8:00 Am a Review of the Diseases of the Upper GI – David Weismiller, MD, Scm, FAAFP

Home , Antimotility agent, Cutibacterium acnes, Pagophagia, Pedialyte

Board Review Express® February 19-22, 2020 Houston, TX Day 4 Saturday, February 22 geor

7:00 – 7:30 am Breakfast Provided

7:30 – 8:00 am A Review of the Diseases of the Upper GI – David Weismiller, MD, ScM, FAAFP

8:00 – 8:30 am Renal Disease I – Gary Levine, MD, FAAFP

8:30 – 9:00 am A Review of the Diseases of the Lower GI – David Weismiller, MD, ScM, FAAFP

9:00 – 9:30 am Renal Disease II – Gary Levine, MD, FAAFP

9:30 – 9:45 am Q&A

9:45 – 10:00 am Break

10:00 – 10:30 am Maternity Care I – David Weismiller, MD, ScM, FAAFP

10:30 – 11:15 am Managing Common Cutaneous Problems – Gary Levine, MD, FAAFP

11:15 – 11:45 am Maternity Care II – David Weismiller, MD, ScM, FAAFP

11:45 – 12:15 pm Management of Chronic Pain – Gary Levine, MD, FAAFP

12:15 – 12:30 pm Q&A

12:30 pm Adjourn Review of the Diseases of the Upper GI Tract

David Glenn Weismiller, MD, ScM, FAAFP Department of Family and Community Medicine University of Nevada, Las Vegas School of Medicine Disclosure Statement

It is the policy of the AAFP that all individuals in a position to control content disclose any relationships with commercial interests upon nomination/invitation of participation. Disclosure documents are reviewed for potential conflicts of interest. If conflicts are identified, they are resolved prior to confirmation of participation. Only participants who have no conflict of interest or who agree to an identified resolution process prior to their participation were involved in this CME activity.

All individuals in a position to control content for this session have indicated they have no relevant financial relationships to disclose. Learning Objectives

1. Determine the approach to the patient with dyspepsia. 2. Discuss the common disorders of the esophagus: motility and GERD. 3. Describe the diagnosis and treatment of PUD and Helicobacter pylori. Esophageal Disorders

▪ Disorders of Motility ▪ Gastro-esophageal Reflux Disease ▪ Inflammatory Diseases ▪ Tumors of the Esophagus Symptoms from the Esophagus History

• Swallowing difficulties – dysphagia • Pain – heartburn, odynophagia, chest pain • Regurgitation – effortless appearance of gastric or esophageal contents in the oral cavity Esophageal Motility Disorders

• Achalasia • Spasm ―Diffuse ―Localized – “nutcracker” esophagus • Scleroderma 1. Which of the following is an indicated treatment for achalasia? A. Beta blockers B. Alpha blockers C. Calcium channel blockers

D. H2 blockers Motility Disorders Disorder Clinical Diagnosis Treatment Achalasia Dysphagia – Barium swallow, Long-acting nitrates, Ca (Absence of peristaltic solids and liquids, manometry channel blockers, progression) increased risk of SCC pneumatic dilatation of LES

Diffuse Esophageal Heartburn, chest pain, or Barium swallow Long-acting nitrates, Ca Spasm dysphagia; often channel blockers (Spastic Motor Disorder) swallow-induced – always exclude CAD.

Scleroderma None to severe reflux; Barium swallow, Manage reflux; treat Esophagus often with strictures, manometry esophagitis with H2 (90% of patients with motility abnormalities blockers, PPIs, prokinetic scleroderma have drugs. esophagus involved.) GERD: Incidence and Prevalence

• Peak prevalence at ages 30-60 years, more common in women • Prevalence 10-20% in the Western world (lower prevalence in Asia) • Most common GI-related diagnosis in the U.S. • 14% of U.S. population has frequent GERD symptoms Arch Intern Med 2001 Jan 8;161(1):45 Am J Gastroenterol 2006 Sep;101(9):2128 Am J Gastroenterol 2013; 108:308 – 328 GERD Symptoms

• Typical Symptoms: heartburn, acid regurgitation • Atypical Symptoms: wheezing, hoarseness, atypical chest pain • Diagnosis usually based on history and physical, and trial of empiric therapy 2. Which of the following diagnostic tests is recommended in the patient with GERD refractory to maximum PPI therapy?

A. Esophageal manometry B. 24 hour pH monitoring C. Barium radiology D. Urea Breath Test GERD Diagnosis • No gold standard; EGD is to assess complications (SOR: A). −Erosive esophagitis −Stricture −Barrett’s esophagus −Cancer • EGD lacks adequate sensitivity in determining pathologic reflux (SOR B) Diagnostic Testing

• Esophageal manometry is NOT recommended in the diagnosis of GERD • Esophageal manometry IS recommended in the pre-operative evaluation, e.g., Nissen fundoplication (SOR: C) • 24-hour pH monitoring IS recommended in patients refractory to PPI therapy OR when the diagnosis is in question (SOR: C) • 24-hour pH monitoring is NOT recommended in the routine diagnosis of GERD and is NOT required in the presence of Barrett’s esophagus (SOR: B) • Barium radiology: Limited usefulness; not recommended (SOR: A)

Am J Gastroenterol. 2013; 108:308–328 Diagnostic Testing

• Screening for Helicobacter pylori infection is NOT recommended (SOR: C) • Eradication of H. pylori is not routinely required as part of antireflux therapy • FDA concluded that there was insufficient evidence to recommend testing of all patients on long-term PPI therapy • Controversial: European recommendation in favor of screening all patients for H. pylori Am J Gastroenterol. 2013; 108:308–328. Gut. 2007;56:772- 81. GERD Diagnosis • An empiric trial of acid • Alarm symptoms suppression therapy BID for ‾ Black or bloody stools ‾ Choking 4-8 weeks can identify ‾ Chronic cough patients with GERD who do ‾ Dysphagia ‾ Early satiety not have alarm symptoms ‾ Hematemesis (SOR: A) ‾ Hoarseness ‾ Iron deficiency anemia • Obtain upper endoscopy in patients with ‾ Odynophagia alarm symptoms or those at high risk for ‾ Weight loss complications (SOR: B) Summary of Diagnostic Testing for GERD

Diagnostic test Indication Highest level of evidence Recommendation

PPI trial Classic symptoms and no Meta-analysis Negative trial does not rule red flags out GERD Barium swallow Not for GERD, use for Case-control Not recommended for dysphagia GERD diagnosis

Upper endoscopy Alarm symptoms or RCT Those at risk for Barrett’s, screening of high-risk non-cardiac CP, patients unresponsive to PPI

Esophageal manometry Pre-operative evaluation Observational Not recommended for GERD diagnosis

24-hour pH monitoring Refractory symptoms or Observational Not recommended for question GERD diagnosis GERD diagnosis

Slide courtesy of Thad Wilkins, MD, with permission Am J Gastroenterol 2013; 108:308 – 328 Treatment

• H2RA less effective than PPIs (less expensive than PPIs) • PPIs are more effective for relieving heartburn than H2RA or prokinetic agents (SOR: A) • Different PPIs have similar efficacy at standard doses (SOR: A) • Long-term PPI use may increase fracture risk, but inconsistent evidence regarding hip fracture (SOR: C) On-demand Maintenance Therapy Versus Continuous PPI Therapy for GERD

Comparisons Severity of Number of Willingness GERD trials (n) to continue with treatment •Systematic review On-demand PPI Nonerosive 1 (622) 93% vs 88%* •16 studies vs continuous PPI •n = 14,142

1 (176) 75% vs 86%† *Statistically significant difference in favor of on-demand PPI. Nonerosive or †Outcome is symptom relief. mildly erosive ‡Statistically significant difference in favor of continuous PPI. Uninvestigated 1 (1292) 52% vs 83%‡ §Outcome is endoscopic remission.

1 (477) 58% vs 81%‡§ Erosive

Slide courtesy of Thad Wilkins, MD, with permission Aliment Pharmacol Ther. 2007;26:195-204. 3. In discussing the initiation of a patient on a proton pump inhibitor (PPI), which of the following is a potential risk of therapy that should be reviewed with the patient? A. Long-term PPI use may increase risk for community acquired pneumonia B. Increased risk of hypermagnesemia

C. Increased risk of Vitamin B12 deficiency D. Increased risk of iron deficiency anemia Potential Risks Associated with PPIs

•Patients with known osteoporosis can remain on PPI therapy (SOR: C) •Increased risk of hypomagnesemia

•Increased risk of vitamin B12 deficiency •Increased risk for Clostridium difficile infection •Short-term PPI use may increase risk for community acquired pneumonia (risk is not elevated in long-term PPI users) •PPI therapy does not need to be altered in concomitant clopidogrel (Plavix) users (SOR: B) Am J Gastroenterol 2013; 108:308 – 328 Treatment

• Limited evidence regarding lifestyle measures for GERD • Weight loss if overweight or obese (SOR: C) • Elevate head of bed if regurgitation or heartburn when lying down (SOR: C)

Gastroenterology 2008 Oct;135(4):1383 Am J Gastroenterol 2013; 108:308–328 Treatment Guidelines

American College of Gastroenterology – 2005 Volume 135, Issue 4; Step 3 1383-1391.e5, October 2008 Severe symptoms Erosive disease Step 2 • Continue with measures. Non-responders • GI workup (+/−) endoscopy • High-dose H2 antagonists Non-erosive disease • Higher dose PPI • • Continue lifestyle/dietary modification.

