, this is an important first step for children’s hospitals to be better able to do comparative analyses and benchmarking with a true relative weight scale that is appropriate for use among hospitalized children.

Disclosure 

The author declares no conflicts of interest.

Fifteen years ago, beepers with 5-digit call-back numbers were the norm. Pushing a call light button outside the patient’s room to flag the desk clerk that a new order had been hand-written was all part of the lived experience of residency. Using that as our baseline, we have clearly come a long way in the way that we communicate with other clinicians in hospitals. Communication among the patient care team in the digital age predominantly involves bidirectional messaging using mobile devices. The approach is both immediate and convenient. Mobile devices can improve work efficiency, patient safety, and quality of care, but their main advantage may be real-time bedside decision support.^1,2 However, the widespread use of mobile devices for communication in healthcare is not without its concerns. First and foremost, there has been abundant literature around short message service (SMS) use in the healthcare setting, and there are concerns surrounding both threats to privacy and the prevalence and impact of interruptions in clinical care.

The first SMS was sent in 1992.³ Text messaging since then has become ubiquitous, even in healthcare, raising concerns around the protection of patient health information under the Health Insurance Portability and Accountability Act (HIPAA). Interestingly, the United States Department of Health and Human Services Office for Civil Rights, enforcer of HIPAA, is tech neutral on the subject.³ Multiple studies have assessed physician stances on SMS communication in the healthcare setting using routine, non-HIPAA-compliant mobile phones. Overall, 60%-80% of respondents admitted to using SMS in patient care, while in another study, 72% and 80% of Internal Medicine residents surveyed found SMS to be the most efficient form of communication and overall preferred method of communication, respectively.^3,4 Interestingly, 82.5% of those same residents preferred the hospital-based alphanumeric paging system for security purposes, even though Freundlich et al. make a compelling argument that unidirectional alphanumeric paging systems are most certainly less HIPAA compliant, lacking encryption and password protection.⁵ Newer platforms that enable HIPAA-compliant messaging are promising, although they may not be fully adopted by clinical teams without full-scale implementation in hospitals.⁶In addition to privacy concerns with SMS applications on mobile phones, interruptions in healthcare – be it from phone calls, emails, text messages, or in-person conversations – are common. In fact, famed communication researcher Enrico Coeira has notoriously described healthcare communication as ”interrupt-driven.”⁷ Prior work has shown that frequent interruptions in the healthcare setting can lead to medication prescription errors, errors in computerized physician order entry, and even surgical procedural errors.^8-10

While studies have focused on interruptions in clinical care in the healthcare setting, little is known about how education may be compromised by interruptions due to mobile devices. Text messaging during dedicated conference time can lead to inadequate learning and a sense of frustration among residents. In this issue of the Journal of Hospital Medicine, Mendel et al. performed a quality improvement study involving eight academic inpatient clinical training units with the aim of reducing nonurgent text messages during education rounds.¹¹ Their unique interventions included learning sessions, posters, adding alerts to the digital communication platform, and alternative messaging options. Of four sequential interventions, a message alerting the sender that they will be interrupting educational rounds and suggesting a “delayed send” or “send as an FYI” showed the greatest impact, reducing the number of text interruptions per team per educational hour from 0.81 to 0.59 (95% CI 0.51-0.67). When comparing a four-week pre-intervention sample with a four-week end-intervention sample, the percentage of nonurgent messages decreased from 82% to 68% (P < .01).

While these results are promising, challenges to large-scale implementation of such a program exist. Buy-in from the ancillary healthcare team is critical for such interventions to succeed and be sustained. It also places a burden of “point triage” on the healthcare team members, who must assess the patient situation and determine the level of urgency and whether to immediately interrupt, delay interrupt or send an FYI message. For example, in the study by Mendel et al.,¹¹ it is noteworthy that urgent patient care issues were mislabeled as “FYI” in 2% of patients. While this is a seemingly low rate, even one of these mislabeled messages could result in significant adverse patient outcomes and should be considered a “never event.” Finally, the study used a messaging platform with programming flexibility and IT personnel to assist. This could be cost prohibitive for some programs, especially if rolled out to an entire institution.

Communication is critical for effective patient care and unfortunately, the timing of such communication is often not orderly but rather, chaotic. Text message communication can introduce interruptions into all aspects of patient care and education, not only dedicated learning conferences. If the goal is for all residents to attend all conferences, it seems impossible (and likely dangerous) to eliminate all messaging interruptions during conference hours. Nevertheless, it is worth noting that Mandel et al. have moved us creatively toward that goal with a multifaceted approach.¹¹ Future work should address more downstream outcomes, such as objective resident learning retention and adverse patient events relative to the number of interruptions per educational hour. If such studies showed improved learning outcomes and fewer adverse patient events, the next step would be to further strengthen and refine their protocol with real-time and scheduled feedback sessions between providers and other patient care team members in addition to the continued search for additional innovative approaches. In addition, combining artificial intelligence or predictive modeling may help us delineate when an interruption is warranted, for example, when a patient is at high clinical risk without intervention. Likewise, human factors research may help us understand the best way to time and execute an interruption to minimize the risk to clinical care or education. After all, the ideal system would not eliminate interruptions entirely but allow clinicians to know when someone should be interrupted and when they do not need to be interrupted.

Disclosures

The authors have no financial relationships relevant to this article to disclose.

Fifteen years ago, beepers with 5-digit call-back numbers were the norm. Pushing a call light button outside the patient’s room to flag the desk clerk that a new order had been hand-written was all part of the lived experience of residency. Using that as our baseline, we have clearly come a long way in the way that we communicate with other clinicians in hospitals. Communication among the patient care team in the digital age predominantly involves bidirectional messaging using mobile devices. The approach is both immediate and convenient. Mobile devices can improve work efficiency, patient safety, and quality of care, but their main advantage may be real-time bedside decision support.^1,2 However, the widespread use of mobile devices for communication in healthcare is not without its concerns. First and foremost, there has been abundant literature around short message service (SMS) use in the healthcare setting, and there are concerns surrounding both threats to privacy and the prevalence and impact of interruptions in clinical care.

The first SMS was sent in 1992.³ Text messaging since then has become ubiquitous, even in healthcare, raising concerns around the protection of patient health information under the Health Insurance Portability and Accountability Act (HIPAA). Interestingly, the United States Department of Health and Human Services Office for Civil Rights, enforcer of HIPAA, is tech neutral on the subject.³ Multiple studies have assessed physician stances on SMS communication in the healthcare setting using routine, non-HIPAA-compliant mobile phones. Overall, 60%-80% of respondents admitted to using SMS in patient care, while in another study, 72% and 80% of Internal Medicine residents surveyed found SMS to be the most efficient form of communication and overall preferred method of communication, respectively.^3,4 Interestingly, 82.5% of those same residents preferred the hospital-based alphanumeric paging system for security purposes, even though Freundlich et al. make a compelling argument that unidirectional alphanumeric paging systems are most certainly less HIPAA compliant, lacking encryption and password protection.⁵ Newer platforms that enable HIPAA-compliant messaging are promising, although they may not be fully adopted by clinical teams without full-scale implementation in hospitals.⁶In addition to privacy concerns with SMS applications on mobile phones, interruptions in healthcare – be it from phone calls, emails, text messages, or in-person conversations – are common. In fact, famed communication researcher Enrico Coeira has notoriously described healthcare communication as ”interrupt-driven.”⁷ Prior work has shown that frequent interruptions in the healthcare setting can lead to medication prescription errors, errors in computerized physician order entry, and even surgical procedural errors.^8-10

While studies have focused on interruptions in clinical care in the healthcare setting, little is known about how education may be compromised by interruptions due to mobile devices. Text messaging during dedicated conference time can lead to inadequate learning and a sense of frustration among residents. In this issue of the Journal of Hospital Medicine, Mendel et al. performed a quality improvement study involving eight academic inpatient clinical training units with the aim of reducing nonurgent text messages during education rounds.¹¹ Their unique interventions included learning sessions, posters, adding alerts to the digital communication platform, and alternative messaging options. Of four sequential interventions, a message alerting the sender that they will be interrupting educational rounds and suggesting a “delayed send” or “send as an FYI” showed the greatest impact, reducing the number of text interruptions per team per educational hour from 0.81 to 0.59 (95% CI 0.51-0.67). When comparing a four-week pre-intervention sample with a four-week end-intervention sample, the percentage of nonurgent messages decreased from 82% to 68% (P < .01).

While these results are promising, challenges to large-scale implementation of such a program exist. Buy-in from the ancillary healthcare team is critical for such interventions to succeed and be sustained. It also places a burden of “point triage” on the healthcare team members, who must assess the patient situation and determine the level of urgency and whether to immediately interrupt, delay interrupt or send an FYI message. For example, in the study by Mendel et al.,¹¹ it is noteworthy that urgent patient care issues were mislabeled as “FYI” in 2% of patients. While this is a seemingly low rate, even one of these mislabeled messages could result in significant adverse patient outcomes and should be considered a “never event.” Finally, the study used a messaging platform with programming flexibility and IT personnel to assist. This could be cost prohibitive for some programs, especially if rolled out to an entire institution.

Communication is critical for effective patient care and unfortunately, the timing of such communication is often not orderly but rather, chaotic. Text message communication can introduce interruptions into all aspects of patient care and education, not only dedicated learning conferences. If the goal is for all residents to attend all conferences, it seems impossible (and likely dangerous) to eliminate all messaging interruptions during conference hours. Nevertheless, it is worth noting that Mandel et al. have moved us creatively toward that goal with a multifaceted approach.¹¹ Future work should address more downstream outcomes, such as objective resident learning retention and adverse patient events relative to the number of interruptions per educational hour. If such studies showed improved learning outcomes and fewer adverse patient events, the next step would be to further strengthen and refine their protocol with real-time and scheduled feedback sessions between providers and other patient care team members in addition to the continued search for additional innovative approaches. In addition, combining artificial intelligence or predictive modeling may help us delineate when an interruption is warranted, for example, when a patient is at high clinical risk without intervention. Likewise, human factors research may help us understand the best way to time and execute an interruption to minimize the risk to clinical care or education. After all, the ideal system would not eliminate interruptions entirely but allow clinicians to know when someone should be interrupted and when they do not need to be interrupted.

Disclosures

The authors have no financial relationships relevant to this article to disclose.

Fifteen years ago, beepers with 5-digit call-back numbers were the norm. Pushing a call light button outside the patient’s room to flag the desk clerk that a new order had been hand-written was all part of the lived experience of residency. Using that as our baseline, we have clearly come a long way in the way that we communicate with other clinicians in hospitals. Communication among the patient care team in the digital age predominantly involves bidirectional messaging using mobile devices. The approach is both immediate and convenient. Mobile devices can improve work efficiency, patient safety, and quality of care, but their main advantage may be real-time bedside decision support.^1,2 However, the widespread use of mobile devices for communication in healthcare is not without its concerns. First and foremost, there has been abundant literature around short message service (SMS) use in the healthcare setting, and there are concerns surrounding both threats to privacy and the prevalence and impact of interruptions in clinical care.

The first SMS was sent in 1992.³ Text messaging since then has become ubiquitous, even in healthcare, raising concerns around the protection of patient health information under the Health Insurance Portability and Accountability Act (HIPAA). Interestingly, the United States Department of Health and Human Services Office for Civil Rights, enforcer of HIPAA, is tech neutral on the subject.³ Multiple studies have assessed physician stances on SMS communication in the healthcare setting using routine, non-HIPAA-compliant mobile phones. Overall, 60%-80% of respondents admitted to using SMS in patient care, while in another study, 72% and 80% of Internal Medicine residents surveyed found SMS to be the most efficient form of communication and overall preferred method of communication, respectively.^3,4 Interestingly, 82.5% of those same residents preferred the hospital-based alphanumeric paging system for security purposes, even though Freundlich et al. make a compelling argument that unidirectional alphanumeric paging systems are most certainly less HIPAA compliant, lacking encryption and password protection.⁵ Newer platforms that enable HIPAA-compliant messaging are promising, although they may not be fully adopted by clinical teams without full-scale implementation in hospitals.⁶In addition to privacy concerns with SMS applications on mobile phones, interruptions in healthcare – be it from phone calls, emails, text messages, or in-person conversations – are common. In fact, famed communication researcher Enrico Coeira has notoriously described healthcare communication as ”interrupt-driven.”⁷ Prior work has shown that frequent interruptions in the healthcare setting can lead to medication prescription errors, errors in computerized physician order entry, and even surgical procedural errors.^8-10

While studies have focused on interruptions in clinical care in the healthcare setting, little is known about how education may be compromised by interruptions due to mobile devices. Text messaging during dedicated conference time can lead to inadequate learning and a sense of frustration among residents. In this issue of the Journal of Hospital Medicine, Mendel et al. performed a quality improvement study involving eight academic inpatient clinical training units with the aim of reducing nonurgent text messages during education rounds.¹¹ Their unique interventions included learning sessions, posters, adding alerts to the digital communication platform, and alternative messaging options. Of four sequential interventions, a message alerting the sender that they will be interrupting educational rounds and suggesting a “delayed send” or “send as an FYI” showed the greatest impact, reducing the number of text interruptions per team per educational hour from 0.81 to 0.59 (95% CI 0.51-0.67). When comparing a four-week pre-intervention sample with a four-week end-intervention sample, the percentage of nonurgent messages decreased from 82% to 68% (P < .01).