Step 1 • H2 antagonists (SOR A) Mild symptoms • Proton pump inhibitor (PPI)* (SOR A) • • Pro-motility agent (SOR A) • Dietary modifications • 8-12 weeks of therapy • Lifestyle modification (SOR C) • Trial of patient-directed therapy with antacids or * PPI should be taken 30-60 minutes prior to a meal (the OTC H2 antagonists first meal of the day) to optimize effectiveness (SOR: B). AGA

• For pharmacological treatment of patients with gastroesophageal reflux disease (GERD), long-term acid suppression therapy (proton pump inhibitors or

histamine2 receptor antagonists) should be titrated to the lowest effective dose needed to achieve therapeutic goals. 4. Risk factors for esophageal intestinal metaplasia (Barrett’s Esophagus) include which one of the following characteristics? A. Female sex B. African American race C.Alcohol dependence D.Hiatal hernia Barrett’s Esophagus

• Risk of intestinal metaplasia (Barrett’s) and adenocarcinoma increases with GERD symptom severity, duration, and frequency. • Endoscopic surveillance for dysplasia is indicated in Barrett’s esophagus - ??? − Surveillance of known Barrett’s esophagus is controversial, because adenocarcinoma of the esophagus is rare in the U.S. (6000-7000 cases/yr)

and GERD/Barrett’s occurs in 0.4-0.8% of the © Floyd E Hosmer, All Rights Reserved population − Risk of developing esophageal adenocarcinoma in patients with Barrett’s esophagus is less than 1% AGA Position Statement on Screening for Barrett’s Esophagus (BE) 2015 • Consider screening in MEN o Chronic (> 5 years) and/or frequent (weekly or more) symptoms of GERD AND o Two or more risk factors for BE or Esophageal Adenocarcinoma (EAC)

• Caucasian race • Age > 50 years • Central obesity (waist circumference > 102 cm or waist-hip ratio (WHR) > 0.9) • Current or past history of smoking • Confirmed family history of BE or esophageal adenocarcinoma (in a first degree relative)

Shaheen NJ et al., ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus. Am J. Gastroenterol. 2015. http://gi.org/wp- content/uploads/2015/11/ACG-2015-Barretts-Esophagus-Guideline.pdf Follow-up (2015) •Initial endoscopic evaluation −Negative for BE, repeating endoscopic evaluation for the presence of BE is NOT recommended. −Reveals esophagitis repeat endoscopic assessment after PPI therapy for 8-12 weeks is recommended to ensure healing of esophagitis and exclude the presence of underlying BE (conditional recommendation, low level of evidence). −Positive for BE, patients without dysplasia, endoscopic surveillance should take place at intervals of 3 to 5 years (strong recommendation, moderate level of evidence). Shaheen NJ et al., ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus. Am J. Gastroenterol. 2015. http://gi.org/wp- content/uploads/2015/11/ACG-2015-Barretts-Esophagus-Guideline.pdf If Dysplasia…(2015)

•Patients with −Confirmed low-grade dysplasia and without life-limiting comorbidity, endoscopic therapy considered as the preferred treatment modality, although endoscopic surveillance every 12 months is an acceptable alternative (strong recommendation, moderate level of evidence). −Confirmed high-grade dysplasia should be managed with endoscopic therapy unless they have life-limiting comorbidity (strong recommendation, high level of evidence).

• For a patient who is diagnosed with Barrett’s esophagus, who has undergone a second endoscopy that confirms the absence of dysplasia on biopsy, a follow-up surveillance examination should not be performed in less than three years as per published guidelines. Medical vs. Surgical Treatment

• Medical treatment as effective as surgery (SOR:B) • Surgery • Laparoscopic fundoplication increases quality of life in patients with GERD but many patients still require medication after surgery (SOR: B) • Endoscopic Procedures • May reduce symptoms in patients with GERD Summary of GERD Treatment Recommendations

Recommendation SOR Obtain upper endoscopy in patients with alarm symptoms or those at high risk for complications B Strong evidence supports association of GERD and esophageal adenocarcinoma with A Barrett esophagus as precursor lesion Chronic reflux has been suspected to play a major role in the development of Barrett’s esophagus, C yet it is unknown if outcomes can be improved through surveillance and medical treatment

PPIs are more effective for relieving heartburn in short term than H2RA or prokinetic agents A Different PPIs have similar efficacy at standard doses A Patients with known osteoporosis can remain on PPI therapy C Concomitant use of PPIs and clopidogrel appears safe B If symptoms remain unchanged in a patient with a prior normal EGD, repeating EGD is not C recommended Anti-secretory therapy has not been shown to reduce the need for recurrent dilation from A esophageal stricture formation Summary of GERD Treatment Recommendations

Recommendation SOR There are no significant differences among equivalent doses of PPIs for A the treatment of nonerosive GERD Anti-reflux surgery should generally be reserved for patients with C contraindications to PPI therapy or when PPI therapy alone is insufficient to control symptoms Screening for Barrett esophagus is NOT routinely recommended in patients with C GERD, but it may be considered in white men 50 years or older who have had GERD symptoms for at least five years Endoscopy should be limited to patients who have alarm symptoms or persistent C GERD symptoms after an adequate trial of PPI therapy Testing for Helicobacter pylori in patients with GERD is NOT recommended A Anderson et. al., Am Fam Physician. 2015;91(10):692-697 Inflammatory Disorders Esophagitis Disorder Offending “Agents” Pill-induced Doxycycline, NSAIDs, steroids Infective* • Viral HSV, CMV • Fungal Candida Corrosive Alkalis or acids Eosinophilic: Allergic or idiopathic; Tx – steroids, diet, anti-allergy pronounced eosinophilic medications infiltration

*Mostly in immunosuppressed patients Esophageal Tumors

• 90% are cancer −Much more common in males; 10% 5-yr survival rate overall (treatment improving) −Equal numbers in Caucasians and African Americans −Dx – endoscopy and radiography • Squamous cell carcinoma −Accounts for < half of esophageal cancers; declining incidence −Predominant esophageal cancer in African Americans −More common with heavy alcohol and tobacco use • Adenocarcinoma Source: Wikimedia −Arise from columnar epithelium in cardia or from Barrett’s −Recall that the lower esophagus is lined by specialized intestinal epithelium. −Predominant esophageal cancer in Caucasians −GERD is a risk factor as well as obesity and tobacco use. Diseases of the Stomach

◼ Acid Peptic Disorders of the Stomach and Duodenum ◼ Infections ◼ Motor Disorders ◼ Cancer 5. A 49 yo female presents with a 4-week history of epigastric pain. She reports the pain gets a bit better when she eats but worse within an hour of eating. She has been using an over the counter liquid antacid which she reports decreases her symptoms. She denies weight loss, hematemesis, melena, or hematochezia. With the exception of midepigastric tenderness, her exam is unremarkable. Her only medication is periodic acetaminophen which she uses for headaches. Which of the following diagnostic tests would you recommend in your evaluation?

A. Serum gastrin B. Helicobacter pylori serology C. Esophagogastroduodenoscopy D. Urea Breath Test Acid Peptic Disorders Stomach and Duodenum • Common Problem ‾ 5-10% of population will have PUD in their lifetimes; 50% recurrence in 5 years ‾ DU/GU 4:1 ‾ 90% DU in duodenal bulb ‾ GU most common on lesser curve

Mortality Rates Ulcer Type Men Women Duodenal Ulcer 1/100,000 0.5/100,000 Gastric Ulcer 1.5/100,000 1.2/100,000 Why Do Acid Peptic Disorders Develop?

• Current theory −PUD is an imbalance between protective and aggressive factors. Protective factors Aggressive factors • Surface epithelial cells with • Production of gastric acid mucus and bicarbonate • NSAIDs secretions • Corticosteroids • Apical surface membrane of • Smoking gastric mucosal cells • Alcohol consumption • Prostaglandins E1 and E2 • Probably not diet • ? Psychological stress Predisposing Factors

• H. pylori infection • Caffeine: No clear evidence of • NSAIDs worsening −Double the annual chance of • Peppers: No slowing of DU complicated PUD from 1-2 to 3-4 healing percent • Alcohol: Worse with NSAIDs; • Worse with alcohol • Longer-acting NSAIDs are worse unclear otherwise • Dose, duration important variables • Tobacco: Much higher rates of • Milk: May slow healing of DU ulcer and slower healing • Stress: Remains controversial PUD and H. pylori

Disorder H. pylori (+) Associated H. Treatment pylori gastritis

Duodenal 90% 70% ▪ Eradication of infection ulcer markedly decreases Gastric ulcer 70% 60-80% recurrences of DU. ▪ A 1-2 week course of H. pylori eradication therapy is an effective treatment for H. pylori (+) PUD. Peptic Ulcer Disease Diagnosis History Laboratory −Persistent pain relieved by food • Limited usefulness, except H. and antacids pylori tests • Pain in upper abdomen or back • Consider serum gastrin • Hematemesis, melena, or (gastronoma, Zollinger-Ellison; hematochezia especially if recurrent ulcer • Cannot usually separate GU from DU by history disease, multiple ulcers) On exam • Hematocrit • Stool guaiac −Mid-epigastric tenderness • Endoscopy (SOR: A) • 90% sensitivity and specificity Diagnostic Tests for Helicobacter pylori

Test Sensitivity Specificity Advantages Disadvantages Noninvasive Urea Breath Test 97% 100% Used for initial diagnosis Expensive and AND test of cure (4-6 inconvenient; 6 hour weeks post treatment) fast required Stool monoclonal antigen tests • Enzyme 92% 94% Detect active infection; Expensive immunoassay use for test of cure May be used in office • Immuno- 69-87% 87-93% Varying reliability chromatography Antibody tests 76-84% 79-80% Lower cost; easily Not useful as test of available cure Diagnostic Tests for Helicobacter pylori

Test Usefulness Sens (%) Specif (%) Invasive Endoscopy with Diagnostic strategy of choice in children with persistent or severe upper biopsy abdominal symptoms Histology Sensitivity reduced by PPIs, antibiotics, bismuth- > 95 100 containing compounds. Urease activity Test of choice when endoscopy indicated; rapid results 93-97 > 95 (20 min); (−) results may need confirmation by histology or other test; sensitivity reduced by PPIs, antibiotics, bismuth-containing compounds, and active bleeding. Culture Technically demanding; only use for resistant organism 70-80 100 or refractory disease. Summary Diagnostic H. pylori Testing

• In patients who do not require endoscopic evaluation for evaluation of new onset dyspepsia (< age 55 and no alarm symptoms), initial diagnosis of H. pylori should be made with a test for active infection (stool antigen or urea breath test). o Serology, as it cannot differentiate between past or current infection and has a low positive predictive value in much of the United States, is not recommended in patients with a low pre-test probability. • Endoscopic biopsy reserved for patients who are undergoing a diagnostic endoscopy and are found to have an ulcer and for those who require endoscopy to follow up a gastric ulcer or for the diagnosis or follow-up of suspected MALT lymphoma. o Biopsy urease testing can be performed in patients not taking antibiotics or a proton pump inhibitor when histopathology is not required. • Confirmation of eradication [because of the availability of accurate, relatively inexpensive, noninvasive tests (stool and breath tests) and because of increased resistance to antibiotic therapy,] at least four weeks after treatment (Grade 2B) Treatment Regimens for H. pylori Infection

Type Regimen Duration* Eradication rate First line Standard triple PPI, amoxicillin 1 g, and clarithromycin 7-10 days (up 70-85% therapy 500 mg (Biaxin) twice daily to 14 days) PPI, clarithromycin 500 mg, and metronidazole 500 mg (Flagyl) twice daily 10-14 days 70-85% Sequential PPI and amoxicillin 1 g twice daily, 10 days (5 >84% therapy followed by PPI, clarithromycin 500 days for each mg, and tinidazole 500 mg (Tindamax) regimen) or metronidazole 500 mg twice daily

* 2016 Toronto Consensus Committee recommends a 14-day regimen; high resistance patterns. (Fallone et al. Gastroenterology. 2016;151:51-69. e14.) Fashner et. al., Am Fam Physician. 2015;91(4):236-242. Treatment Regimens for H. pylori Infection Type Regimen Duration* Eradication rate Second line Non-bismuth-based PPI, amoxicillin 1 g, clarithromycin 10 days 90% quadruple therapy 500 mg, and tinidazole 500 mg or (concomitant therapy) metronidazole 500 mg twice daily Bismuth-based Bismuth subsalicylate 525 mg or 10-14 days 75-90% quadruple therapy subcitrate 300 mg, metronidazole 250 mg, and tetracycline 500 mg, four times daily; and PPI twice daily Levofloxacin-based PPI and amoxicillin 1 g twice daily, 10 days ----- triple therapy and levofloxacin 500 mg (Levaquin) once daily

* 2016 Toronto Consensus Committee recommends a 14-day regimen; high resistance patterns. (Fallone et al. Gastroenterology. 2016;151:51-69. e14.) Fashner et. al., Am Fam Physician. 2015;91(4):236-242. Specific Ulcer Treatment Anti-secretory • Anti-secretory therapy −Mainstay of therapy in uninfected patients

• PPI, H2 blocker −Appropriate for maintenance therapy in selected cases −Usually 4-6 weeks for DU −Generally longer for GU – 12 weeks

−PPIs lead to faster healing than H2 blockers. Treatment for H. pylori Infection Summary • Most important therapy in affected individuals • No therapy 100% effective • Triple or quadruple therapy most effective • Use of anti-secretory agents with antimicrobials increases eradication rate. −Increased gastric pH increases efficacy of some antibiotics. −PPIs have intrinsic in vivo activity against H. pylori. −Anti-secretory therapy hastens relief of ulcer symptoms. • Compliance is essential for eradication. 6. In considering NSAID-induced ulcers, which of the following statements is true? A. Peptic ulcers are less common in patients taking NSAIDS who are H. pylori (+) compared with those who are (-) B. Eradicating H. pylori in NSAID users reduces the likelihood of peptic ulcer by about one-half C. The use of a maintenance PPI is less effective than H. pylori eradication therapy for preventing NSAID-related ulcers D. Patients who will be on long term NSAID therapy should be empirically treated for H. pylori NSAID Ulcers • Risk factors −Prior adverse GI event (ulcer, hemorrhage) −Age > 60 (Older age) −High-dose NSAID (> twice normal) −Use of • Glucocorticoid use • Anticoagulant use • Aspirin • Risk for NSAID-induced GI toxicity 9% at 6 months with multiple risk factors present • In naïve NSAID users, H. pylori is significant risk factor for complicated ulcer disease – screening may be indicated. Recommendations for Prevention of NSAID- Related Ulcer Complications Cardiovascular Risk Gastrointestinal Risk ACG Recommendation (2009) Low Low (No risk factors) NSAID Moderate (1 or 2 risk NSAID plus PPI or misoprostol factors) High (> 2 risk factors) Alternative therapy IF POSSOBLE, or COX-2 inhibitor plus PPI or misoprostol High Low Naproxen plus PPI or misoprostol Moderate Naproxen plus PPI or misoprostol High Avoid NSAID and COX-2 inhibitor; alternative therapy

Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104(3):728-738. NSAID Users: Medical Treatment of Peptic Ulcer Practice Guidelines • Treatment of NSAID ulcers −D/C NSAIDs

−PPIs superior to H2 receptor antagonists • The ACG guideline recommends that patients who will be on long-term NSAID therapy be tested for H. pylori infection and eradication therapy

given if (+) NEJM. 1998;338:727. Primary Care. September, 2001:28(3):487-503. Am J Gastrolenterol. 2009;104(3) :728-738 Conclusion • For patients who have multiple risk factors for NSAID- related gastroduodenal toxicity – FDA approved options include: • COX-2 selective inhibitor or • Nonselective NSAID in combination with a proton pump inhibitor (PPI) or misoprostol. High dose H2 receptor antagonists are a reasonable alternative to a PPI or misoprostol • Approved doses of these drugs: Misoprostol (200 mcg QID), Lansoprazole (15 or 30 mg daily), and esomeprazole (20 or 40 mg daily). Treatment Non−H. pylori PUD • Withdrawal of potential offending or contributing agents ―NSAIDs, cigarettes, excess ETOH • No firm dietary recommendations – avoid foods that precipitate dyspepsia. • Address psychosocial issues and comorbidities – no firm evidence, but may have deleterious health consequences. Controversy: Treatment of H. pylori in Non-ulcer Dyspepsia • Efficacy of treatment is controversial. • Recent review of RCTs: Eradication provides small but significant benefit for dyspeptic symptoms.* • Eradication may be cost-effective intervention for non-ulcer dyspepsia. • And … H. pylori appears to have a net suppressive effect on acid production, so treating may make GERD worse.

*Practice Guideline. Moayyedi P, Soo S, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. The Cochrane Database of Systematic Reviews. 2005. http://www.cochrane.org/cochrane/revabstr/ab002096.htm An Approach to Dyspepsia 55 years old No alarm features Dyspepsia

H. pylori H. Pylori prevalence ≥ 10% prevalence < 10%

Fails Fails Test and treat for > 55 years old or presence of alarm Trial of PPl H. pylori. symptoms, family or personal Hx GI CA or PUD, wt. loss, GI bleeding, Fails Fails anemia, or dysphagia

Test and treat Trial of PPl for H. pylori.

Consider upper Consider upper Upper endoscopy endoscopy. Endoscopy. Information from American College Gastroenterology Risk Factors for Ulcer Complications

• Previous history of complications • Prior refractory or protracted course • Big ulcers (> 2 cm) • Deformed ulcer bed or dense fibrosis Complications of PUD • Bleeding − Most common complication and leading cause of death (4-9% mortality rate) − Occurs in 10-20% − Patients with 1 episode of bleeding more likely to re- bleed − 90% stop without specific treatment. − Increased morbidity with associated portal hypertension*

* Am J Gastro 1998;93:336 Complications of PUD

• Gastric outlet obstruction −Usually mechanical obstruction due to edema or scar −Most due to DU −Rare: 2% of ulcer patients • Perforation and penetration −2% of ulcers perforate. −Average duration of Sx prior to perforation: 5 years • NOTE: Complicated ulcer disease less likely to involve H. pylori PUD Surgical Treatment/Management

• Dramatically declined over past two decades • Indications −Hemorrhage not responsive to medical therapy −Gastric outlet obstruction not reversed by medical treatment −Perforation −Malignancy SORT: Key Recommendations for Practice Fashner et. al. Diagnosis and Treatment of PUD and H. pylori Infection. Am Fam Physician. 2015;91(4):236-242 Clinical Recommendation Evidence Rating Use the test-and-treat strategy for patients with dyspepsia who are <55 years and have no alarm symptoms for gastric cancer. Use endoscopy for all other patients A Confirm eradication of H. pylori after therapy in patients with H. pylori-associated ulcer, continued dyspeptic symptoms, mucosa-associated lymphoid tissue lymphoma, C and resection of gastric cancer. Non–bismuth-based quadruple therapy (10 days of a proton pump inhibitor, amoxicillin 1 g, clarithromycin 500 mg [Biaxin], and metronidazole 500 mg [Flagyl] or tinidazole 500 mg [Tindamax] twice daily) has the highest success rate in eradicating A H. pylori, although other regimens may also be used. For patients at low risk of gastrointestinal complications, nonsteroidal anti- inflammatory drugs may be used, whereas cotherapy with a proton pump inhibitor or misoprostol (Cytotec) is recommended for patients with moderate risk of ulcer, and C they should be avoided in those with a high risk of ulcer. Gastric Dysmotility Gastric Dysmotility Slow or Delayed Emptying