While these results are promising, challenges to large-scale implementation of such a program exist. Buy-in from the ancillary healthcare team is critical for such interventions to succeed and be sustained. It also places a burden of “point triage” on the healthcare team members, who must assess the patient situation and determine the level of urgency and whether to immediately interrupt, delay interrupt or send an FYI message. For example, in the study by Mendel et al.,¹¹ it is noteworthy that urgent patient care issues were mislabeled as “FYI” in 2% of patients. While this is a seemingly low rate, even one of these mislabeled messages could result in significant adverse patient outcomes and should be considered a “never event.” Finally, the study used a messaging platform with programming flexibility and IT personnel to assist. This could be cost prohibitive for some programs, especially if rolled out to an entire institution.

Communication is critical for effective patient care and unfortunately, the timing of such communication is often not orderly but rather, chaotic. Text message communication can introduce interruptions into all aspects of patient care and education, not only dedicated learning conferences. If the goal is for all residents to attend all conferences, it seems impossible (and likely dangerous) to eliminate all messaging interruptions during conference hours. Nevertheless, it is worth noting that Mandel et al. have moved us creatively toward that goal with a multifaceted approach.¹¹ Future work should address more downstream outcomes, such as objective resident learning retention and adverse patient events relative to the number of interruptions per educational hour. If such studies showed improved learning outcomes and fewer adverse patient events, the next step would be to further strengthen and refine their protocol with real-time and scheduled feedback sessions between providers and other patient care team members in addition to the continued search for additional innovative approaches. In addition, combining artificial intelligence or predictive modeling may help us delineate when an interruption is warranted, for example, when a patient is at high clinical risk without intervention. Likewise, human factors research may help us understand the best way to time and execute an interruption to minimize the risk to clinical care or education. After all, the ideal system would not eliminate interruptions entirely but allow clinicians to know when someone should be interrupted and when they do not need to be interrupted.

Disclosures

The authors have no financial relationships relevant to this article to disclose.

This issue of the Journal of Hospital Medicine addresses an emerging trend in internal medicine graduate medical education: the hospitalist rotation.

In the article, Training Residents in Hospital Medicine: The Hospitalist Elective National Survey (HENS). by Ludwin et al., the authors present a descriptive overview of the composition of hospital medicine rotations, as described by program directors from some of the largest training programs. ¹ It can be said for sure that hospital medicine rotations exist: half of the 82 programs that replied to the survey noted that a hospital medicine rotation was already in place. That is where the certainty ends. Although there are common themes across these rotations, there is no one clear definition of such a rotation. Like all good contributions to the medical literature, this study inspires more questions than it answers.

The Mark Twain-inspired cynic would be quick to make an interpretation of the hospital medicine rotation: Is this not just a clever way to coax residents into using their elective time to cover the service needs left over from Accreditation Council for Graduate Medical Education (ACGME)-mandated shift limits and admission caps? Seventy-one percent of these rotations were involved in “admitting new patients.” And since forty-six percent were tasked with taking hold-over admissions, it is reasonable to surmise that these rotations are playing a role in covering patient care duties left over from traditional ward services.

But is there anything wrong with that? Within the confines of reasonable intensity, caring for more patients usually benefits a resident’s education. And if the resident is learning knowledge, skills and attitudes that are unique from those that are acquired on a traditional ward service, painting the fence for free might not be that bad. The question is: “Does the hospitalist rotation help in the acquisition of those unique knowledge, skills and attitudes?” Although this study alludes to such unique components via its qualitative analysis (ie, more autonomy, co-management of non-medicine services, etc.), it does not fully answer that question. It does, however, inspire the next study: How do residents perceive the unique and additional value (if any) of the hospital medicine rotation?

For the sake of argument, let’s say that residents’ perception of the hospital medicine rotation is one of meaning and value. Does that matter? It is great if they do, but equally important is the question of whether or not hospital medicine rotations are effective in preparing resident graduates for a career in hospital medicine. This study suggests that those who have designed these rotations have tried to anticipate and address this need. Components such as quality, patient safety, co-management, and billing and compliance are all clearly a part of a hospitalist’s practice, and all are elements that have not been traditionally emphasized in residency training. The question is: ”Are these elements the knowledge, skills and attitudes that are most lacking in the residency graduate as he/she enters the practice of hospital medicine?” The unfortunate answer is that we do not know for sure, and this uncertainty has been the Achilles heel of our current residency-training infrastructure. Not unique to hospital medicine, there is simply not a well-defined feedback loop between practice requirements and residency training requirements. A structured and regular gap analysis comparing the residents’ areas of competence at the end of training to what they need in practice, would go a long way in answering questions such as this one, and would most certainly inform the components of a hospital medicine elective going forward.

Even if the components of a hospital medicine rotation are valuable, and even if they do align with what the practice needs, there is still the question of whether a month-long hospital medicine rotation can even come close to closing the gap of what is needed versus what is delivered. One can surmise that the answer to that question is what has extended the “hospital medicine rotation” to the “hospital medicine track,” comprised of a multiple of such rotations. Like all discussions on time-constrained medical education curricula, what will be discarded to make room for these rotations? In thirty-six months of training, there is opportunity cost: every month spent on a hospital medicine elective is a month that could have been spent on something else (rheumatology, nephrology, etc.). Again, this is not unique to hospital medicine; the same could be said of the resident who does too many cardiology electives at the exclusion of learning about endocrinology. It would be overly dramatic to say that devoting a month to a hospital medicine rotation, or any elective for that matter, meaningfully compromises the resident’s overall competence as an internist. It is, instead, a question of degree: an excessive number of these electives would likely compromise the resident’s overall competence. The likelihood of this happening is proportional to the size of the gap between what is required to effectively enter hospital medicine practice and what can be delivered in a month-long hospital medicine rotation. We return, then, to the question: How much hospital medicine training in residency would be required to fully prepare a resident for the current practice of a hospitalist?

Whatever the answer might be, that question takes us to a difficult dilemma that has lurked in the background of residency training for some time now; one that is not at all unique to hospital medicine. Should residency training be “voc-tech” or “liberal arts”? A purist would argue that an understanding and appreciation of all things not hospital medicine is what truly makes for the great hospitalist. An understanding of primary care, for example, would seem to optimize a hospitalist’s performance with respect to transitions of care. Adding to the gravity of such an argument is that residency might be the last time to acquire such “non-hospital-medicine” experiences.

Noting that the practice of hospital medicine being so dynamic and heterogeneous, the realist might pile on by saying that it is simply impossible to fully prepare a resident for the actual practice of hospital medicine. Further, many of these skills might be impossible to fully master outside of being fully immersed in the practice of hospital medicine (i.e., billing and coding). The best that can be done is to set a solid foundation that would enable them to learn further as they practice; there will be opportunities to learn the specific components of the field later on.

On the other hand, it is hard to justify residency training if the graduate is unprepared to practice, and without the fundamental knowledge, skills and attitudes specific to their career as they practice. For example, it is reasonable to suspect that a new hospitalist who has had no prior training in quality improvement will, because of the inertia that comes with engaging in any new and foreign skill, find it much harder to engage in quality improvement as a part of her career. It is also worth considering the role that mastery, autonomy and purpose have upon the overall residency experience. Engaging in electives that have a palpable purpose for the resident’s eventual career, and engender an opportunity to begin developing a sense of mastery in that field, could be an effective antidote in mitigating the burn-out that is far too common in residency training today.

For residents engaged in a future practice of hospital medicine, the hospital medicine rotation seems like a promising way out of this dilemma. An effectively designed elective approach could enable maintaining a core foundational education, while getting an early start on the specific components necessary for a promising career in hospital medicine. The operative words, of course, are “effectively designed.” What exactly does that entail? That is why this study is so important; even if we do not fully know what it should look like, we now have our first glimpse of what it is.

Disclosures

The author has nothing to disclose.

This issue of the Journal of Hospital Medicine addresses an emerging trend in internal medicine graduate medical education: the hospitalist rotation.

In the article, Training Residents in Hospital Medicine: The Hospitalist Elective National Survey (HENS). by Ludwin et al., the authors present a descriptive overview of the composition of hospital medicine rotations, as described by program directors from some of the largest training programs. ¹ It can be said for sure that hospital medicine rotations exist: half of the 82 programs that replied to the survey noted that a hospital medicine rotation was already in place. That is where the certainty ends. Although there are common themes across these rotations, there is no one clear definition of such a rotation. Like all good contributions to the medical literature, this study inspires more questions than it answers.

The Mark Twain-inspired cynic would be quick to make an interpretation of the hospital medicine rotation: Is this not just a clever way to coax residents into using their elective time to cover the service needs left over from Accreditation Council for Graduate Medical Education (ACGME)-mandated shift limits and admission caps? Seventy-one percent of these rotations were involved in “admitting new patients.” And since forty-six percent were tasked with taking hold-over admissions, it is reasonable to surmise that these rotations are playing a role in covering patient care duties left over from traditional ward services.

But is there anything wrong with that? Within the confines of reasonable intensity, caring for more patients usually benefits a resident’s education. And if the resident is learning knowledge, skills and attitudes that are unique from those that are acquired on a traditional ward service, painting the fence for free might not be that bad. The question is: “Does the hospitalist rotation help in the acquisition of those unique knowledge, skills and attitudes?” Although this study alludes to such unique components via its qualitative analysis (ie, more autonomy, co-management of non-medicine services, etc.), it does not fully answer that question. It does, however, inspire the next study: How do residents perceive the unique and additional value (if any) of the hospital medicine rotation?

For the sake of argument, let’s say that residents’ perception of the hospital medicine rotation is one of meaning and value. Does that matter? It is great if they do, but equally important is the question of whether or not hospital medicine rotations are effective in preparing resident graduates for a career in hospital medicine. This study suggests that those who have designed these rotations have tried to anticipate and address this need. Components such as quality, patient safety, co-management, and billing and compliance are all clearly a part of a hospitalist’s practice, and all are elements that have not been traditionally emphasized in residency training. The question is: ”Are these elements the knowledge, skills and attitudes that are most lacking in the residency graduate as he/she enters the practice of hospital medicine?” The unfortunate answer is that we do not know for sure, and this uncertainty has been the Achilles heel of our current residency-training infrastructure. Not unique to hospital medicine, there is simply not a well-defined feedback loop between practice requirements and residency training requirements. A structured and regular gap analysis comparing the residents’ areas of competence at the end of training to what they need in practice, would go a long way in answering questions such as this one, and would most certainly inform the components of a hospital medicine elective going forward.

Even if the components of a hospital medicine rotation are valuable, and even if they do align with what the practice needs, there is still the question of whether a month-long hospital medicine rotation can even come close to closing the gap of what is needed versus what is delivered. One can surmise that the answer to that question is what has extended the “hospital medicine rotation” to the “hospital medicine track,” comprised of a multiple of such rotations. Like all discussions on time-constrained medical education curricula, what will be discarded to make room for these rotations? In thirty-six months of training, there is opportunity cost: every month spent on a hospital medicine elective is a month that could have been spent on something else (rheumatology, nephrology, etc.). Again, this is not unique to hospital medicine; the same could be said of the resident who does too many cardiology electives at the exclusion of learning about endocrinology. It would be overly dramatic to say that devoting a month to a hospital medicine rotation, or any elective for that matter, meaningfully compromises the resident’s overall competence as an internist. It is, instead, a question of degree: an excessive number of these electives would likely compromise the resident’s overall competence. The likelihood of this happening is proportional to the size of the gap between what is required to effectively enter hospital medicine practice and what can be delivered in a month-long hospital medicine rotation. We return, then, to the question: How much hospital medicine training in residency would be required to fully prepare a resident for the current practice of a hospitalist?

Whatever the answer might be, that question takes us to a difficult dilemma that has lurked in the background of residency training for some time now; one that is not at all unique to hospital medicine. Should residency training be “voc-tech” or “liberal arts”? A purist would argue that an understanding and appreciation of all things not hospital medicine is what truly makes for the great hospitalist. An understanding of primary care, for example, would seem to optimize a hospitalist’s performance with respect to transitions of care. Adding to the gravity of such an argument is that residency might be the last time to acquire such “non-hospital-medicine” experiences.

Noting that the practice of hospital medicine being so dynamic and heterogeneous, the realist might pile on by saying that it is simply impossible to fully prepare a resident for the actual practice of hospital medicine. Further, many of these skills might be impossible to fully master outside of being fully immersed in the practice of hospital medicine (i.e., billing and coding). The best that can be done is to set a solid foundation that would enable them to learn further as they practice; there will be opportunities to learn the specific components of the field later on.

On the other hand, it is hard to justify residency training if the graduate is unprepared to practice, and without the fundamental knowledge, skills and attitudes specific to their career as they practice. For example, it is reasonable to suspect that a new hospitalist who has had no prior training in quality improvement will, because of the inertia that comes with engaging in any new and foreign skill, find it much harder to engage in quality improvement as a part of her career. It is also worth considering the role that mastery, autonomy and purpose have upon the overall residency experience. Engaging in electives that have a palpable purpose for the resident’s eventual career, and engender an opportunity to begin developing a sense of mastery in that field, could be an effective antidote in mitigating the burn-out that is far too common in residency training today.