• Etiology −Mechanical or outlet obstruction

• PUD, bezoar, etc. Trichobezoar being extracted through a gastrotomy −Functional obstruction (gastroparesis) • Drugs – opiates, anticholinergics, beta and Ca channel blockers • Diabetes, Parkinson’s, hypothyroidism, hypoparathyroidism • Pregnancy • Post-vagotomy Gastric Dysmotility Slow or Delayed Emptying • Diagnosis • Nausea, vomiting, dysphagia, post-prandial abdominal pain, GERD • Tests: Scintigraphy, electrogastrogram (evaluate gastric myoelectrical utility), ultrasonography • Treatment • Remove causes • Low-fat diet; avoid large meals • Metoclopramide, erythromycin, prokinetics Gastric Dysmotility Rapid Gastric Emptying • Dumping Syndrome −Most commonly seen post-operatively from gastric surgery or a truncal vagotomy • Symptoms −15-30 minutes after eating – nausea, non-productive vomiting, sweating, flushing, abdominal cramping, diarrhea • Treatment −6-8 small, low-CHO meals/day; avoid excessive liquids; use of opiates and anticholinergic drugs; fiber products; possibly surgery 7. A 65 yo male smoker complains of dyspepsia, weight loss, early satiety, and occasional nausea and vomiting. Which one of the following would be the initial diagnostic method of choice? A. Upper GI endoscopy B. CT of the upper abdomen C. Single-contrast upper GI barium swallow D. Endoscopic ultrasonography Cancer of the Stomach • One of the most common internal malignancies in the world −95% are adenocarcinomas. • Chronic GERD is the leading cause of esophageal adenocarcinoma (68-90%). −Only 10-20% of US GI tumors – probably because of lower rates of H. pylori in U.S., due to cleaner food and water • H. pylori can cause chronic active gastritis and atrophic gastritis, early steps in the carcinogenesis sequence • 2x as common in ♂ as in ♀ • 2x as common in African Americans and Hispanics as in Caucasians • Dx: Endoscopic biopsy in patients with upper GI symptoms or high-risk or double-contrast barium swallow • Tx: Surgical excision; 5-yr survival rate < 10% Pancreatic Cancer • Fourth leading cause of cancer-related death; second only to CRC as cause of GI cancer-related death −Higher incidence: ♂ and African Americans −Risk factors: Smoking, chronic pancreatitis, diabetes, hereditary predisposition • History/PE −Abd pain, weight loss, jaundice, pancreatitis −Jaundice, abdominal mass, ascites Pancreatic Cancer

• Diagnosis −U/S, EUS CT, MRI ERCP, FNA, CA19-9 −All sensitive and specific • Treatment −Surgical resection only potential curable treatment • Prognosis – 5-yr survival −Node (−) 25%-30% −Node (+) 10% Thank You Answers 1. C 2. B 3. C 4. D 5. D 6. B 7. A © 2020 American Academy of Family Physicians. All rights reserved.

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Renal Disease I: Acute Kidney Injury

Gary I Levine, MD, FAAFP Associate Professor Department of Family Medicine The Brody School of Medicine at East Carolina University Greenville, North Carolina Disclosure Statement

All individuals in a position to control content for this session have indicated they have no relevant financial relationships to disclose. Learning Objectives

1. Cite the causes and explain the management of acute kidney injury. 2. Discuss the common metabolic issues seen in the critically ill patient as a result of renal compromise. 3. Discuss the principles of neurohormonal antagonism and the role of the kidney in the management of heart failure. Functions of the Kidney

Maintenance of the extracellular fluid environment • Excretion of metabolic waste products −Urea • Water balance • Electrolyte balance • Acid-base balance Functions of the Kidney

Hormone secretion • Regulation of systemic and renal hemodynamics •Renin •Angiotensin II • Red blood cell production •Erythropoietin • Calcium/phosphorus regulation •1,25-dihydroxycholecalciferol; calcitriol Urinalysis

• “Big 3” on dipstick • Blood • Protein • Leukocyte esterase • Always perform your own microscopic exam • Don’t just rely on “dipstick” Urinalysis

• If there is a positive dipstick test for blood - But no RBCs • Hemolysis • Rhabdomyolysis • Urinary dipstick for protein only measures albumin - Bence Jones protein will be missed Urinalysis

• Positive leukocyte esterase dipstick test - Usually indicates UTI • WBCs and no bacteria - Urethritis - Prostatitis - Interstitial nephritis • Eosinophils Urinalysis

• Hyaline and granular casts can be normal • RBC casts are always abnormal - Glomerulonephritis • WBC casts are always abnormal - Pyelonephritis Measurement of Renal Function

•Glomerular filtration rate (GFR) - Flow rate of filtered fluid through kidney - Inulin, Technetium 99 - Holy grail •Creatinine clearance - Uses measured serum creatinine/24 hr urine collection - Approximates GFR (may overestimate it by 15%) •Cystatin C levels - Less affected by age & sex - May estimate GFR better than serum creatinine - May be better predictor of adverse events in the elderly Measurement of Renal Function • Modified MDRD (Modification of Diet in Renal Disease) formula • Estimated GFR • Commonly used by clinical labs • Cockcroft-Gault formula • Estimated CrCl • CKD-EPI Measurement of Renal Function

• MDRD (eGFR) eGFR = 186 x (SeCr mg/dL) - 1.154 x (age yrs) - 0.203 x (0.742 if female) x (1.212 if African American) • Less precise with fairly normal renal function • Underestimate GFR if obese, overestimate if underweight Formulas to Assess Renal Function

• Cockcroft-Gault (eCCr) - eCrCl (cc/min) = (140 - age yrs) x IBW kg/SeCr mg/dL x 72) x (0.85 if female) - Less accurate for renal function, but better for renally dosing meds Cockcroft-Gault – eCCr

•70 kg man with creat = 1.0 (women = 0.8) - eCCr = 140 minus age •Each doubling of serum creat - results in approximately 50% decrease in eCCr Measurement of Renal Function

•GFR & CC calculators & everything you wanted to know about estimating renal function but were afraid to ask https://www.kidney.org/professionals/KDOQI/gfr Protein Excretion

• 24-hour urine collection • Random spot urine protein excretion –Normal • < 150 mg/24 hour in the non-pregnant patient • < 300 mg/24 hour in the pregnant patient 3 grams/24 hr = nephrotic syndrome • Urine microalbumin/creat - < 30 mg/g – normal - 30-300 mg/g – microalbuminuria - > 300 mg/g – macroalbuminuria Acute Kidney Injury (AKI)

• Acute kidney injury (AKI) - Historically referred to as acute renal failure (ARF) Acute Kidney Injury

• Early recognition facilitates interventions - Prevent worsening - Prevent multiorgan system failure (SOR C) • Most common causes of death are - Infectious complications - Cardiopulmonary complications Acute Kidney Injury

• Dx based on - Changes in serum creatinine - Urine output Acute Kidney Injury

• KDIGO (Kidney Disease: Improving Global Outcomes) minimal criteria for Dx of AKI - Increase in serum creat of ≥ 0.3 mg/dL within 48 hours OR - Increase in serum creat of ≥ 1.5 times baseline within the prior 7 days OR - Urine volume < 0.5 mL/kg per hour for more than 6 hours 1. The most common cause of acute kidney injury is which of the following?

A. Ureteral calculus with hydronephrosis B. Diuretic-induced volume depletion C. Acute tubular necrosis D. Acute interstitial nephritis Causes of AKI

•Acute tubular necrosis (ATN) - 45% •Prerenal disease - 21% •Acute on chronic kidney disease - 13% - ATN with prerenal disease •Urinary tract obstruction - 10% - BPH •Glomerulonephritis or vasculitis - 4% •Acute interstitial nephritis - 2% •Thromboembolic disease - 1% Causes of AKI

• Prerenal Account for 75% of all AKI • Intrarenal •Tubular •Glomerular •Interstitial •Vascular • Postrenal Causes of AKI Prerenal • Actual intravascular volume depletion • Diseases that lead to decreases in the effective arterial blood volume • Medications that reduce renal perfusion Prerenal Causes of AKI

• Volume depletion - Bleeding - Dehydration • Gastrointestinal volume loss • Urinary volume loss • Cutaneous losses Prerenal Causes of AKI • Decreased effective renal perfusion - Shock - CHF • Effective circulating volume depletion - Cardiorenal syndrome - Cirrhosis • Hepatorenal syndrome - Thromboembolic disease Causes of AKI- Intrarenal • Tubular/interstitial - Most common • Glomerular • Vascular Intrarenal Causes Acute Tubular Necrosis (ATN) • Most often caused by –Hypotension/sepsis –Ischemia –Surgery/burns –Nephrotoxins & poisons –Rhabdomyolysis –No specific therapy has been shown to hasten recovery Intrarenal Causes Acute Interstitial Nephritis (AIN) • Causes –Drugs (60-70%) – Allergic interstitial nephritis –Autoimmune diseases –Infection –Infiltrative diseases • Symptoms/Signs/Evaluation –Fever –Rash –Elevated serum and urine eosinophils • Immediate withdrawal of drug and supportive care are essential –Corticosteroids may be beneficial 2. Which of the following drugs is most commonly associated with allergic interstitial nephritis? A. Pregabalin B. Ertapenem C. Omeprazole D. Fluoxetine Drugs Commonly Associated With AIN

Cephalosporins Sulfonamides Ciprofloxacin Allopurinol Penicillin Rifampin Thiazides Furosemide

Cimetidine NSAIDs Phenytoin Drug-Induced AIN-PPIs

•PPIs -- The new kids on the block •Probably a class effect •Not dose-related •4-5 x increased risk of AIN •Seen more often after 60 yo •Also has increased risk of CKD −NNH = 30-60 Intrarenal Causes of AKI

•Other tubulointerstitial diseases - Multiple myeloma - Hypercalcemia - Tumor lysis syndrome - Acute phosphate nephropathy • Following a phosphate-containing bowel preparation prior to colonoscopy or surgery Intrarenal Causes Glomerular • Uncommon cause of AKI • Systemic manifestations –Fever –Rash –Arthritis –Edema • Urine findings –RBC casts –Hematuria –Proteinuria • Renal consult and biopsy may be required Glomerular Diseases

•Nephritic - RBCs/RBC casts in urine - Hypertension - Mild proteinuria •Nephrotic - Massive proteinuria - Edema/hypoalbuminemia - Hyperlipidemia - Hypercoagulable Intrarenal Causes of AKI • Glomerular diseases (Nephritic) - Postinfectious glomerulonephritis - IgA nephropathy - Rapidly progressive glomerulonephritis - Membranoproliferative glomerulonephritis - Henoch-Schönlein purpura - Vasculitis Intrarenal Causes of AKI •Glomerular diseases (Nephrotic) - Diabetic nephropathy - Minimal change disease - Focal segmental glomerulosclerosis - Mesangial proliferative glomerulonephritis - Membranous glomerulonephritis - Primary amyloidosis - Preeclampsia Intrarenal Causes - Vascular • Vascular disease - Vasculitis •Wegener's granulomatosis - Thromboembolic disease - Hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura - Malignant or chronic hypertension - Scleroderma - Renal artery stenosis Causes of AKI Postrenal •Obstruction of the outflow tracts of the kidneys •Most are readily reversible •Recovery of renal function is directly proportional to the duration of the obstruction •Renal US recommended to assess for hydronephrosis Postrenal Causes of AKI

•Obstructive uropathy - Anatomic abnormalities • Urethral valves • Ureterovesical or ureteropelvic junction stenosis - Urethral stricture - Renal/ureteral calculi - BPH - Prostate cancer - Retroperitoneal or pelvic neoplasms Renal Biopsy in AKI

• Clinical findings - Oliguria - Rapidly worsening GFR • Cause of intrinsic renal injury is unclear • Pre-renal and post-renal causes of acute kidney injury have been excluded • Clinical assessment and laboratory investigations suggest a diagnosis that requires confirmation before disease-specific therapy is instituted - Immunosuppressants 3. An 70 y/o male is scheduled to have a CT of his abdomen with IV contrast to assess for a tumor. He has type II DM, with a serum Cr of 2.8 mg/dL (nl = 0.6-1.5). Which one of the following would most likely decrease the possibility of contrast-related nephropathy?

A. Hydration with isotonic solution B. Oral acetylcysteine BID for 48 hrs beginning the day following the procedure C. Acidification of the urine with ascorbic acid beginning 24 hrs prior to the procedure and continuing for 48 hrs afterward D. Use of a hyperosmolar contrast medium Contrast-Induced Nephropathy (post-contrast acute kidney injury) • Controversial- risk is probably overstated • Due to iodinated contrast agents • Decline in renal function following the procedure - Inc in serum creat ≥ 0.5 mg/dL - Inc > 25% above baseline • Follows a predictable time course • begins to improve in 3-7 days • Usually reversible – only 1% require dialysis • Preventable Contrast-Induced Nephropathy (post-contrast acute kidney injury) •Radiocontrast media - Best avoided in patients with, or at risk for, AKI - Major risk factors • CKD – GFR < 30 • Dehydration - Others • DM • SS disease • Elderly Contrast-Induced Nephropathy (post-contrast acute kidney injury) • Modern IV contrast not associated with an increased frequency of AKI - Hinson - Ann Emerg Med - 3/2017 • Retrospective, 17,000 pts • Regardless of baseline renal function - Adcock – Ann Emerg Med – 8/2017 • Meta-analysis, 28 observational studies, 100,000 pts • Contrast CT vs non-contrast CT Management of At-Risk Patients Before a Dye Study • Stop metformin x 48 hrs (particularly if eGFR < 60) • Isotonic solution IV hydration - Favored over hypotonic solutions & oral hydration • Alkalinize the urine (inconsistent data) - D5W with 3 amps NaHCO3 1 cc/kg/hr at least 4-6 hrs prior to exam - 1/4NS with 2 amps NaHCO3 (patients with diabetes) • Acetylcysteine 1200 mg bid the day before and the day of the exam (inconsistent data) - Lower risk of CIN, compared with 600-mg doses (3.5% versus 11%) •High dose statins may be useful. Drugs Associated With Nephrotoxicity

Analgesics Antimicrobials (cont) Cardiovascular agents Drugs of abuse (cont) Acetaminophen Foscarnet ACE –I Methadone ASA Ganciclovir ARB Methamphetamine NSAIDS Pentamidine Clopidogrel Quinolones Ticlopidine Herbals Antidepressants Rifampin Statins Chinese herbals with Amitriptyline Sulfonamides aristolochic acid Doxepin Vancomycin Chemotherapeutics Fluoxetine Carmustine Proton pump inhibitors Antiretrovirals Cisplatin Lansoprazole Lithium Adefovir Interferon-alfa Omeprazole Cidofovir Methotrexate Pantoprazole Antihistamines Tenofovir Mitomycin-C Diphenhydramine, Indinavir doxylamine Contrast dye Others Benzodiazepines Allopurinol Diuretics Gold therapy Antimicrobials Loops Acyclovir Calcineurin inhibitors Haloperidol Thiazides Pamidronate Aminoglycosides Cyclosporine Triamterene Amphotericin B Tacrolimus Phenytoin Beta-lactams Drugs of abuse Quinine Cocaine Ranitidine Heroin Zoledronate Ketamine Nephrotoxic Meds

• NSAIDs • Lithium • Antibiotics - Aminoglycosides - Vancomycin - Amphotericin B - IV Acyclovir Nephrotoxic Meds

• ACE/ARB • Diuretics • PPIs • Methotrexate Other Important Medications in Renal Disease • Metformin ➢ Increased risk of lactic acidosis - FDA guidelines (4/16) ➢ Do not start if eGFR < 45 mL/min • Consider reducing dose by 50% at that eGFR ➢ Do not use if eGFR < 30 mL/min Other Important Medications in Renal Disease • Enoxaparin - Cautious use if creatinine > 2 mg/dL - Reduce dose by 50% if CC < 30 mL/min • Nitrofurantoin - Needs CC > 60 mL/min for clinical effectiveness & avoid toxicity 4. You are reviewing the lab findings of a 64 yo male hospitalized with AKI, who has no h/o any long-term medication use. Renal function had been normal, but now the Cr = 2.8 mg/dL, BUN = 60 mg/dL. Urine sp gr = 1.025, and urine sediment shows only hyaline casts. His FENa = 0.75%. Based on these findings, which one of the following conditions is most likely? A. Hypovolemia due to vomiting B. Acute pyelonephritis C. Interstitial nephritis D. Obstruction due to BPH FENa • Fractional excretion of sodium - FENa = 100 x (U Na x Plasma Creat) / (Plasma Na x U Creat) • FENa interpretation - < 1% = prerenal - 1% - 2% = renal - > 2-3% = ATN FENa- Limitations •Prerenal - AKI - Diuretic use ➢FENa can be > 1-2% and look like intrinsic renal • Due to diuretic induced Na excretion ➢Consider obtaining fractional excretion of urea (FeUrea) • BUN, serum creatinine, urine urea, urine creatinine • FeUrea < 35% - prerenal • FeUrea > 50% - ATN FENa- Limitations •Intrarenal - AKI • FENa may be < 1% if ➢ATN superimposed on chronic prerenal disease (CHF, cirrhosis) ➢Contrast induced nephropathy •Obstruction - AKI • FENA can be < 1% in early obstruction • FENa can be > 1% with chronic obstruction 5. Systemic manifestations of acute kidney injury include which of the following abnormalities?

A. Metabolic alkalosis B. Metabolic acidosis C. Hypophosphatemia D. Hypokalemia Systemic Manifestations of AKI Fluid, electrolyte, & serum Gastrointestinal disturbances Hematological disturbances biochemical disturbances

Anuria, oliguria, polyuria/polydipsia Anorexia Platelet function defect/bleeding tendencies Dehydration Vomiting and diarrhea Blood loss anemia Azotemia: increased urea and Halitosis Lymphopenia creatinine Metabolic acidosis Oral ulceration/stomatitis Neutrophilia •Hyperphosphatemia •Hyperkalemia •Hypercalcemia/hypocalcemia Peripheral insulin resistance and Gastropathy, gastritis, gastric and glucose intolerance duodenal ulceration and bleeding Systemic Manifestations of AKI

Cardiovascular and pulmonary disturbances Neuromuscular disturbances

Systemic arterial hypertension Weakness

Uremic pneumonitis Lethargy

Depression

Uremic encephalopathy

Coma/death Management of AKI

• Patients with AKI generally should be hospitalized - Unless mild and clearly resulting from an easily reversible cause • Close collaboration among primary care physicians, nephrologists, hospitalists, and other subspecialists is essential • Management is primarily supportive Management of AKI

• Treat underlying cause if identified - Hypotension, Sepsis, CHF, DKA, etc. Management of AKI

• Ensure adequate renal perfusion - Achieve and maintain hemodynamic stability • Volume repletion • Vasopressors - Goal is mean arterial pressure > 65 mm Hg • MAP = Systolic + 2x Diastolic 3 Management of AKI

• Avoid exposure to aggravating factors - Contrast studies - Toxic medications/NSAIDs - ACE-inhibitors/ARB (rare) Management of AKI