For residents engaged in a future practice of hospital medicine, the hospital medicine rotation seems like a promising way out of this dilemma. An effectively designed elective approach could enable maintaining a core foundational education, while getting an early start on the specific components necessary for a promising career in hospital medicine. The operative words, of course, are “effectively designed.” What exactly does that entail? That is why this study is so important; even if we do not fully know what it should look like, we now have our first glimpse of what it is.

Disclosures

The author has nothing to disclose.

This issue of the Journal of Hospital Medicine addresses an emerging trend in internal medicine graduate medical education: the hospitalist rotation.

In the article, Training Residents in Hospital Medicine: The Hospitalist Elective National Survey (HENS). by Ludwin et al., the authors present a descriptive overview of the composition of hospital medicine rotations, as described by program directors from some of the largest training programs. ¹ It can be said for sure that hospital medicine rotations exist: half of the 82 programs that replied to the survey noted that a hospital medicine rotation was already in place. That is where the certainty ends. Although there are common themes across these rotations, there is no one clear definition of such a rotation. Like all good contributions to the medical literature, this study inspires more questions than it answers.

The Mark Twain-inspired cynic would be quick to make an interpretation of the hospital medicine rotation: Is this not just a clever way to coax residents into using their elective time to cover the service needs left over from Accreditation Council for Graduate Medical Education (ACGME)-mandated shift limits and admission caps? Seventy-one percent of these rotations were involved in “admitting new patients.” And since forty-six percent were tasked with taking hold-over admissions, it is reasonable to surmise that these rotations are playing a role in covering patient care duties left over from traditional ward services.

But is there anything wrong with that? Within the confines of reasonable intensity, caring for more patients usually benefits a resident’s education. And if the resident is learning knowledge, skills and attitudes that are unique from those that are acquired on a traditional ward service, painting the fence for free might not be that bad. The question is: “Does the hospitalist rotation help in the acquisition of those unique knowledge, skills and attitudes?” Although this study alludes to such unique components via its qualitative analysis (ie, more autonomy, co-management of non-medicine services, etc.), it does not fully answer that question. It does, however, inspire the next study: How do residents perceive the unique and additional value (if any) of the hospital medicine rotation?

For the sake of argument, let’s say that residents’ perception of the hospital medicine rotation is one of meaning and value. Does that matter? It is great if they do, but equally important is the question of whether or not hospital medicine rotations are effective in preparing resident graduates for a career in hospital medicine. This study suggests that those who have designed these rotations have tried to anticipate and address this need. Components such as quality, patient safety, co-management, and billing and compliance are all clearly a part of a hospitalist’s practice, and all are elements that have not been traditionally emphasized in residency training. The question is: ”Are these elements the knowledge, skills and attitudes that are most lacking in the residency graduate as he/she enters the practice of hospital medicine?” The unfortunate answer is that we do not know for sure, and this uncertainty has been the Achilles heel of our current residency-training infrastructure. Not unique to hospital medicine, there is simply not a well-defined feedback loop between practice requirements and residency training requirements. A structured and regular gap analysis comparing the residents’ areas of competence at the end of training to what they need in practice, would go a long way in answering questions such as this one, and would most certainly inform the components of a hospital medicine elective going forward.

Even if the components of a hospital medicine rotation are valuable, and even if they do align with what the practice needs, there is still the question of whether a month-long hospital medicine rotation can even come close to closing the gap of what is needed versus what is delivered. One can surmise that the answer to that question is what has extended the “hospital medicine rotation” to the “hospital medicine track,” comprised of a multiple of such rotations. Like all discussions on time-constrained medical education curricula, what will be discarded to make room for these rotations? In thirty-six months of training, there is opportunity cost: every month spent on a hospital medicine elective is a month that could have been spent on something else (rheumatology, nephrology, etc.). Again, this is not unique to hospital medicine; the same could be said of the resident who does too many cardiology electives at the exclusion of learning about endocrinology. It would be overly dramatic to say that devoting a month to a hospital medicine rotation, or any elective for that matter, meaningfully compromises the resident’s overall competence as an internist. It is, instead, a question of degree: an excessive number of these electives would likely compromise the resident’s overall competence. The likelihood of this happening is proportional to the size of the gap between what is required to effectively enter hospital medicine practice and what can be delivered in a month-long hospital medicine rotation. We return, then, to the question: How much hospital medicine training in residency would be required to fully prepare a resident for the current practice of a hospitalist?

Whatever the answer might be, that question takes us to a difficult dilemma that has lurked in the background of residency training for some time now; one that is not at all unique to hospital medicine. Should residency training be “voc-tech” or “liberal arts”? A purist would argue that an understanding and appreciation of all things not hospital medicine is what truly makes for the great hospitalist. An understanding of primary care, for example, would seem to optimize a hospitalist’s performance with respect to transitions of care. Adding to the gravity of such an argument is that residency might be the last time to acquire such “non-hospital-medicine” experiences.

Noting that the practice of hospital medicine being so dynamic and heterogeneous, the realist might pile on by saying that it is simply impossible to fully prepare a resident for the actual practice of hospital medicine. Further, many of these skills might be impossible to fully master outside of being fully immersed in the practice of hospital medicine (i.e., billing and coding). The best that can be done is to set a solid foundation that would enable them to learn further as they practice; there will be opportunities to learn the specific components of the field later on.

On the other hand, it is hard to justify residency training if the graduate is unprepared to practice, and without the fundamental knowledge, skills and attitudes specific to their career as they practice. For example, it is reasonable to suspect that a new hospitalist who has had no prior training in quality improvement will, because of the inertia that comes with engaging in any new and foreign skill, find it much harder to engage in quality improvement as a part of her career. It is also worth considering the role that mastery, autonomy and purpose have upon the overall residency experience. Engaging in electives that have a palpable purpose for the resident’s eventual career, and engender an opportunity to begin developing a sense of mastery in that field, could be an effective antidote in mitigating the burn-out that is far too common in residency training today.

For residents engaged in a future practice of hospital medicine, the hospital medicine rotation seems like a promising way out of this dilemma. An effectively designed elective approach could enable maintaining a core foundational education, while getting an early start on the specific components necessary for a promising career in hospital medicine. The operative words, of course, are “effectively designed.” What exactly does that entail? That is why this study is so important; even if we do not fully know what it should look like, we now have our first glimpse of what it is.

Disclosures

The author has nothing to disclose.

For more than 75 years, pediatrics has sought sound guidelines for prescribing maintenance intravenous fluid (mIVF) for children. In 1957, Holliday and Segar (H&S)¹ introduced a breakthrough method for estimating mIVF needs. Their guidelines for calculating free-water and electrolyte needs for mIVF gained wide-spread acceptance and became the standard of care for decades.

Over the last two decades, awareness has grown around the occurrence of rare, life-threatening hyponatremic conditions, especially hyponatremic encephalopathy, in hospitalized children. Concomitantly, an increasing awareness shows that serum levels of antidiuretic hormone (ADH) are often elevated in sick children and triggered by nonosmotic conditions (pain, vomiting, perioperative state, meningitis, and pulmonary disease). This situation led to heightened concern of clinicians and investigators who assumed that hospitalized patients would exhibit reduced tolerance for hypotonic mIVF the mainstay of the H&S method. The possibility that the H&S method could be a significant contributing factor to the development of hyponatremic encephalopathy in hospitalized children became a research topic. This research speculated that even mildly reduced serum sodium levels might be a marker for the much rarer condition of hyponatremic encephalopathy. A number of hospitalists also switched from quarter-normal to half-normal saline in mIVF.

The substitution of hypotonic fluids with isotonic fluids (eg, 0.9% normal saline or lactated Ringer’s) is the current front-runner alternative to increase sodium delivery. The hypothesis is that the delivery of additional sodium, while maintaining the same H&S method volume/rate of fluid delivery, will protect against life-threatening hyponatremic events.

The challenge we face is whether we are moving from mIVF therapy, which features a long track record of success and an excellent safety profile, to a safer or more effective therapeutic approach. We should consider the burden of proof which should be satisfied to support creating new guidelines which center on changing from hypotonic mIVF to isotonic mIVF.

Is there sufficient scientific proof that isotonic mIVF is safer and/or more effective than hypotonic mIVF in preventing life-threatening hyponatremic events?

Is there compelling biologic plausibility for this change for patients with risk factors that are associated with elevated serum ADH levels?

What is the magnitude of the benefit?

What is the magnitude of unintended harms?

We offer our perspective on each of these questions.

The primary difficulty with addressing the adverse events of catastrophic hyponatremia (encephalopathy, seizures, cerebral edema, and death) is their rarity. The events stand out when they occur, prompting mortality and morbidity (M&M) conferences to blunder into action. But that action is not evidence-based, even if a rationale mentions a meta-analysis, because the rationales lack estimates of the number needed to treat (NNT) to prevent one catastrophic event. Estimates of the NNT to prevent mild hypernatremia are not useful. Furthermore, estimates of the number needed to harm (NNH) via unintended consequences of infusing extra sodium chloride are unavailable. True evidence-based medicine (EBM) is rigorous in requiring NNT and NNH. Anything less is considered M&M-based medicine masquerading as EBM.

No technical jargon distinguishes the profound and catastrophic events from the common, mild hyponatremia frequently observed in ill toddlers upon admission. As an analogy, in dealing with fever, astute pediatricians recognize that a moderate fever of 103.4 °F is not halfway to a heatstroke of 108 °F. Fever is not a near miss for heatstroke. Physicians do not recommend acetaminophen to prevent heatstroke, although many parents act that way.

No published randomized controlled trials (RCTs) showed the incidence of these catastrophic hyponatremic events. In the meta-analysis of 10 disparate and uncoordinated trials in 2014,² no serious adverse events were noted among the 1,000 patients involved. Since then, newer RCTs have added another 1,000 patients to the meta-analysis pool, but still no serious adverse event has been observed.

The H&S method features 60 years of proven safety and remains the appropriate estimate when composing long-term parenteral nutrition. No recommendation is perfect for all situations. Many hospitalized children will exhibit an increased level of ADH. A very small fraction of those children will present a sufficiently elevated ADH level long enough to risk creating profound hyponatremia. An approximation is in the order of magnitude of 1 per 100,000 pediatric medical admissions and 1 per 10,000 postoperative patients. With 3 million pediatric admissions yearly in the United States, such numbers mean that large children’s hospitals might see one or two catastrophic adverse events each decade due to mIVF in previously healthy children. The risk in chronically ill children and in the ICU will be higher. The potential for causing unintended greater harm amongst the other millions of patients is high, requiring application of the precautionary principle.

Thus, EBM and RCTs are poor methodologies for quality improvement of this issue. Assigning surrogate measures, such as moderate hyponatremia or even mild hyponatremia, to increase sensitivity and incidence for research purposes lacks a validated scientific link to the much rarer profound hyponatremic events. The resulting nonvalid extrapolation is precisely what true EBM seeks to avoid. A serum sodium of 132 mEq/L is not a near miss. The NNT to prevent the catastrophic events is unknown. Indeed, no paper advocating adoption of isotonic mIVF has even ventured an approximation.

The RCTs are also, therefore, underpowered to identify harms from using normal saline as a maintenance fluid. A few studies mention hypernatremia, but serum sodium is not a statistical variable. Renal physiology predicts that kidneys can easily handle excess infused sodium and can protect against hypernatremia. However, the extra chloride load risks creating hyperchloremic acidosis, particularly when a patient with respiratory insufficiency cannot compensate by lowering pCO₂ through increased minute ventilation. Edema is another risk. Both respiratory insufficiency and edema already occur more frequently (by orders of magnitude) in hospitalized patients on any mIVF than the profound hyponatremia events in hospitalized patients on hypotonic mIVF. For instance, about 1% of hospitalized infants with bronchiolitis are ventilated for respiratory failure. If hyperchloremic acidosis unintentionally caused by isotonic mIVF slightly increases the frequency of intubation, then such result far outweighs any benefit from reducing catastrophic hyponatremic events. Difficulty will also arise in detecting this unintended increase in the rate of intubation compared with the current background frequency. Detecting these unintended harms becomes impossible if the RCT is underpowered by 100-fold due to utilizing a surrogate measure, such as serum sodium <135 mEq/L, as the dependent variable instead of measuring serious hyponatremic adverse events.

All claims that “no evidence of harm” was found from using normal saline as mIVF are type II statistical errors. There is little chance of detecting any harm with a grossly underpowered study or a meta-analysis of 10 such studies. Simply put, EBM is impossible to use for events that occur less than 1 per 10,000 patients using RCTs with 1,000 patients. No usable safety data are available for normal saline as mIVF in any published RCT. As the RCTs are underpowered, one should rely on science to guide therapy, rather than on invalid statistics.

Using the precautionary principle, hypothetically, adding extra sodium chloride to maintenance fluids should be considered in the same manner as adding any other drug. Based on the current evidence, would the Food and Drug Administration approve the drug intravenous sodium chloride for the prevention of hyponatremia induced by maintenance fluids? An increasing evidence of a minimal beneficial effect is observed, but no evidence of safety nor physiology is available. A new drug application for using normal saline as a default maintenance fluid would be soundly rejected by an FDA panel, just as it has been rejected by the majority of pediatric hospitalists throughout the past 15 years since the idea was proposed in 2003.

With the lack of compelling statistical evidence to guide practice, clinicians often rely on biologic plausibility. Relatively recent studies have revealed that many sick children develop elevated blood levels of ADH due to nonosmotic and nonhemodynamic triggers. Fortunately, we also possess a strong body of knowledge around management of children with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). We understand that elevated levels of ADH in the blood causes an increase in the resorption of free water from the renal collecting tubules. No increase in loss of renal sodium nor chloride is associated with this hormonal influence. The resultant hyponatremia is due to excess free-water retention and not the excess loss of sodium or chloride. To manage this condition, patients are not given a salt shaker and then allowed to drink ad libitum. The standard and well-accepted management of patients with SIADH is the restriction of free-water intake because this step addresses the dysfunctional renal process. Administering sodium chloride to a child with SIADH might possibly slow down the progression of hyponatremia but would also expand the total fluid volumes of the patient and would indirectly deal with a problem that could be addressed directly.

Understandably, in an intensive care setting, when hemodynamics is dicey, and when fluid-restriction could risk hypovolemia, employing a volume-expanding solution for mIVF therapy might be reasonable. However, in an ICU setting, SIADH is routinely treated with free-water restriction, and careful calculations of an individual patient’s fluid and electrolyte losses and needs are made.

In conclusion, we recognize the motivation for questioning the H&S method for mIVF as our field surveilles more than a half-century of accumulated experience with this method and the advances in our understanding of physiology and pathophysiology. However, we believe that the current body of evidence fails to substantiate the proposed recommendations.³ The avoidance of laboratory-detectable decreases in serum sodium levels is an unproven marker for the development of life-threatening hyponatremic events. Concerns for untoward effects (eg, excessive volume expansion and effects of hyperchloremia toward acidosis) and the exploration of alternative approaches (eg, modifications in volumes/rates of fluid delivery) have been inadequately explored. The proposed changes in practice may provide no mitigation in the rare events we hope to avoid, may fail to serve all subpopulations within the proposed scope of patients, and will likely create unintended new problems.

Disclosures

Dr. Powell and Dr. Zaoutis have nothing to disclose.

For more than 75 years, pediatrics has sought sound guidelines for prescribing maintenance intravenous fluid (mIVF) for children. In 1957, Holliday and Segar (H&S)¹ introduced a breakthrough method for estimating mIVF needs. Their guidelines for calculating free-water and electrolyte needs for mIVF gained wide-spread acceptance and became the standard of care for decades.

Over the last two decades, awareness has grown around the occurrence of rare, life-threatening hyponatremic conditions, especially hyponatremic encephalopathy, in hospitalized children. Concomitantly, an increasing awareness shows that serum levels of antidiuretic hormone (ADH) are often elevated in sick children and triggered by nonosmotic conditions (pain, vomiting, perioperative state, meningitis, and pulmonary disease). This situation led to heightened concern of clinicians and investigators who assumed that hospitalized patients would exhibit reduced tolerance for hypotonic mIVF the mainstay of the H&S method. The possibility that the H&S method could be a significant contributing factor to the development of hyponatremic encephalopathy in hospitalized children became a research topic. This research speculated that even mildly reduced serum sodium levels might be a marker for the much rarer condition of hyponatremic encephalopathy. A number of hospitalists also switched from quarter-normal to half-normal saline in mIVF.

The substitution of hypotonic fluids with isotonic fluids (eg, 0.9% normal saline or lactated Ringer’s) is the current front-runner alternative to increase sodium delivery. The hypothesis is that the delivery of additional sodium, while maintaining the same H&S method volume/rate of fluid delivery, will protect against life-threatening hyponatremic events.

The challenge we face is whether we are moving from mIVF therapy, which features a long track record of success and an excellent safety profile, to a safer or more effective therapeutic approach. We should consider the burden of proof which should be satisfied to support creating new guidelines which center on changing from hypotonic mIVF to isotonic mIVF.

Is there sufficient scientific proof that isotonic mIVF is safer and/or more effective than hypotonic mIVF in preventing life-threatening hyponatremic events?

Is there compelling biologic plausibility for this change for patients with risk factors that are associated with elevated serum ADH levels?

What is the magnitude of the benefit?

What is the magnitude of unintended harms?

We offer our perspective on each of these questions.

The primary difficulty with addressing the adverse events of catastrophic hyponatremia (encephalopathy, seizures, cerebral edema, and death) is their rarity. The events stand out when they occur, prompting mortality and morbidity (M&M) conferences to blunder into action. But that action is not evidence-based, even if a rationale mentions a meta-analysis, because the rationales lack estimates of the number needed to treat (NNT) to prevent one catastrophic event. Estimates of the NNT to prevent mild hypernatremia are not useful. Furthermore, estimates of the number needed to harm (NNH) via unintended consequences of infusing extra sodium chloride are unavailable. True evidence-based medicine (EBM) is rigorous in requiring NNT and NNH. Anything less is considered M&M-based medicine masquerading as EBM.

No technical jargon distinguishes the profound and catastrophic events from the common, mild hyponatremia frequently observed in ill toddlers upon admission. As an analogy, in dealing with fever, astute pediatricians recognize that a moderate fever of 103.4 °F is not halfway to a heatstroke of 108 °F. Fever is not a near miss for heatstroke. Physicians do not recommend acetaminophen to prevent heatstroke, although many parents act that way.

No published randomized controlled trials (RCTs) showed the incidence of these catastrophic hyponatremic events. In the meta-analysis of 10 disparate and uncoordinated trials in 2014,² no serious adverse events were noted among the 1,000 patients involved. Since then, newer RCTs have added another 1,000 patients to the meta-analysis pool, but still no serious adverse event has been observed.

The H&S method features 60 years of proven safety and remains the appropriate estimate when composing long-term parenteral nutrition. No recommendation is perfect for all situations. Many hospitalized children will exhibit an increased level of ADH. A very small fraction of those children will present a sufficiently elevated ADH level long enough to risk creating profound hyponatremia. An approximation is in the order of magnitude of 1 per 100,000 pediatric medical admissions and 1 per 10,000 postoperative patients. With 3 million pediatric admissions yearly in the United States, such numbers mean that large children’s hospitals might see one or two catastrophic adverse events each decade due to mIVF in previously healthy children. The risk in chronically ill children and in the ICU will be higher. The potential for causing unintended greater harm amongst the other millions of patients is high, requiring application of the precautionary principle.

Thus, EBM and RCTs are poor methodologies for quality improvement of this issue. Assigning surrogate measures, such as moderate hyponatremia or even mild hyponatremia, to increase sensitivity and incidence for research purposes lacks a validated scientific link to the much rarer profound hyponatremic events. The resulting nonvalid extrapolation is precisely what true EBM seeks to avoid. A serum sodium of 132 mEq/L is not a near miss. The NNT to prevent the catastrophic events is unknown. Indeed, no paper advocating adoption of isotonic mIVF has even ventured an approximation.

The RCTs are also, therefore, underpowered to identify harms from using normal saline as a maintenance fluid. A few studies mention hypernatremia, but serum sodium is not a statistical variable. Renal physiology predicts that kidneys can easily handle excess infused sodium and can protect against hypernatremia. However, the extra chloride load risks creating hyperchloremic acidosis, particularly when a patient with respiratory insufficiency cannot compensate by lowering pCO₂ through increased minute ventilation. Edema is another risk. Both respiratory insufficiency and edema already occur more frequently (by orders of magnitude) in hospitalized patients on any mIVF than the profound hyponatremia events in hospitalized patients on hypotonic mIVF. For instance, about 1% of hospitalized infants with bronchiolitis are ventilated for respiratory failure. If hyperchloremic acidosis unintentionally caused by isotonic mIVF slightly increases the frequency of intubation, then such result far outweighs any benefit from reducing catastrophic hyponatremic events. Difficulty will also arise in detecting this unintended increase in the rate of intubation compared with the current background frequency. Detecting these unintended harms becomes impossible if the RCT is underpowered by 100-fold due to utilizing a surrogate measure, such as serum sodium <135 mEq/L, as the dependent variable instead of measuring serious hyponatremic adverse events.

All claims that “no evidence of harm” was found from using normal saline as mIVF are type II statistical errors. There is little chance of detecting any harm with a grossly underpowered study or a meta-analysis of 10 such studies. Simply put, EBM is impossible to use for events that occur less than 1 per 10,000 patients using RCTs with 1,000 patients. No usable safety data are available for normal saline as mIVF in any published RCT. As the RCTs are underpowered, one should rely on science to guide therapy, rather than on invalid statistics.

Using the precautionary principle, hypothetically, adding extra sodium chloride to maintenance fluids should be considered in the same manner as adding any other drug. Based on the current evidence, would the Food and Drug Administration approve the drug intravenous sodium chloride for the prevention of hyponatremia induced by maintenance fluids? An increasing evidence of a minimal beneficial effect is observed, but no evidence of safety nor physiology is available. A new drug application for using normal saline as a default maintenance fluid would be soundly rejected by an FDA panel, just as it has been rejected by the majority of pediatric hospitalists throughout the past 15 years since the idea was proposed in 2003.

With the lack of compelling statistical evidence to guide practice, clinicians often rely on biologic plausibility. Relatively recent studies have revealed that many sick children develop elevated blood levels of ADH due to nonosmotic and nonhemodynamic triggers. Fortunately, we also possess a strong body of knowledge around management of children with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). We understand that elevated levels of ADH in the blood causes an increase in the resorption of free water from the renal collecting tubules. No increase in loss of renal sodium nor chloride is associated with this hormonal influence. The resultant hyponatremia is due to excess free-water retention and not the excess loss of sodium or chloride. To manage this condition, patients are not given a salt shaker and then allowed to drink ad libitum. The standard and well-accepted management of patients with SIADH is the restriction of free-water intake because this step addresses the dysfunctional renal process. Administering sodium chloride to a child with SIADH might possibly slow down the progression of hyponatremia but would also expand the total fluid volumes of the patient and would indirectly deal with a problem that could be addressed directly.

Understandably, in an intensive care setting, when hemodynamics is dicey, and when fluid-restriction could risk hypovolemia, employing a volume-expanding solution for mIVF therapy might be reasonable. However, in an ICU setting, SIADH is routinely treated with free-water restriction, and careful calculations of an individual patient’s fluid and electrolyte losses and needs are made.

In conclusion, we recognize the motivation for questioning the H&S method for mIVF as our field surveilles more than a half-century of accumulated experience with this method and the advances in our understanding of physiology and pathophysiology. However, we believe that the current body of evidence fails to substantiate the proposed recommendations.³ The avoidance of laboratory-detectable decreases in serum sodium levels is an unproven marker for the development of life-threatening hyponatremic events. Concerns for untoward effects (eg, excessive volume expansion and effects of hyperchloremia toward acidosis) and the exploration of alternative approaches (eg, modifications in volumes/rates of fluid delivery) have been inadequately explored. The proposed changes in practice may provide no mitigation in the rare events we hope to avoid, may fail to serve all subpopulations within the proposed scope of patients, and will likely create unintended new problems.

Disclosures

Dr. Powell and Dr. Zaoutis have nothing to disclose.

For more than 75 years, pediatrics has sought sound guidelines for prescribing maintenance intravenous fluid (mIVF) for children. In 1957, Holliday and Segar (H&S)¹ introduced a breakthrough method for estimating mIVF needs. Their guidelines for calculating free-water and electrolyte needs for mIVF gained wide-spread acceptance and became the standard of care for decades.

Over the last two decades, awareness has grown around the occurrence of rare, life-threatening hyponatremic conditions, especially hyponatremic encephalopathy, in hospitalized children. Concomitantly, an increasing awareness shows that serum levels of antidiuretic hormone (ADH) are often elevated in sick children and triggered by nonosmotic conditions (pain, vomiting, perioperative state, meningitis, and pulmonary disease). This situation led to heightened concern of clinicians and investigators who assumed that hospitalized patients would exhibit reduced tolerance for hypotonic mIVF the mainstay of the H&S method. The possibility that the H&S method could be a significant contributing factor to the development of hyponatremic encephalopathy in hospitalized children became a research topic. This research speculated that even mildly reduced serum sodium levels might be a marker for the much rarer condition of hyponatremic encephalopathy. A number of hospitalists also switched from quarter-normal to half-normal saline in mIVF.

The substitution of hypotonic fluids with isotonic fluids (eg, 0.9% normal saline or lactated Ringer’s) is the current front-runner alternative to increase sodium delivery. The hypothesis is that the delivery of additional sodium, while maintaining the same H&S method volume/rate of fluid delivery, will protect against life-threatening hyponatremic events.

The challenge we face is whether we are moving from mIVF therapy, which features a long track record of success and an excellent safety profile, to a safer or more effective therapeutic approach. We should consider the burden of proof which should be satisfied to support creating new guidelines which center on changing from hypotonic mIVF to isotonic mIVF.

Is there sufficient scientific proof that isotonic mIVF is safer and/or more effective than hypotonic mIVF in preventing life-threatening hyponatremic events?

Is there compelling biologic plausibility for this change for patients with risk factors that are associated with elevated serum ADH levels?

What is the magnitude of the benefit?

What is the magnitude of unintended harms?

We offer our perspective on each of these questions.

The primary difficulty with addressing the adverse events of catastrophic hyponatremia (encephalopathy, seizures, cerebral edema, and death) is their rarity. The events stand out when they occur, prompting mortality and morbidity (M&M) conferences to blunder into action. But that action is not evidence-based, even if a rationale mentions a meta-analysis, because the rationales lack estimates of the number needed to treat (NNT) to prevent one catastrophic event. Estimates of the NNT to prevent mild hypernatremia are not useful. Furthermore, estimates of the number needed to harm (NNH) via unintended consequences of infusing extra sodium chloride are unavailable. True evidence-based medicine (EBM) is rigorous in requiring NNT and NNH. Anything less is considered M&M-based medicine masquerading as EBM.