• Nonoliguric renal failure patients fare better than those with oliguria • However, use of diuretics to stimulate urine output (in absence of volume overload) - increases mortality - does not promote recovery of renal function (SOR B) Management of AKI

•Dopamine (low-dose) - No benefit (SOR A) •Preventing AKI •Need for dialysis •Reduce hospital or ICU lengths of stay •Mortality - Bellomo R, Chapman M, Finfer S, et al. Lancet, 2000. Treatment of AKI Complications

• AKI with volume overload –Furosemide IV q 6 hrs is the initial Rx • 20-100 mg initially • If inadequate response after 1 hr, double the dose • Repeat process until adequate urine output • IV drip 5-40 mg/hr • Can substitute bumetanide –Ultrafiltration via dialysis (last resort) Treatment of AKI Complications – Hyperkalemia (Initial Rx) • Calcium –Calcium gluconate 10% solution – 10 mL IV • Cardio protective/membrane stabilizer • Temporarily reverses the neuromuscular effects of hyperkalemia Treatment of AKI Complications - Hyperkalemia (Temporizing Rx) • Temporarily shifts K+ intracellularly - Insulin* –10 units IV and glucose 25 gm - Inhaled beta-agonists* - Sodium bicarbonate* –3 ampules in 1 L of 5% dextrose Treatment of AKI Complications- Hyperkalemia—(K+ Elimination) • Sodium polystyrene sulfonate –Orally • 25-50 g –Rectally • 50 g with 150 mL of tap water •Use without sorbital if possible - Sorbital may cause colonic necrosis •Limited data of effectiveness despite duration of use Treatment of AKI Complications Hyperkalemia Rx—(K+ Elimination) • Patiromer (Veltassa) - 8.4 – 25.2 grams once daily - Not for life threatening hyperkalemia • Slow onset - Avoid if bowel obstruction, severe constipation Treatment of AKI Complications-- Acidosis • Sodium bicarbonate - If serum level < 15 mEq/L or pH < 7.2 - Given IV or PO 6. In patients with AKI, urgent dialysis is not indicated in which of the following situations?

A. Hyperkalemia refractory to medical therapy B. Volume overload unresponsive to diuretics C. Metabolic acidosis with pH = 7.25 D. Uremic pericarditis Acute Kidney Injury

•Indications for dialysis in patients with AKI - Metabolic acidosis • pH < 7.1 • Administration of bicarbonate is not indicated or ineffective • Volume overload • Ketoacidosis - Uremia • Encephalopathy/altered MS • Pericarditis/pleuritis • Neuropathy Acute Kidney Injury

•Indications for dialysis in patients with AKI - Fluid overload refractory to diuretics - Hyperkalemia • K+ > 6.5 or rapidly rising • Refractory to medical therapy •Poisonings and intoxications • Ethylene glycol, lithium AKI—Prevention

• Vasopressors are recommended for persistent hypotension despite fluid resuscitation • Hepatic failure/cirrhosis - Avoid hypotension/GI bleeding - Albumin infusion during large volume paracentesis AKI—Prevention

• Cancer chemotherapy - Hydration and allopurinol (Zyloprim) administration a few days before chemotherapy initiation • Prevents acute urate nephropathy • Avoid nephrotoxic medications • Avoid unnecessary exposure to radiographic contrast agents (particularly if preexisting CKD) - Optimize volume status - Isotonic normal saline in high-risk patients who are not at risk of volume overload AKI—Prevention • Rhabdomyolysis - Maintain adequate hydration - Alkalinization of the urine with intravenous sodium bicarbonate • Surgery – Preop - Adequate volume resuscitation/prevention of hypotension - Consider holding ACE/ARB/aldosterone blockers AKI—Prognosis

• Patients with acute kidney injury - More likely to develop chronic kidney disease - Higher risk of end-stage renal disease - Higher risk of premature death Neurohormonal Antagonism & The Role of the Kidney in Heart Failure Heart Disease and Kidney Disease

• Acute or chronic dysfunction of the heart or kidneys can induce acute or chronic dysfunction in the other organ. • Mortality is increased in patients with heart failure (HF) who have a reduced glomerular filtration rate (GFR) • Patients with chronic kidney disease have an increased risk of both atherosclerotic cardiovascular disease and heart failure • Cardiovascular disease is responsible for up to 50% of deaths in patients with renal failure Cardiorenal Syndrome (CRS)

• National Heart, Lung, and Blood Institute definition • Type 1 - Acute CHF causes acute kidney injury (AKI). • Type 2 - Chronic cardiac dysfunction (chronic CHF) causes progressive chronic kidney disease (CKD) Cardiorenal Syndrome (CRS)

• Type 3 - AKI causes acute cardiac dysfunction • Type 4 - Primary CKD contributes to cardiac dysfunction • Manifested by coronary disease, HF, or arrhythmia • Type 5 (secondary) - Acute or chronic systemic disorders cause both cardiac and renal dysfunction • Sepsis, diabetes 7. Which one of the following statements is true?

A. ACE inhibitors enhance angiotensin 2 mediated vasoconstriction B. Angiotensin 2 inhibits secretion of aldosterone and vasopressin C. ACE inhibitor therapy should be stopped if a 10-15% increase in serum creatinine is noted D. ACE inhibitors dilate efferent arterioles © National Kidney Foundation Neurohormonal Renal Effects • Renin - Released by renal juxtaglomerular apparatus In response to • Fall in BP • Decreased blood volume • Decreased sodium concentration in the distal tubule • Sympathetic stimulation • Angiotensin 1 - Formed from renin-mediated conversion of angiotensinogen • Angiotensin 2 - Formed from angiotensin 1 via ACE • Conversion inhibited by ACE inhibitors • Action blocked at angiotensin 2 AT1 receptor by ARB Neurohormonal Renal Effects

• Angiotensin 2 - Direct arterial vasoconstriction • Constriction of efferent arterioles - Results in aldosterone secretion from adrenal gland • Sodium retention - Results in vasopressin release from posterior pituitary • H2O retention at distal tubule ACE-Inhibitors

• Block the conversion of angiotensin I to angiotensin II • Increase levels of renin, angiotensin 1, and bradykinin • Lower arteriolar resistance • Increase venous capacity • Increase sodium excretion ACE-Inhibitors

•Cause a central enhancement of parasympathetic activity - Break cycle of sympathetic system activation - Reduce plasma norepinephrine levels in CHF • May reduce the prevalence of malignant cardiac arrhythmias • Reduction in sudden death • Interrupt the downward spiral in cardiac function in congestive heart failure Treatment-Induced Decline in Renal Function

•ACE-I/ARB dilate efferent arteriole −Increases flow through glomerulus −Decreases IG pressure −Decreases creatinine excretion • Increases serum creatinine

KH Maen/Wikipedia Treatment-Induced Decline in Renal Function • A 20-30% increase in creatinine, which then stabilizes, largely represents a hemodynamic change, and not a structural change. • 1997 study following GFR after initiation of ACE-I - Those with largest initial increase in creatinine had most stable renal function over time - Creatinine elevation reversed with discontinuation of drug • Advance trial- 2019 - “Acutely increased creatinine after ACE was associated with greater risk of subsequent major clinical outcomes” - “However, continuation of ACE may be beneficial and reduce long term risk of major clinical outcomes”

Kidney Int 997;51:793-7. Treatment-Induced Decline in Renal Function

•If creatinine increases by more than 30%, agent (ACE-I or ARB) should be discontinued and other causes of renal dysfunction should be evaluated. Causes of > 30% ACE-I/ARB-Induced Decline in Renal Function • Bilateral renal-artery obstruction (> 70%) • Absolute or effective reduction in intravascular volume: - Aggressive diuresis - Poor oral intake - Moderate-to-severe congestive heart failure • Renal vasoconstriction: - NSAIDs - Early sepsis Answers

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Review of the Diseases of the Lower GI Tract

David Glenn Weismiller, MD, ScM, FAAFP Department of Family and Community Medicine University of Nevada, Las Vegas School of Medicine Disclosure Statement

All individuals in a position to control content for this session have indicated they have no relevant financial relationships to disclose. Learning Objectives

1. Discuss the diagnosis and treatment of irritable bowel syndrome. 2. Recognize the common forms of malabsorption. 3. Review the diagnosis and treatment of cancer of the small intestine, large intestine, and anus. 4. Summarize other clinical entities of the lower GI tract, including constipation and infections. 1. A 20 yo college student comes to student health services to discuss her 3-year history of abdominal pain and constipation. It has gotten worse since she returned to school this fall. She describes crampy pain and bloating that eases after defecation. Her bowel movements are firm and difficult to pass, and occur about every 4 days on average. She denies vomiting, weight loss, blood in the stool, or melena. Her menses are regular and she is otherwise healthy. She reports using a soluble fiber (psyllium) once daily. Her family history is negative for any gastrointestinal or genitourinary diseases. Her abdominal examination is normal. You diagnose her with irritable bowel syndrome. Which ONE of the following would be most appropriate at this time?

A. A therapeutic trial of increased soluble fiber intake B. A therapeutic trial of lubiprostone (Amitiza) C. Abdominal CT D. Colonoscopy Irritable Bowel Syndrome

• Defined −GI syndrome characterized by altered bowel habits and abdominal pain, in the absence of detectable structural abnormalities −Prevalence • 10-15% in North America − 4 Subtypes • IBS-C: constipation-predominant • IBS-D: diarrhea-predominant Based on patient’s report of the • IBS-M: mixed symptoms frequency of types based on the • IBS-U: unsubtyped standard Bristol Stool Scale Irritable Bowel Syndrome Pathophysiology

• Remains uncertain • Heredity and environmental factors play a potential role. • Abnormal myoelectric activity −Basal rhythm 3 cycles/min in IBS (6 cycles/min is normal) • Visceral afferent hypersensitivity • Microscopic mucosal inflammation • Psychosocial dysfunction Irritable Bowel Syndrome Diagnosis – Rome IV Diagnostic Criteria

Pain related to defecation

Recurrent abdominal pain Associated with on average at least a change in 1d/week in the last 3 frequency of months associated with stool >2 of the following: Associated with change in form (consistency) of stool Gastroenterology, May 2016 Initial Diagnostic Evaluation

Patient History • Symptom severity/duration • Family History • Psychosocial factors

No alarm symptoms or “red flags” Meets Rome IV Diagnostic Criteria

Further work-up only if clinical evidence suggests organic disease • Laboratory Tests (CBC, FOBT, ESR, Serum Chemistry, TFTs, stool studies) • Colonoscopy or sigmoidoscopy Differential Diagnosis of IBS Symptoms

• Carcinoid Tumor • Gastrointestinal Infection (e.g., Giardia, Amoeba, HIV, • Celiac Disease bacterial overgrowth) • Colorectal Cancer • Hyperthyroidism • Diverticular Disease • Hypothyroidism • Drug Use (Opiate analgesics, • Inflammatory Bowel Disease calcium channel blockers, • Ischemic Colitis antidepressants) • Lactose Intolerance

Am Fam Physician. 2012;86(5):419-426. In Our Case…

• Patient’s symptoms are consistent • No Red Flags with irritable bowel syndrome (IBS). −Unintentional and unexplained weight loss • History, physical examination, and −Rectal bleeding laboratory evaluation did not show any −Family history of bowel or evidence of peptic ulcer disease, ovarian cancer celiac disease, thyroid disease, or −Change in bowel habits inflammatory bowel disease. persisting MORE than 6 weeks in a person > 60

The patient does not have any of these findings and therefore does not require any additional testing to confirm the diagnosis of IBS. Model to Individualize Treatment for IBS Treatment Goals: Symptom Relief and Improved QOL

Psychological Treatments Severe Continuing Care Improve Functioning

Follow-up Visit Moderate Manage Stress Pharmacotherapy

Diet, Lifestyle, Advice Positive Diagnosis Mild Explain, Reassure Diarrhea • Loperamide • Alosetron* (5HT3 antagonist) • Antibiotics • Bile acid sequestrants Bloating/Distention Abdominal Pain/Discomfort • Probiotics • Antispasmodics • Antibiotics • Antidepressants (TCA/SSRI) • Rifaximin (IBS-D or IBS-M) • Linaclotide • Neomycin (IBS-C) • Kubiprostone • Linaclotide Constipation • Alosetron • Lubiprostone • Psyllium • Antibiotics • Osmotic laxatives • Linaclotide • Lubiprostone Peppermint oil (enteric coated) is superior to placebo in *Restricted-use program improving global symptoms (SOR B) SSRI, selective serotonin reuptake inhibitor Am J Gastroenterol. 2009;104(Suppl):S1. Symptom-Based Treatment Choices Irritable Bowel Syndrome Treatment

• Self-help, patient education, cognitive behavioral treatment • Fiber is ineffective in the treatment of adult IBS (SOR A) • Lubiprostone (Amitiza) and Linaclotide (Linzess) are effective for constipation- predominant IBS. (SOR B) −Works by increasing the amount of fluid in intestine, making it easier for stool to pass • Antispasmodics −Dicyclomine, tincture of belladonna, hyoscyamine • Antidepressants (citalopram, fluoxetine, paroxetine; tricyclic antidepressants have been studied) (SOR B) −Low dose: Analgesia, mood, colonic transit slowing • Antidiarrheal agents −Diphenoxylate, loperamide; no help with pain

Wilkins T, Pepitone C, Alex B, Schade RR: Diagnosis and management of IBS in adults. Am Fam Physician.2012;86(5):419-426; and Ruepert L, Quartero AO, de Wit NJ, et al. Bulking agents, antispasmodic and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2011;(8):CD003460. Irritable Bowel Syndrome Treatment

• Psychological treatment (NNT=4)* −Hypnotherapy (SOR B) −Cognitive-behavioral therapy (SOR B) −Psychotherapy*

essentialevidenceplus.com *Ford et al. Am J Gastroenterol. 2014;109(9):1350-1365 AGA

• For a patient with functional abdominal pain syndrome (as per ROME IV criteria), computed tomography (CT) scans should not be repeated unless there is a major change in clinical findings or symptoms. 2. A 19 yo patient presents to your office for follow-up. She reports continued intermittent abdominal cramping and bloating, diarrhea, fatigue, and a 4.5-kg weight loss. She initially was diagnosed with irritable bowel syndrome, but you suspect celiac disease. Which one of the following should be used to establish the diagnosis?

A. Colonoscopy B. Serologic testing C. Serologic testing initially, followed by endoscopy if test results are positive D. Serologic testing initially, followed by colonoscopy Celiac Disease

• Chronic intestinal malabsorption disorder −Intolerance to the gliadin fraction of gluten in wheat • Features −Flat jejunal (small intestine) mucosa with clinical and/or histologic improvement following withdrawal of dietary gluten Celiac Disease

• Symptoms and signs • Laboratory – No typical presentation – Fe deficiency anemia in children – May be asymptomatic – Adults • Iron deficiency – Steatorrhea common • Folate deficiency – Failure to thrive • Vitamin D deficiency – Anemia – Symptoms of various deficiency states – Bone loss – Arthritis – Neuropsychiatric disease Celiac Disease Diagnosis • Several serologic tests are readily available for diagnosis. −IgA anti-tissue transglutaminase antibody*§ (sensitivity 79-90%, specificity 98%) −Endomysial antibody* (sensitivity 81%, specificity 97%) −Deaminated gliadin peptide antibody (IgG/IgA) (sensitivity 95-98%) • No one test has been demonstrated in clinical studies to be more accurate than another. • Test while consuming a diet of gluten-containing foods. • Gold standard: Histologic assessment of distal duodenum – villous flattening/atrophy (SOR: C) * AGA recommends these tests as initial serologic testing in adults. §If you only choose one test, then IgA is first-line test for serologic diagnosis (SOR: C) Celiac Disease Treatment

• Gluten avoidance (SOR: B) • A gluten-free diet improves the quality of life in those with symptomatic celiac disease (SOR: B) 3. A 32 yo male presents to your office as a new patient and requests a refill of sulfasalazine (Azulfidine) tablets for maintaining remission of his ulcerative colitis. The initial presentation of his disease was at 17 and involved inflammation of the entire colon. He was then started on sulfasalazine, which has worked well for controlling his symptoms. He had one flare when he ran out of medicine two years ago. He cannot recall the last time he saw a gastroenterologist. Which one of the following is an appropriate management plan for this patient?

A. Refill his sulfasalazine and continue usual care unless symptoms recur B. Attempt to gradually discontinue the sulfasalazine C. Stop sulfasalazine and start azathioprine D. Continue sulfasalazine and arrange for colonoscopy to screen for colorectal cancer Inflammatory Bowel Disease

• Onset −Usually young adults −Affects men and women equally −More common among Caucasians in N. America and N. Europe Inflammatory Bowel Disease

• Spectrum −Crohn’s, indeterminate, ulcerative colitis −600,000 people in the US have some form of inflammatory bowel disease. • Pathogenesis −Some genetic role −No identified infectious agent −Strong evidence for immune role as mediator of tissue injury - unknown trigger −Serologic markers can be helpful in differentiating UC and Crohn’s • Laboratory −Fecal lactoferrin and calprotectin levels (surrogate markers for bowel inflammation) and may help distinguish between inflammatory conditions and IBS Ulcerative Colitis

• Incidence: 10/100,000, 25% family history • Pathology −CONFINED TO MUCOSA −Starts in rectum, moves proximally WITHOUT skips • Clinical features −Mild to severe at start −Abrupt onset −Rectal bleeding, diarrhea, fever, cramping pain, weight loss −Clinical symptoms are inadequate for assessing need for ongoing therapy • Serologic marker −Perinuclear antineutrophil cytoplasmic antibody is more suggestive of UC Differential Diagnosis of Ulcerative Colitis and Recommended Testing Disease Findings that suggest diagnosis Evaluation

Amebic dysentery Travel to endemic areas or exposure to Anti-amebiasis antibodies, illness microscopy (O&P) Bacterial colitis Should be routinely considered; exposure Stool culture, including testing for E. history may increase suspicion coli 0157:H7

Clostridium difficile infection Recent antibiotic use Stool studies for C. difficile toxin

Crohn’s disease Increased suspicion with disease not Endoscopic biopsy limited to colon Ischemic colitis Risk factors for vascular disease Endoscopic biopsy Microscopic colitis Nonbloody stools Endoscopic biopsy Viral or parasite-induced Immunocompromised Endoscopic biopsy colitis Medication Dosage for active Maintenance dosage Adverse effects disease Sulfasalazine (first line 4-6 g/day divided QID 2-4 g/day HA, interstitial nephritis, N/V; one of therapy for UC) most effective agents for remission 5-Aminosalicylic acid Oral 2-4.8 g/d, divided TID 1.2-2.4 g/d Interstitial nephritis Suppository 1000 mg/d 500 mg 1-2x/d Anal irritation Enema 1-4g/d 2-4g daily to every third day Difficulty retaining, rectal irritation Hydrocortisone Enema 100 mg Not recommended Rectal irritation Foam 90 mg 1-2X/d Not recommended Rectal irritation Prednisone 40-60 mg/d until clinical Not recommended Adrenal suppression, impaired wound improvement, then taper healing, PUD, etc. 5-10 mg/w Methylprednisolone 40-60 mg/d Not recommended Infliximab 5-10 mg/kg weeks 0, 2, 5-10 mg/kg q 4-8 weeks Increased risk infection, lymphoma Anti-tumor necrosis factor and 6 agents (biologics) Azathioprine Not recommended 1.5-2.5 mg/kg/d Allergic reactions, BM suppression, infection Cyclosporine 2-4 mg/kg/d Not recommended Infection, nephrotoxicity, seizures Ulcerative Colitis − SORT: Key Recommendations for Practice

Clinical recommendation Evidence rating 5-aminosalicylic acid is highly effective for inducing remission and A preventing relapse. Oral corticosteroids are effective for inducing remission. B Infliximab is effective for inducing remission in corticosteroid- A refractory UC. Azathioprine is effective for preventing relapse. B Probiotics Lactobacillus GG and E. coli Nissle 1917 (Mutaflor) are as B effective as 5-ASA in maintaining remission.