No technical jargon distinguishes the profound and catastrophic events from the common, mild hyponatremia frequently observed in ill toddlers upon admission. As an analogy, in dealing with fever, astute pediatricians recognize that a moderate fever of 103.4 °F is not halfway to a heatstroke of 108 °F. Fever is not a near miss for heatstroke. Physicians do not recommend acetaminophen to prevent heatstroke, although many parents act that way.

No published randomized controlled trials (RCTs) showed the incidence of these catastrophic hyponatremic events. In the meta-analysis of 10 disparate and uncoordinated trials in 2014,² no serious adverse events were noted among the 1,000 patients involved. Since then, newer RCTs have added another 1,000 patients to the meta-analysis pool, but still no serious adverse event has been observed.

The H&S method features 60 years of proven safety and remains the appropriate estimate when composing long-term parenteral nutrition. No recommendation is perfect for all situations. Many hospitalized children will exhibit an increased level of ADH. A very small fraction of those children will present a sufficiently elevated ADH level long enough to risk creating profound hyponatremia. An approximation is in the order of magnitude of 1 per 100,000 pediatric medical admissions and 1 per 10,000 postoperative patients. With 3 million pediatric admissions yearly in the United States, such numbers mean that large children’s hospitals might see one or two catastrophic adverse events each decade due to mIVF in previously healthy children. The risk in chronically ill children and in the ICU will be higher. The potential for causing unintended greater harm amongst the other millions of patients is high, requiring application of the precautionary principle.

Thus, EBM and RCTs are poor methodologies for quality improvement of this issue. Assigning surrogate measures, such as moderate hyponatremia or even mild hyponatremia, to increase sensitivity and incidence for research purposes lacks a validated scientific link to the much rarer profound hyponatremic events. The resulting nonvalid extrapolation is precisely what true EBM seeks to avoid. A serum sodium of 132 mEq/L is not a near miss. The NNT to prevent the catastrophic events is unknown. Indeed, no paper advocating adoption of isotonic mIVF has even ventured an approximation.

The RCTs are also, therefore, underpowered to identify harms from using normal saline as a maintenance fluid. A few studies mention hypernatremia, but serum sodium is not a statistical variable. Renal physiology predicts that kidneys can easily handle excess infused sodium and can protect against hypernatremia. However, the extra chloride load risks creating hyperchloremic acidosis, particularly when a patient with respiratory insufficiency cannot compensate by lowering pCO₂ through increased minute ventilation. Edema is another risk. Both respiratory insufficiency and edema already occur more frequently (by orders of magnitude) in hospitalized patients on any mIVF than the profound hyponatremia events in hospitalized patients on hypotonic mIVF. For instance, about 1% of hospitalized infants with bronchiolitis are ventilated for respiratory failure. If hyperchloremic acidosis unintentionally caused by isotonic mIVF slightly increases the frequency of intubation, then such result far outweighs any benefit from reducing catastrophic hyponatremic events. Difficulty will also arise in detecting this unintended increase in the rate of intubation compared with the current background frequency. Detecting these unintended harms becomes impossible if the RCT is underpowered by 100-fold due to utilizing a surrogate measure, such as serum sodium <135 mEq/L, as the dependent variable instead of measuring serious hyponatremic adverse events.

All claims that “no evidence of harm” was found from using normal saline as mIVF are type II statistical errors. There is little chance of detecting any harm with a grossly underpowered study or a meta-analysis of 10 such studies. Simply put, EBM is impossible to use for events that occur less than 1 per 10,000 patients using RCTs with 1,000 patients. No usable safety data are available for normal saline as mIVF in any published RCT. As the RCTs are underpowered, one should rely on science to guide therapy, rather than on invalid statistics.

Using the precautionary principle, hypothetically, adding extra sodium chloride to maintenance fluids should be considered in the same manner as adding any other drug. Based on the current evidence, would the Food and Drug Administration approve the drug intravenous sodium chloride for the prevention of hyponatremia induced by maintenance fluids? An increasing evidence of a minimal beneficial effect is observed, but no evidence of safety nor physiology is available. A new drug application for using normal saline as a default maintenance fluid would be soundly rejected by an FDA panel, just as it has been rejected by the majority of pediatric hospitalists throughout the past 15 years since the idea was proposed in 2003.

With the lack of compelling statistical evidence to guide practice, clinicians often rely on biologic plausibility. Relatively recent studies have revealed that many sick children develop elevated blood levels of ADH due to nonosmotic and nonhemodynamic triggers. Fortunately, we also possess a strong body of knowledge around management of children with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). We understand that elevated levels of ADH in the blood causes an increase in the resorption of free water from the renal collecting tubules. No increase in loss of renal sodium nor chloride is associated with this hormonal influence. The resultant hyponatremia is due to excess free-water retention and not the excess loss of sodium or chloride. To manage this condition, patients are not given a salt shaker and then allowed to drink ad libitum. The standard and well-accepted management of patients with SIADH is the restriction of free-water intake because this step addresses the dysfunctional renal process. Administering sodium chloride to a child with SIADH might possibly slow down the progression of hyponatremia but would also expand the total fluid volumes of the patient and would indirectly deal with a problem that could be addressed directly.

Understandably, in an intensive care setting, when hemodynamics is dicey, and when fluid-restriction could risk hypovolemia, employing a volume-expanding solution for mIVF therapy might be reasonable. However, in an ICU setting, SIADH is routinely treated with free-water restriction, and careful calculations of an individual patient’s fluid and electrolyte losses and needs are made.

In conclusion, we recognize the motivation for questioning the H&S method for mIVF as our field surveilles more than a half-century of accumulated experience with this method and the advances in our understanding of physiology and pathophysiology. However, we believe that the current body of evidence fails to substantiate the proposed recommendations.³ The avoidance of laboratory-detectable decreases in serum sodium levels is an unproven marker for the development of life-threatening hyponatremic events. Concerns for untoward effects (eg, excessive volume expansion and effects of hyperchloremia toward acidosis) and the exploration of alternative approaches (eg, modifications in volumes/rates of fluid delivery) have been inadequately explored. The proposed changes in practice may provide no mitigation in the rare events we hope to avoid, may fail to serve all subpopulations within the proposed scope of patients, and will likely create unintended new problems.

Disclosures

Dr. Powell and Dr. Zaoutis have nothing to disclose.

Click here to access the September 2018 Digital Edition.

Table of Contents

• Huddling for High-Performing
• Flexible Bronchoscopic Removal of 3 Foreign Objects
• Improved Transitional Care Through an Innovative Hospitalist Model
• Reducing Prescribing of Benzodiazepines in Older Veterans
• Outcomes of Palliative Care Consults With Hospitalized Veterans
• Transforming Primary Care Clinical Learning Environments to Optimize Education, Outcomes, and Satisfaction

Click here to access the September 2018 Digital Edition.

Table of Contents

• Huddling for High-Performing
• Flexible Bronchoscopic Removal of 3 Foreign Objects
• Improved Transitional Care Through an Innovative Hospitalist Model
• Reducing Prescribing of Benzodiazepines in Older Veterans
• Outcomes of Palliative Care Consults With Hospitalized Veterans
• Transforming Primary Care Clinical Learning Environments to Optimize Education, Outcomes, and Satisfaction

Click here to access the September 2018 Digital Edition.

Table of Contents

• Huddling for High-Performing
• Flexible Bronchoscopic Removal of 3 Foreign Objects
• Improved Transitional Care Through an Innovative Hospitalist Model
• Reducing Prescribing of Benzodiazepines in Older Veterans
• Outcomes of Palliative Care Consults With Hospitalized Veterans
• Transforming Primary Care Clinical Learning Environments to Optimize Education, Outcomes, and Satisfaction

The use of pharmacogenetic testing to help drive decisions for medication management of patients with psychiatric illnesses is growing. It’s becoming increasingly common for patients or the parents of pediatric patients to request pharmacogenetic testing or to bring the results of prior testing to their appointment. In these situations, patients may ask clinicians to consider the recommendations from these testing reports, which rarely provide guidance specific to pediatric patients. However, this can be difficult for clinicians who did not receive education in pharmacogenetics and may not be familiar with the evidence or options for pharmacogenetic testing. Many of the pharmacogenetic associations identified thus far have been discovered in adults, but studies in pediatric patients are relatively rare. This article reviews pharmacogenetic testing and the evidence supporting it, and describes implementation of routine pharmacogenetics testing at a children’s hospital.

CASE
Testing leads to dose adjustment, improvement

Ms. R, age 16, presents with treatment-resistant major depressive disorder that is characterized by a significant neurovegetative burden and prominent anhedonia, as well as intermittent suicidal ideation without intent or plan. She reportedly did not improve after multiple medication trials, including citalopram (maximum dose 30 mg/d, treatment duration 8 weeks, good compliance), sertraline (maximum dose 150 mg/d, treatment duration 10 weeks, good compliance), fluoxetine (maximum dose 40 mg/d, treatment duration 8 weeks, good compliance, mild improvement in neurovegetative symptoms and depressed mood), and duloxetine (maximum dose 90 mg/d, treatment duration 6 weeks, good compliance, mild benefit but intolerable nausea).

Augmentation strategies included risperidone, 1 mg/d at bedtime, but it failed to ameliorate her depressive symptoms. At the time of pharmacogenetic testing, she is taking aripiprazole, 2 mg/d at bedtime, and venlafaxine ER, 37.5 mg/d. Some benefit was noted, but her symptoms recrudesced within several weeks. Because both of these medications are metabolized by the cytochrome P450 (CYP) 2D6 enzyme, Ms. R is tested for CYP2D6 variants and is determined to be a CYP2D6 ultra-rapid metabolizer. Her venlafaxine ER is quickly titrated from 37.5 to 112.5 mg/d and aripiprazole is titrated from 2 to 10 mg/d. The patient’s anergia, amotivation, and mood improve.

_

Drug metabolism and genetic variants

It is common for patients with psychiatric disorders to receive trials of multiple psychotropic medications prior to identifying one that reduces symptom burden without producing intolerable adverse effects. Due to the high frequency of toxicity-related adverse effects (observed in 20% to 70% of patients),¹ these medications are frequently initiated at low doses and titrated slowly until the patient either experiences an intolerable adverse effect or achieves symptomatic remission.^1,2 The practice of slow titration at the start of treatment increases the risk of undertreatment in many patients, and may ultimately lead to a medication change due to the lack of response.

Many of the medications used to treat psychiatric illnesses are primarily metabolized by 2 CYP enzymes expressed in the liver, encoded by the CYP2D6 and CYP2C19 genes³ (Table 1^3-7 and Table 2^3,6,7). These drug-metabolizing enzymes affect the pharmacokinetics of many medications. Some medications are converted to an active form by these enzymes, and some are inactivated. The contributions of CYP enzymes to the pharmacokinetics of neuro­psychiatric medications have been well-described; however, there is less evidence on whether variants in these genes are associated with treatment efficacy, especially in pediatric patients.^8,9 CYP2D6 enzyme activity reaches adult levels soon after birth, but children may have higher CYP2C19 activity than adults.⁴ CYP3A4 also contributes to the metabolism of many medications; however, there is only weak evidence that genetic variants in CYP3A4 contribute to variability in the pharmacokinetics of these medications, and there are currently no dosing guidelines based on pharmacogenetics available for this gene.¹⁰

As is common in the pharmacogenetic field, genotypes are denoted with a “star allele” (eg, *2) rather than positional nomenclature (eg, c.681G>A). The normal allele is usually designated as *1, and this result is given in the absence of the tested alleles. There is no consensus on the minimum set of alleles to be tested for most genes,¹¹ so commercially available tests vary widely in what alleles are tested (and therefore what they exclude before calling a normal allele).¹² The metabolizer phenotype for a patient is determined by taking into account the activity of each of the patient’s 2 alleles (eg, *1/*2). A patient is categorized as a poor-, intermediate-, normal- (extensive-), or ultra-rapid metabolizer. Generally, the allele definitions are widely agreed upon (what genetic variant or variants comprise the *2 allele) due to nomenclature committees for each gene; however, because there are no standards for interpretation, the interpretation of the activity of the alleles and conversion to metabolizer phenotype varies among clinics.¹³

Continue to: Guidelines help with genotype-guided dosing

 

 

Guidelines help with genotype-guided dosing

Each CPIC guideline specifically addresses use in pediatric patients, indicating that there are relatively few studies in pediatrics, but “it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring.”⁴ The DPWG guidelines do not mention whether or not the recommendations are applicable to children. Neither CPIC nor the DPWG provides guidance on when to test; however, the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique) recommends CYP2D6 and CYP2C19 genotyping before initiating antidepressant treatment, especially in patients with a high risk of toxicity.¹⁶

In the case above, Ms. R was determined to be a CYP2D6 ultra-rapid metabolizer. Because she showed some initial response to aripiprazole and venlafaxine ER, which are both metabolized by CYP2D6, these medications were very quickly titrated up, and the increased dosages produced the desired response. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine by CYP2D6. The DPWG recommends increasing the dose of venlafaxine in CYP2D6 ultra-rapid metabolizers to 150% of the normal dose based on the decreased serum concentrations of venlafaxine and O-desmethylvenlafaxine in these patients.⁶ Aripiprazole is also metabolized by CYP2D6; however, the FDA and DPWG give no recommendations for ultra-rapid metabolizers, but do recommend reducing the dose of aripiprazole in CYP2D6 poor metabolizers.

Multiple studies in adults have analyzed the association between pharmacokinetic (CYP2D6 and CYP2C19) or pharmacodynamic genes (SLC6A4, HTR2A, and GRIK4) and outcomes,¹⁷ including some large clinical trials that conducted genome-wide association studies^18-20 and meta-analyses across multiple studies.^21,22 Most pharmacogenetic studies in psychiatric patients are small, and very few have included pediatric patients. However, with more interest in neuropsychiatric pharmacogenetics, these studies are becoming more common.^23-26

Continue to: Limited evidence from studies of commercially available tests

 

 

Limited evidence from studies of commercially available tests

Several pharmacogenetic tests are commercially available, including some that focus on providing information that can be used specifically when prescribing psychiatric medications, such as the GeneSight Psychotropic test, CNSdose, Genomind, and Neuropharmagen.

In an industry-sponsored, nonrandomized clinical trial that included patients for whom prescribing decisions were made based on the GeneSight test, outcomes in adults were improved compared with treatment as usual,²⁷ inpatient stays were shorter,²⁸ and pharmacy costs were reduced.²⁹ In one of these studies, the authors noted that the traditional, single-gene analysis was not associated with improved outcomes, whereas the multiple gene combination (pharmacokinetic and pharmacodynamic genes) was associated with improved outcomes among patients with depression.²⁷ However, when GeneSightwas compared with treatment as usual in a small randomized trial, there was not a significant association between use of the test and improved outcomes among patients with treatment-resistant depression.³⁰ The results of a much larger randomized trial (N = 1,167) are available³¹ and expected to be published, but patients younger than age 18 were excluded from this study.³² A retrospective study conducted in adult psychiatric patients found that patients whose treatment followed recommendations of a pharmacogenetic test including 20 genes were almost 4 times more likely to improve than patients whose treatment did not follow the recommendations.³³

Pharmacogenetic testing at our pediatric inpatient unit

The Cincinnati Children’s Division of Child and Adolescent Psychiatry is the largest psychiatric inpatient service in a U.S. pediatric hospital. Starting in 2004, we adopted pharmacogenetically-guided dosing of psychiatric medications.³⁴ CYP2D6 and CYP2C19 were chosen for testing because the enzymes encoded by these genes metabolize many of the antidepressants and antipsychotics that patients admitted to our unit will receive, and the clinicians wanted all available tools to help improve the care of these patients. To date, the Genetic Pharmacology Service (GPS) has performed >25,000 tests for variants in CYP2D6 and CYP2C19 as part of inpatient care. Patients provide a specimen (blood or buccal swab) at the time of admission to inpatient psychiatry, genotyping is performed onsite by the Molecular Genetics Laboratory (certified by the College of American Pathologists [CAP]/Clinical Laboratory Improvement Amendments [CLIA]) and the results are posted to the medical record within 2 business days. The report contains the patient’s alleles for CYP2D6 and CYP2C19, the genotype-predicted metabolizer phenotype, and dosing recommendations for 19 drugs (provided as a percentage of the standard dose). Insurance is billed for the test, and reimbursement is usually received when the test is performed as part of an inpatient stay.

The GPS team performed a retrospective chart review after the first panel was implemented in 2005.²³ The study included 279 patients who were receiving a medication metabolized by one of the 2 genes tested. The poor metabolizers had the highest efficacy and highest number of adverse drug reactions, while ultra-rapid metabolizers had the lowest efficacy and lowest number of adverse reactions during their initial inpatient stay. In patients not treated with medications metabolized by CYP2D6 or CYP2C19, there was no association between metabolizer status and efficacy or adverse drug reactions. In this retrospective study, there was no association between metabolizer status and length of stay.

Overcoming the challenges

One challenge with many of the pharmacogenetic tests is interpretation of the results. The reports can span more than 20 pages, and clinicians may not have time to thoroughly read and understand how best to use all of this information. Sometimes the reports can make it seem like the first-line medication for the patient’s condition is not the best choice, but it could work well when dosed appropriately based on the patient’s genotype. Each commercially available test has a different way of presenting results,¹³ so when choosing a pharmacogenetic test, one should be sure to see a sample report. Vo et al³⁵ recently reviewed factors to consider when choosing a pharmacogenetic test.

Continue to: Because patients and families also have difficulty understanding the reports...

Because patients and families also have difficulty understanding the reports, we created patient education sheets,³⁶ written at an eighth grade level with feedback from parents and modeled on those provided by St. Jude Children’s Research Hospital.³⁷ St. Jude Children’s Research Hospital also has pharmacogenetic competencies that pharmacists and nurses must pass.^38,39 The following is a sample explanation that one of our nurses uses to educate parents on what is being tested and what effect the results will have on the treatment plan.

“During your child’s stay we will be completing a genetic test to help us understand how he/she processes the types of medications that we may be likely to start during their hospitalization. This does not tell us which medication will be best—unfortunately within the field of psychiatry there is still some unavoidable trial and error; rather, what it will do is tell us how to make sure that the dosing is at a level that would be safe for the way your child’s body breaks down the medicine, so that he/she can get the intended benefit of the medicine’s effects, while decreasing the risk of uncomfortable side effects, where possible.”

Other challenges in pharmacogenetic testing are the cost, disease risk, and concern about how genetic information will be used. Because these tests are often not covered by health insurance, some commercial pharmacogenetic testing companies offer an out-of-pocket maximum in the $250 to $350 range to reduce the cost to the patient. Some pharmacogenetic testing companies also test for genes associated with disease, so if a clinician orders the test, he or she may be responsible for sharing that information with the patient. For most pharmacogenetic testing companies, the turn-around time is 2 to 10 days. Genetic information is protected by federal laws, including Genetic Information Nondiscrimination Act (GINA) and Health Insurance Portability and Accountability Act (HIPAA).

The choice of psychotropic medication is complex, and although we would like pharmacogenetics to be the only answer to why every patient does or does not respond to a medication, it is not. Response to medication is influenced by age, comorbidities, illness severity, illness duration, compliance, gender, concomitant medications, and potentially more.⁴⁰ Pharmacogenetics is another tool at the clinician’s disposal to help in choosing a medication and dose. There is a clear association between CYP2D6 and CYP2C19 and exposure to many antidepressants and antipsychotics (reviewed by Stingl et al³); however, the link between exposure and response is much weaker. It may be strengthened by the inclusion of pharmacodynamic information (the level of expression of the drug target), which can be influenced by genetic variants.⁴¹ At the present time, the most evidence exists for testing CYP2D6 and CYP2C19, and the CPIC^4,5,15 and DWPG⁶ guidelines provide evidence-based recommendations for how to adjust medication dosages based on the results.

There is clearly much more research that needs to be done in the field of neuropsychi­atric pharmacogenetics, especially in pediatric populations. As we see increased utilization of pharmacogenetic tests in psychiatry, there is also a need for pharmaco­genetic education of patients, families, nurses, pharmacists, and psychiatrists. Several good pharmacogenetic resources that contain up-to-date summaries of the available evidence linking pharmacogenetic variants to medication response, implementation resources, and educational resources are available. These include CPIC (www.cpicpgx.org), PharmGKB (www.pharmgkb.org), and the IGNITE Spark Toolbox (https://ignite-genomics.org/spark-toolbox/clinicians/).

Acknowledgements

The author thanks Jen Milau, APRN, for the case study and sample explanation, and Jeffrey Strawn, MD, FAACP, Ethan Poweleit, and Stacey Aldrich, MS, for help with preparing this manuscript.

The use of pharmacogenetic testing to help drive decisions for medication management of patients with psychiatric illnesses is growing. It’s becoming increasingly common for patients or the parents of pediatric patients to request pharmacogenetic testing or to bring the results of prior testing to their appointment. In these situations, patients may ask clinicians to consider the recommendations from these testing reports, which rarely provide guidance specific to pediatric patients. However, this can be difficult for clinicians who did not receive education in pharmacogenetics and may not be familiar with the evidence or options for pharmacogenetic testing. Many of the pharmacogenetic associations identified thus far have been discovered in adults, but studies in pediatric patients are relatively rare. This article reviews pharmacogenetic testing and the evidence supporting it, and describes implementation of routine pharmacogenetics testing at a children’s hospital.

CASE
Testing leads to dose adjustment, improvement

Ms. R, age 16, presents with treatment-resistant major depressive disorder that is characterized by a significant neurovegetative burden and prominent anhedonia, as well as intermittent suicidal ideation without intent or plan. She reportedly did not improve after multiple medication trials, including citalopram (maximum dose 30 mg/d, treatment duration 8 weeks, good compliance), sertraline (maximum dose 150 mg/d, treatment duration 10 weeks, good compliance), fluoxetine (maximum dose 40 mg/d, treatment duration 8 weeks, good compliance, mild improvement in neurovegetative symptoms and depressed mood), and duloxetine (maximum dose 90 mg/d, treatment duration 6 weeks, good compliance, mild benefit but intolerable nausea).

Augmentation strategies included risperidone, 1 mg/d at bedtime, but it failed to ameliorate her depressive symptoms. At the time of pharmacogenetic testing, she is taking aripiprazole, 2 mg/d at bedtime, and venlafaxine ER, 37.5 mg/d. Some benefit was noted, but her symptoms recrudesced within several weeks. Because both of these medications are metabolized by the cytochrome P450 (CYP) 2D6 enzyme, Ms. R is tested for CYP2D6 variants and is determined to be a CYP2D6 ultra-rapid metabolizer. Her venlafaxine ER is quickly titrated from 37.5 to 112.5 mg/d and aripiprazole is titrated from 2 to 10 mg/d. The patient’s anergia, amotivation, and mood improve.

_

Drug metabolism and genetic variants

It is common for patients with psychiatric disorders to receive trials of multiple psychotropic medications prior to identifying one that reduces symptom burden without producing intolerable adverse effects. Due to the high frequency of toxicity-related adverse effects (observed in 20% to 70% of patients),¹ these medications are frequently initiated at low doses and titrated slowly until the patient either experiences an intolerable adverse effect or achieves symptomatic remission.^1,2 The practice of slow titration at the start of treatment increases the risk of undertreatment in many patients, and may ultimately lead to a medication change due to the lack of response.

Many of the medications used to treat psychiatric illnesses are primarily metabolized by 2 CYP enzymes expressed in the liver, encoded by the CYP2D6 and CYP2C19 genes³ (Table 1^3-7 and Table 2^3,6,7). These drug-metabolizing enzymes affect the pharmacokinetics of many medications. Some medications are converted to an active form by these enzymes, and some are inactivated. The contributions of CYP enzymes to the pharmacokinetics of neuro­psychiatric medications have been well-described; however, there is less evidence on whether variants in these genes are associated with treatment efficacy, especially in pediatric patients.^8,9 CYP2D6 enzyme activity reaches adult levels soon after birth, but children may have higher CYP2C19 activity than adults.⁴ CYP3A4 also contributes to the metabolism of many medications; however, there is only weak evidence that genetic variants in CYP3A4 contribute to variability in the pharmacokinetics of these medications, and there are currently no dosing guidelines based on pharmacogenetics available for this gene.¹⁰

As is common in the pharmacogenetic field, genotypes are denoted with a “star allele” (eg, *2) rather than positional nomenclature (eg, c.681G>A). The normal allele is usually designated as *1, and this result is given in the absence of the tested alleles. There is no consensus on the minimum set of alleles to be tested for most genes,¹¹ so commercially available tests vary widely in what alleles are tested (and therefore what they exclude before calling a normal allele).¹² The metabolizer phenotype for a patient is determined by taking into account the activity of each of the patient’s 2 alleles (eg, *1/*2). A patient is categorized as a poor-, intermediate-, normal- (extensive-), or ultra-rapid metabolizer. Generally, the allele definitions are widely agreed upon (what genetic variant or variants comprise the *2 allele) due to nomenclature committees for each gene; however, because there are no standards for interpretation, the interpretation of the activity of the alleles and conversion to metabolizer phenotype varies among clinics.¹³

Continue to: Guidelines help with genotype-guided dosing

 

 

Guidelines help with genotype-guided dosing

Each CPIC guideline specifically addresses use in pediatric patients, indicating that there are relatively few studies in pediatrics, but “it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring.”⁴ The DPWG guidelines do not mention whether or not the recommendations are applicable to children. Neither CPIC nor the DPWG provides guidance on when to test; however, the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique) recommends CYP2D6 and CYP2C19 genotyping before initiating antidepressant treatment, especially in patients with a high risk of toxicity.¹⁶

In the case above, Ms. R was determined to be a CYP2D6 ultra-rapid metabolizer. Because she showed some initial response to aripiprazole and venlafaxine ER, which are both metabolized by CYP2D6, these medications were very quickly titrated up, and the increased dosages produced the desired response. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine by CYP2D6. The DPWG recommends increasing the dose of venlafaxine in CYP2D6 ultra-rapid metabolizers to 150% of the normal dose based on the decreased serum concentrations of venlafaxine and O-desmethylvenlafaxine in these patients.⁶ Aripiprazole is also metabolized by CYP2D6; however, the FDA and DPWG give no recommendations for ultra-rapid metabolizers, but do recommend reducing the dose of aripiprazole in CYP2D6 poor metabolizers.

Multiple studies in adults have analyzed the association between pharmacokinetic (CYP2D6 and CYP2C19) or pharmacodynamic genes (SLC6A4, HTR2A, and GRIK4) and outcomes,¹⁷ including some large clinical trials that conducted genome-wide association studies^18-20 and meta-analyses across multiple studies.^21,22 Most pharmacogenetic studies in psychiatric patients are small, and very few have included pediatric patients. However, with more interest in neuropsychiatric pharmacogenetics, these studies are becoming more common.^23-26

Continue to: Limited evidence from studies of commercially available tests

 

 

Limited evidence from studies of commercially available tests

Several pharmacogenetic tests are commercially available, including some that focus on providing information that can be used specifically when prescribing psychiatric medications, such as the GeneSight Psychotropic test, CNSdose, Genomind, and Neuropharmagen.

In an industry-sponsored, nonrandomized clinical trial that included patients for whom prescribing decisions were made based on the GeneSight test, outcomes in adults were improved compared with treatment as usual,²⁷ inpatient stays were shorter,²⁸ and pharmacy costs were reduced.²⁹ In one of these studies, the authors noted that the traditional, single-gene analysis was not associated with improved outcomes, whereas the multiple gene combination (pharmacokinetic and pharmacodynamic genes) was associated with improved outcomes among patients with depression.²⁷ However, when GeneSightwas compared with treatment as usual in a small randomized trial, there was not a significant association between use of the test and improved outcomes among patients with treatment-resistant depression.³⁰ The results of a much larger randomized trial (N = 1,167) are available³¹ and expected to be published, but patients younger than age 18 were excluded from this study.³² A retrospective study conducted in adult psychiatric patients found that patients whose treatment followed recommendations of a pharmacogenetic test including 20 genes were almost 4 times more likely to improve than patients whose treatment did not follow the recommendations.³³

Pharmacogenetic testing at our pediatric inpatient unit

The Cincinnati Children’s Division of Child and Adolescent Psychiatry is the largest psychiatric inpatient service in a U.S. pediatric hospital. Starting in 2004, we adopted pharmacogenetically-guided dosing of psychiatric medications.³⁴ CYP2D6 and CYP2C19 were chosen for testing because the enzymes encoded by these genes metabolize many of the antidepressants and antipsychotics that patients admitted to our unit will receive, and the clinicians wanted all available tools to help improve the care of these patients. To date, the Genetic Pharmacology Service (GPS) has performed >25,000 tests for variants in CYP2D6 and CYP2C19 as part of inpatient care. Patients provide a specimen (blood or buccal swab) at the time of admission to inpatient psychiatry, genotyping is performed onsite by the Molecular Genetics Laboratory (certified by the College of American Pathologists [CAP]/Clinical Laboratory Improvement Amendments [CLIA]) and the results are posted to the medical record within 2 business days. The report contains the patient’s alleles for CYP2D6 and CYP2C19, the genotype-predicted metabolizer phenotype, and dosing recommendations for 19 drugs (provided as a percentage of the standard dose). Insurance is billed for the test, and reimbursement is usually received when the test is performed as part of an inpatient stay.

The GPS team performed a retrospective chart review after the first panel was implemented in 2005.²³ The study included 279 patients who were receiving a medication metabolized by one of the 2 genes tested. The poor metabolizers had the highest efficacy and highest number of adverse drug reactions, while ultra-rapid metabolizers had the lowest efficacy and lowest number of adverse reactions during their initial inpatient stay. In patients not treated with medications metabolized by CYP2D6 or CYP2C19, there was no association between metabolizer status and efficacy or adverse drug reactions. In this retrospective study, there was no association between metabolizer status and length of stay.

Overcoming the challenges

One challenge with many of the pharmacogenetic tests is interpretation of the results. The reports can span more than 20 pages, and clinicians may not have time to thoroughly read and understand how best to use all of this information. Sometimes the reports can make it seem like the first-line medication for the patient’s condition is not the best choice, but it could work well when dosed appropriately based on the patient’s genotype. Each commercially available test has a different way of presenting results,¹³ so when choosing a pharmacogenetic test, one should be sure to see a sample report. Vo et al³⁵ recently reviewed factors to consider when choosing a pharmacogenetic test.

Continue to: Because patients and families also have difficulty understanding the reports...

Because patients and families also have difficulty understanding the reports, we created patient education sheets,³⁶ written at an eighth grade level with feedback from parents and modeled on those provided by St. Jude Children’s Research Hospital.³⁷ St. Jude Children’s Research Hospital also has pharmacogenetic competencies that pharmacists and nurses must pass.^38,39 The following is a sample explanation that one of our nurses uses to educate parents on what is being tested and what effect the results will have on the treatment plan.

“During your child’s stay we will be completing a genetic test to help us understand how he/she processes the types of medications that we may be likely to start during their hospitalization. This does not tell us which medication will be best—unfortunately within the field of psychiatry there is still some unavoidable trial and error; rather, what it will do is tell us how to make sure that the dosing is at a level that would be safe for the way your child’s body breaks down the medicine, so that he/she can get the intended benefit of the medicine’s effects, while decreasing the risk of uncomfortable side effects, where possible.”

Other challenges in pharmacogenetic testing are the cost, disease risk, and concern about how genetic information will be used. Because these tests are often not covered by health insurance, some commercial pharmacogenetic testing companies offer an out-of-pocket maximum in the $250 to $350 range to reduce the cost to the patient. Some pharmacogenetic testing companies also test for genes associated with disease, so if a clinician orders the test, he or she may be responsible for sharing that information with the patient. For most pharmacogenetic testing companies, the turn-around time is 2 to 10 days. Genetic information is protected by federal laws, including Genetic Information Nondiscrimination Act (GINA) and Health Insurance Portability and Accountability Act (HIPAA).

The choice of psychotropic medication is complex, and although we would like pharmacogenetics to be the only answer to why every patient does or does not respond to a medication, it is not. Response to medication is influenced by age, comorbidities, illness severity, illness duration, compliance, gender, concomitant medications, and potentially more.⁴⁰ Pharmacogenetics is another tool at the clinician’s disposal to help in choosing a medication and dose. There is a clear association between CYP2D6 and CYP2C19 and exposure to many antidepressants and antipsychotics (reviewed by Stingl et al³); however, the link between exposure and response is much weaker. It may be strengthened by the inclusion of pharmacodynamic information (the level of expression of the drug target), which can be influenced by genetic variants.⁴¹ At the present time, the most evidence exists for testing CYP2D6 and CYP2C19, and the CPIC^4,5,15 and DWPG⁶ guidelines provide evidence-based recommendations for how to adjust medication dosages based on the results.

There is clearly much more research that needs to be done in the field of neuropsychi­atric pharmacogenetics, especially in pediatric populations. As we see increased utilization of pharmacogenetic tests in psychiatry, there is also a need for pharmaco­genetic education of patients, families, nurses, pharmacists, and psychiatrists. Several good pharmacogenetic resources that contain up-to-date summaries of the available evidence linking pharmacogenetic variants to medication response, implementation resources, and educational resources are available. These include CPIC (www.cpicpgx.org), PharmGKB (www.pharmgkb.org), and the IGNITE Spark Toolbox (https://ignite-genomics.org/spark-toolbox/clinicians/).

Acknowledgements

The author thanks Jen Milau, APRN, for the case study and sample explanation, and Jeffrey Strawn, MD, FAACP, Ethan Poweleit, and Stacey Aldrich, MS, for help with preparing this manuscript.

The use of pharmacogenetic testing to help drive decisions for medication management of patients with psychiatric illnesses is growing. It’s becoming increasingly common for patients or the parents of pediatric patients to request pharmacogenetic testing or to bring the results of prior testing to their appointment. In these situations, patients may ask clinicians to consider the recommendations from these testing reports, which rarely provide guidance specific to pediatric patients. However, this can be difficult for clinicians who did not receive education in pharmacogenetics and may not be familiar with the evidence or options for pharmacogenetic testing. Many of the pharmacogenetic associations identified thus far have been discovered in adults, but studies in pediatric patients are relatively rare. This article reviews pharmacogenetic testing and the evidence supporting it, and describes implementation of routine pharmacogenetics testing at a children’s hospital.

CASE
Testing leads to dose adjustment, improvement

Ms. R, age 16, presents with treatment-resistant major depressive disorder that is characterized by a significant neurovegetative burden and prominent anhedonia, as well as intermittent suicidal ideation without intent or plan. She reportedly did not improve after multiple medication trials, including citalopram (maximum dose 30 mg/d, treatment duration 8 weeks, good compliance), sertraline (maximum dose 150 mg/d, treatment duration 10 weeks, good compliance), fluoxetine (maximum dose 40 mg/d, treatment duration 8 weeks, good compliance, mild improvement in neurovegetative symptoms and depressed mood), and duloxetine (maximum dose 90 mg/d, treatment duration 6 weeks, good compliance, mild benefit but intolerable nausea).

Augmentation strategies included risperidone, 1 mg/d at bedtime, but it failed to ameliorate her depressive symptoms. At the time of pharmacogenetic testing, she is taking aripiprazole, 2 mg/d at bedtime, and venlafaxine ER, 37.5 mg/d. Some benefit was noted, but her symptoms recrudesced within several weeks. Because both of these medications are metabolized by the cytochrome P450 (CYP) 2D6 enzyme, Ms. R is tested for CYP2D6 variants and is determined to be a CYP2D6 ultra-rapid metabolizer. Her venlafaxine ER is quickly titrated from 37.5 to 112.5 mg/d and aripiprazole is titrated from 2 to 10 mg/d. The patient’s anergia, amotivation, and mood improve.

_

Drug metabolism and genetic variants

It is common for patients with psychiatric disorders to receive trials of multiple psychotropic medications prior to identifying one that reduces symptom burden without producing intolerable adverse effects. Due to the high frequency of toxicity-related adverse effects (observed in 20% to 70% of patients),¹ these medications are frequently initiated at low doses and titrated slowly until the patient either experiences an intolerable adverse effect or achieves symptomatic remission.^1,2 The practice of slow titration at the start of treatment increases the risk of undertreatment in many patients, and may ultimately lead to a medication change due to the lack of response.

Many of the medications used to treat psychiatric illnesses are primarily metabolized by 2 CYP enzymes expressed in the liver, encoded by the CYP2D6 and CYP2C19 genes³ (Table 1^3-7 and Table 2^3,6,7). These drug-metabolizing enzymes affect the pharmacokinetics of many medications. Some medications are converted to an active form by these enzymes, and some are inactivated. The contributions of CYP enzymes to the pharmacokinetics of neuro­psychiatric medications have been well-described; however, there is less evidence on whether variants in these genes are associated with treatment efficacy, especially in pediatric patients.^8,9 CYP2D6 enzyme activity reaches adult levels soon after birth, but children may have higher CYP2C19 activity than adults.⁴ CYP3A4 also contributes to the metabolism of many medications; however, there is only weak evidence that genetic variants in CYP3A4 contribute to variability in the pharmacokinetics of these medications, and there are currently no dosing guidelines based on pharmacogenetics available for this gene.¹⁰

As is common in the pharmacogenetic field, genotypes are denoted with a “star allele” (eg, *2) rather than positional nomenclature (eg, c.681G>A). The normal allele is usually designated as *1, and this result is given in the absence of the tested alleles. There is no consensus on the minimum set of alleles to be tested for most genes,¹¹ so commercially available tests vary widely in what alleles are tested (and therefore what they exclude before calling a normal allele).¹² The metabolizer phenotype for a patient is determined by taking into account the activity of each of the patient’s 2 alleles (eg, *1/*2). A patient is categorized as a poor-, intermediate-, normal- (extensive-), or ultra-rapid metabolizer. Generally, the allele definitions are widely agreed upon (what genetic variant or variants comprise the *2 allele) due to nomenclature committees for each gene; however, because there are no standards for interpretation, the interpretation of the activity of the alleles and conversion to metabolizer phenotype varies among clinics.¹³

Continue to: Guidelines help with genotype-guided dosing

 

 

Guidelines help with genotype-guided dosing

Each CPIC guideline specifically addresses use in pediatric patients, indicating that there are relatively few studies in pediatrics, but “it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring.”⁴ The DPWG guidelines do not mention whether or not the recommendations are applicable to children. Neither CPIC nor the DPWG provides guidance on when to test; however, the French National Network of Pharmacogenetics (Réseau national de pharmacogénétique) recommends CYP2D6 and CYP2C19 genotyping before initiating antidepressant treatment, especially in patients with a high risk of toxicity.¹⁶

In the case above, Ms. R was determined to be a CYP2D6 ultra-rapid metabolizer. Because she showed some initial response to aripiprazole and venlafaxine ER, which are both metabolized by CYP2D6, these medications were very quickly titrated up, and the increased dosages produced the desired response. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine by CYP2D6. The DPWG recommends increasing the dose of venlafaxine in CYP2D6 ultra-rapid metabolizers to 150% of the normal dose based on the decreased serum concentrations of venlafaxine and O-desmethylvenlafaxine in these patients.⁶ Aripiprazole is also metabolized by CYP2D6; however, the FDA and DPWG give no recommendations for ultra-rapid metabolizers, but do recommend reducing the dose of aripiprazole in CYP2D6 poor metabolizers.

Multiple studies in adults have analyzed the association between pharmacokinetic (CYP2D6 and CYP2C19) or pharmacodynamic genes (SLC6A4, HTR2A, and GRIK4) and outcomes,¹⁷ including some large clinical trials that conducted genome-wide association studies^18-20 and meta-analyses across multiple studies.^21,22 Most pharmacogenetic studies in psychiatric patients are small, and very few have included pediatric patients. However, with more interest in neuropsychiatric pharmacogenetics, these studies are becoming more common.^23-26

Continue to: Limited evidence from studies of commercially available tests

 

 

Limited evidence from studies of commercially available tests

Several pharmacogenetic tests are commercially available, including some that focus on providing information that can be used specifically when prescribing psychiatric medications, such as the GeneSight Psychotropic test, CNSdose, Genomind, and Neuropharmagen.

In an industry-sponsored, nonrandomized clinical trial that included patients for whom prescribing decisions were made based on the GeneSight test, outcomes in adults were improved compared with treatment as usual,²⁷ inpatient stays were shorter,²⁸ and pharmacy costs were reduced.²⁹ In one of these studies, the authors noted that the traditional, single-gene analysis was not associated with improved outcomes, whereas the multiple gene combination (pharmacokinetic and pharmacodynamic genes) was associated with improved outcomes among patients with depression.²⁷ However, when GeneSightwas compared with treatment as usual in a small randomized trial, there was not a significant association between use of the test and improved outcomes among patients with treatment-resistant depression.³⁰ The results of a much larger randomized trial (N = 1,167) are available³¹ and expected to be published, but patients younger than age 18 were excluded from this study.³² A retrospective study conducted in adult psychiatric patients found that patients whose treatment followed recommendations of a pharmacogenetic test including 20 genes were almost 4 times more likely to improve than patients whose treatment did not follow the recommendations.³³

Pharmacogenetic testing at our pediatric inpatient unit

The Cincinnati Children’s Division of Child and Adolescent Psychiatry is the largest psychiatric inpatient service in a U.S. pediatric hospital. Starting in 2004, we adopted pharmacogenetically-guided dosing of psychiatric medications.³⁴ CYP2D6 and CYP2C19 were chosen for testing because the enzymes encoded by these genes metabolize many of the antidepressants and antipsychotics that patients admitted to our unit will receive, and the clinicians wanted all available tools to help improve the care of these patients. To date, the Genetic Pharmacology Service (GPS) has performed >25,000 tests for variants in CYP2D6 and CYP2C19 as part of inpatient care. Patients provide a specimen (blood or buccal swab) at the time of admission to inpatient psychiatry, genotyping is performed onsite by the Molecular Genetics Laboratory (certified by the College of American Pathologists [CAP]/Clinical Laboratory Improvement Amendments [CLIA]) and the results are posted to the medical record within 2 business days. The report contains the patient’s alleles for CYP2D6 and CYP2C19, the genotype-predicted metabolizer phenotype, and dosing recommendations for 19 drugs (provided as a percentage of the standard dose). Insurance is billed for the test, and reimbursement is usually received when the test is performed as part of an inpatient stay.

The GPS team performed a retrospective chart review after the first panel was implemented in 2005.²³ The study included 279 patients who were receiving a medication metabolized by one of the 2 genes tested. The poor metabolizers had the highest efficacy and highest number of adverse drug reactions, while ultra-rapid metabolizers had the lowest efficacy and lowest number of adverse reactions during their initial inpatient stay. In patients not treated with medications metabolized by CYP2D6 or CYP2C19, there was no association between metabolizer status and efficacy or adverse drug reactions. In this retrospective study, there was no association between metabolizer status and length of stay.

Overcoming the challenges

One challenge with many of the pharmacogenetic tests is interpretation of the results. The reports can span more than 20 pages, and clinicians may not have time to thoroughly read and understand how best to use all of this information. Sometimes the reports can make it seem like the first-line medication for the patient’s condition is not the best choice, but it could work well when dosed appropriately based on the patient’s genotype. Each commercially available test has a different way of presenting results,¹³ so when choosing a pharmacogenetic test, one should be sure to see a sample report. Vo et al³⁵ recently reviewed factors to consider when choosing a pharmacogenetic test.

Continue to: Because patients and families also have difficulty understanding the reports...

Because patients and families also have difficulty understanding the reports, we created patient education sheets,³⁶ written at an eighth grade level with feedback from parents and modeled on those provided by St. Jude Children’s Research Hospital.³⁷ St. Jude Children’s Research Hospital also has pharmacogenetic competencies that pharmacists and nurses must pass.^38,39 The following is a sample explanation that one of our nurses uses to educate parents on what is being tested and what effect the results will have on the treatment plan.

“During your child’s stay we will be completing a genetic test to help us understand how he/she processes the types of medications that we may be likely to start during their hospitalization. This does not tell us which medication will be best—unfortunately within the field of psychiatry there is still some unavoidable trial and error; rather, what it will do is tell us how to make sure that the dosing is at a level that would be safe for the way your child’s body breaks down the medicine, so that he/she can get the intended benefit of the medicine’s effects, while decreasing the risk of uncomfortable side effects, where possible.”

Other challenges in pharmacogenetic testing are the cost, disease risk, and concern about how genetic information will be used. Because these tests are often not covered by health insurance, some commercial pharmacogenetic testing companies offer an out-of-pocket maximum in the $250 to $350 range to reduce the cost to the patient. Some pharmacogenetic testing companies also test for genes associated with disease, so if a clinician orders the test, he or she may be responsible for sharing that information with the patient. For most pharmacogenetic testing companies, the turn-around time is 2 to 10 days. Genetic information is protected by federal laws, including Genetic Information Nondiscrimination Act (GINA) and Health Insurance Portability and Accountability Act (HIPAA).

The choice of psychotropic medication is complex, and although we would like pharmacogenetics to be the only answer to why every patient does or does not respond to a medication, it is not. Response to medication is influenced by age, comorbidities, illness severity, illness duration, compliance, gender, concomitant medications, and potentially more.⁴⁰ Pharmacogenetics is another tool at the clinician’s disposal to help in choosing a medication and dose. There is a clear association between CYP2D6 and CYP2C19 and exposure to many antidepressants and antipsychotics (reviewed by Stingl et al³); however, the link between exposure and response is much weaker. It may be strengthened by the inclusion of pharmacodynamic information (the level of expression of the drug target), which can be influenced by genetic variants.⁴¹ At the present time, the most evidence exists for testing CYP2D6 and CYP2C19, and the CPIC^4,5,15 and DWPG⁶ guidelines provide evidence-based recommendations for how to adjust medication dosages based on the results.

There is clearly much more research that needs to be done in the field of neuropsychi­atric pharmacogenetics, especially in pediatric populations. As we see increased utilization of pharmacogenetic tests in psychiatry, there is also a need for pharmaco­genetic education of patients, families, nurses, pharmacists, and psychiatrists. Several good pharmacogenetic resources that contain up-to-date summaries of the available evidence linking pharmacogenetic variants to medication response, implementation resources, and educational resources are available. These include CPIC (www.cpicpgx.org), PharmGKB (www.pharmgkb.org), and the IGNITE Spark Toolbox (https://ignite-genomics.org/spark-toolbox/clinicians/).

Acknowledgements

The author thanks Jen Milau, APRN, for the case study and sample explanation, and Jeffrey Strawn, MD, FAACP, Ethan Poweleit, and Stacey Aldrich, MS, for help with preparing this manuscript.

Photo courtesy of Janssen

The European Commission (EC) has approved a new indication for daratumumab (Darzalex®).

The drug is now authorized for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat adults with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

Daratumumab was previously approved by the EC for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat adults with MM who have received at least one prior therapy.

In addition, daratumumab is EC-approved as monotherapy for adults with relapsed and refractory MM whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on their last therapy.

The EC’s latest approval for daratumumab is based on results from the phase 3 ALCYONE (MMY3007) study.

Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).

The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.

The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.

The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).

Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.

Photo courtesy of Janssen

The European Commission (EC) has approved a new indication for daratumumab (Darzalex®).

The drug is now authorized for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat adults with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

Daratumumab was previously approved by the EC for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat adults with MM who have received at least one prior therapy.

In addition, daratumumab is EC-approved as monotherapy for adults with relapsed and refractory MM whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on their last therapy.

The EC’s latest approval for daratumumab is based on results from the phase 3 ALCYONE (MMY3007) study.

Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).

The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.

The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.

The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).

Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.

Photo courtesy of Janssen

The European Commission (EC) has approved a new indication for daratumumab (Darzalex®).

The drug is now authorized for use in combination with bortezomib, melphalan, and prednisone (VMP) to treat adults with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

Daratumumab was previously approved by the EC for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat adults with MM who have received at least one prior therapy.

In addition, daratumumab is EC-approved as monotherapy for adults with relapsed and refractory MM whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on their last therapy.

The EC’s latest approval for daratumumab is based on results from the phase 3 ALCYONE (MMY3007) study.

Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine.

ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).

The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.

The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.

The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).

Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.

Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Alcohol use during breastfeeding linked to cognitive harms in children

To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019

2. Cigarette smoking epidemic among HCV-infected individuals

To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019

3. Pancreatic surveillance identified resectable cancers

To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019

4. Autoimmune connective tissue disease predicted by interferon status, family history

To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019

Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Alcohol use during breastfeeding linked to cognitive harms in children

To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019

2. Cigarette smoking epidemic among HCV-infected individuals

To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019

3. Pancreatic surveillance identified resectable cancers

To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019

4. Autoimmune connective tissue disease predicted by interferon status, family history

To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019

Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Alcohol use during breastfeeding linked to cognitive harms in children

To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019

2. Cigarette smoking epidemic among HCV-infected individuals

To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019

3. Pancreatic surveillance identified resectable cancers

To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019

4. Autoimmune connective tissue disease predicted by interferon status, family history

To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019

CMS has released its proposed rule (see related articles and a commentary) and included changes as substantial as I have seen in the last two decades. Additionally, the Affordable Care Act has been under continued attack despite its majority support from our citizenry. Loss of the individual mandate, allowance of “skinny” health plans, a rewrite of association plan rules, elimination of cost-sharing reductions and premium support – all have contributed to a shifting away from socialized medical costs and toward a system of individual responsibility for health. Depending on one’s political philosophy (and income), that may be bad or good.

Our article list this month will be interesting to many. The AGA produced a Clinical Practice Update about tumor seeding with endoscopic procedures. This should give us pause and make us reconsider our endoscopic practices. My wife (an endoscopy nurse in Minneapolis) has been asking for years whether pulling a PEG tube past an esophageal cancer might cause tumor seeding, and physicians have reassured her that there is no cause for worry. Turns out she was right (as usual). Deaths from liver disease in the U.S. have seen a dramatic increase since 1999, driven substantially by increasing alcohol use. Fecal transplants in irritable bowel syndrome? Possibly helpful, as reported in an article from Digestive Disease Week.^®

As summer comes to an end, we head into a tumultuous fall that will be dominated by November elections.

John I. Allen, MD, MBA, AGAF
Editor in Chief

CMS has released its proposed rule (see related articles and a commentary) and included changes as substantial as I have seen in the last two decades. Additionally, the Affordable Care Act has been under continued attack despite its majority support from our citizenry. Loss of the individual mandate, allowance of “skinny” health plans, a rewrite of association plan rules, elimination of cost-sharing reductions and premium support – all have contributed to a shifting away from socialized medical costs and toward a system of individual responsibility for health. Depending on one’s political philosophy (and income), that may be bad or good.

Our article list this month will be interesting to many. The AGA produced a Clinical Practice Update about tumor seeding with endoscopic procedures. This should give us pause and make us reconsider our endoscopic practices. My wife (an endoscopy nurse in Minneapolis) has been asking for years whether pulling a PEG tube past an esophageal cancer might cause tumor seeding, and physicians have reassured her that there is no cause for worry. Turns out she was right (as usual). Deaths from liver disease in the U.S. have seen a dramatic increase since 1999, driven substantially by increasing alcohol use. Fecal transplants in irritable bowel syndrome? Possibly helpful, as reported in an article from Digestive Disease Week.^®

As summer comes to an end, we head into a tumultuous fall that will be dominated by November elections.

John I. Allen, MD, MBA, AGAF
Editor in Chief

CMS has released its proposed rule (see related articles and a commentary) and included changes as substantial as I have seen in the last two decades. Additionally, the Affordable Care Act has been under continued attack despite its majority support from our citizenry. Loss of the individual mandate, allowance of “skinny” health plans, a rewrite of association plan rules, elimination of cost-sharing reductions and premium support – all have contributed to a shifting away from socialized medical costs and toward a system of individual responsibility for health. Depending on one’s political philosophy (and income), that may be bad or good.

Our article list this month will be interesting to many. The AGA produced a Clinical Practice Update about tumor seeding with endoscopic procedures. This should give us pause and make us reconsider our endoscopic practices. My wife (an endoscopy nurse in Minneapolis) has been asking for years whether pulling a PEG tube past an esophageal cancer might cause tumor seeding, and physicians have reassured her that there is no cause for worry. Turns out she was right (as usual). Deaths from liver disease in the U.S. have seen a dramatic increase since 1999, driven substantially by increasing alcohol use. Fecal transplants in irritable bowel syndrome? Possibly helpful, as reported in an article from Digestive Disease Week.^®

As summer comes to an end, we head into a tumultuous fall that will be dominated by November elections.

John I. Allen, MD, MBA, AGAF
Editor in Chief