Am Fam Physician. 2013; 87(10):699-705. Ulcerative Colitis Link with Colon Cancer

• 2.8-15x as likely to develop colon cancer if there is history of moderate or extensive involvement of the colon • Colonoscopy q 2-5 years* [SOR: C] −Initiated 10 years after UC is diagnosed −Interval based on findings

• Kornbluth A, Sachar DB. Practice Parameters Committee of the ACG. Ulcerative colitis practice guidelines in adults. Am J Gastroenterol. 2010;105(3):501-523. • Adams SM, Bornemann PH: Ulcerative colitis. Am Fam Physician 2013;87(10):699-705. • Ford AC, Moayyedi P, Hanauer SB: Ulcerative colitis. BMJ 2013;346:f432. Crohn’s Disease

• Pathology −FULL WALL THICKNESS −Any part of GI tract may be affected. −Terminal ileum most common site −SKIPS Similar cancer risk as UC after • Clinical features long-standing disease – similar −Insidious onset screening recommendation and −Commonly with mild diarrhea and pain controversy* • Diagnosis −Laboratory Diagnostic Studies

• Laboratory Testing • Initial • CBC, C-Reactive protein, ESR, BMP, LFTs • Stool cultures, testing for Clostridium difficile toxin; O&P • Subsequent • Iron studies, Albumin, Vitamin D, Calcium • Presence of antibodies to E. coli outer membrane porin and Saccharomyces cerevisiae is suggestive of Crohn’s Diagnostic Studies

• Endoscopy and Related Investigations ― Colonoscopy and ileoscopy and biopsy ▪ Skip lesions, cobblestoning, ulcerations, strictures ― Capsule endoscopy ― CT enterography ― MR enterography ― EGD ― Upper GI symptoms ― Asymptomatic patients with iron deficiency anemia ― Active Crohn’s with a normal colonoscopy Crohn’s and Treatment Disease Medications Comments Activity Mild Mesalamine Products Pancreatitis and pneumonitis can occur with • Sulfasalazine these agents • 5-aminosalicylic acid 5 ASA – Ineffective in maintaining remission

Budesonide Budesonide – useful for treating disease at the junction of the ileum and colon or ascending colon; ineffective for maintaining remission Moderate Corticosteroids Corticosteroids ineffective in maintaining remission Azathioprine Azathioprine is effective for maintenance of 6-mercaptopurine remission Methotrexate Anti-TNF Agents Increasing evidence supports that anti-TNF • Infliximab or Azathioprine may offer corticosteroid • Adalimumab (Humira) sparing benefits for corticosteroid-naïve • Certolizumab pegol (Cimzia) patients Severe Use of anti-TNF agents is controversial; failure to respond or worsening symptoms may require surgical intervention Crohn’s – SORT: Key Recommendations for Practice Clinical Recommendation (Am Fam Physician. 2011; 84(12):1365-1375.) SOR Ultrasonography, CT, scintigraphy, and MRI are helpful for excluding extramural complications C Colonoscopy with ileoscopy and biopsy is a valuable initial test in diagnosis of ileocolonic C Crohn’s disease EGD is recommended if patients have upper GI symptoms C No difference between elemental and nonelemental diets in inducing remission in A patients with Crohn’s disease Budesonide is effective in inducing, but not maintaining, remission B Corticosteroids are more effective than placebo and 5-ASA products in inducing A remission Azathioprine and 6-MP are effective in inducing remission in patients with active disease A Methotrexate is effective in inducing and maintaining remission B Summary – Serologic Tests

IBS Celiac Disease IBD None • Serum IgA tissue • Fecal lactoferrin and fecal calprotectin are transglutaminase (TTG) tests of gut inflammation and may be antibodies (first–line) helpful in distinguishing IBD and IBS • Endomysial antibody • Presence of antibodies to E. coli outer membrane porin and Saccharomyces cerevisiae is suggestive of Crohn’s • Perinuclear antineutrophil cytoplasmic antibody is more suggestive of UC

Arch Intern Med. 2009 Apr 13;169(7):651-8. Aliment Pharmacol Ther. 2010 Jun;31(12):1365-70. Eur J Gastroenterol Hepatol. 2010 Mar;22(3):340-5. GI Infections Common GI Infections • Goals −Replace the fluid lost through diarrhea and vomiting −Identify and eradicate the causative agent • Diagnosis −History: Work, travel, eating, others ill, recent antibiotics, immunocompromised, HIV −Vomiting implies gastric involvement with preformed toxin −Pain implies distention and inflammation −Lab: Stool for fecal blood and leukocytes, cultures, O&P* −Sigmoidoscopy

* Most acute diarrhea is viral and self-limited. Order O&P if history of travel or diarrhea is chronic. Rehydration Recommendations • Oral rehydration therapy (ORT) –Recommended by the AAP as “the preferred treatment of fluid and electrolyte losses caused by diarrhea in children with mild to moderate dehydration.” –WHO reduced-osmolarity oral rehydration solution (ORS) now recommended for all rehydration in children, both cholera-endemic areas and non-cholera endemic. –Pedialyte, Rehydrolyte, Ceralyte, Infalyte –Sports drinks, diluted fruit juices, watery soups (adults) • Intravenous therapy –Parenteral saline and electrolytes –Ringer’s lactate • Dietary adjustments (following rehydration) –Boiled vegetables, starches, soups, yogurt –Avoid high fat. –Simple sugars as opposed to complex carbohydrates Gavin N, et al. Pediatrics. 1996;98(1):45-51. 4. Which of the following is the most common cause of infectious diarrhea in children both in developed and developing countries? A. Campylobacter B. Rotavirus C. Shigella D. Norovirus Common GI Infections

• Rotavirus • Pseudomembranous • Norovirus enterocolitis • Traveler’s diarrhea • Campylobacter • Vibrio cholerae • Salmonellosis • Shigella • Amebiasis • Giardiasis • Cryptosporidium (Viral) Gastroenteritis Majority of Gastroenteritis Is Viral

• Rotavirus • Rotavirus is the most common • Norovirus cause in children and produces • Adenovirus similar incidence rates in both the • Astrovirus developed and developing world. • Norovirus is the leading cause of gastroenteritis among adults in America, causing greater than 90% of outbreaks. Rotavirus

• Most important viral cause of severe gastroenteritis in children worldwide −Most common cause in US −Large-volume diarrhea without blood or leukocytes in stool −Daycare centers – fecal oral spread • Dx: Immune-based assays of stool, PCR • Complications: Necrotizing enteritis, biliary atresia, intussusception, chronic diarrhea Rotavirus

• Treatment is generally supportive. • Immunization (SOR A) −CDC/AAP recommend universal immunization in U.S. with oral PRV vaccine. • 2 months ✔First dose minimum 6 weeks, maximum < 15 weeks • 4 months • 6 months ✔Must complete by 8 months Norovirus

• Norovirus is the leading cause of gastroenteritis among adults in America, causing greater than 90% of outbreaks. oTop pathogen contributing to domestically acquired foodborne illness oSecond most common foodborne illness resulting in hospitalization oFourth in terms of domestically acquired foodborne illness resulting in death oAbrupt onset (12-48 hours after exposure) and prompt resolution (1-3 days) 5. A 52 yo female with hypertension presents with a 2-day history of profuse bloody diarrhea, moderate to severe abdominal cramping, and fever. She has recently returned from a week-long trip to Singapore. Her stool culture is positive for Campylobacter. Which one of the following is the treatment of choice?

A. Azithromycin (Zithromax) B. Ciprofloxacin (Cipro) C. Metronidazole (Flagyl) D. Rifaximin (Xifaxan) Bacterial Gastroenteritis

• Adults • Children o Salmonella o Salmonella o Campylobacter o Campylobacter o Shigella o Shigella Campylobacter

• 10-15% of U.S. acute diarrhea • Animal reservoir oMost human cases are contaminated poultry (~50%) • Severe cramps, bloody diarrhea, anorexia, malaise; rarely, Guillain-Barre, reactive arthritis • Diagnosis: Culture • Treatment oSpontaneous clearing without antibiotics or oAzithromycin, erythromycin if culture proven oFQ > resistance Shigella

• Bloody diarrhea • Fecal oral spread oHighly contagious • Principal effect on colon mucosa oLow-volume diarrhea oBlood oMucus oFever oTenesmus • Diagnosis oCulture Shigella

• Clinical oSelf-limiting oRarely ▪ Rectal prolapse, proctitis, toxic megacolon, perforation, obstruction, seizures in children, HUS • Treatment oTMP-SMX (children) oQuinolone oFluids oNo vaccine Salmonellosis • 10-15% of US acute diarrhea oSecond leading cause of acquired foodborne illness in US oTop pathogen of domestically acquired foodborne illness resulting in hospitalization and death • Nontyphoidal starts 6-48 hours after exposure, resolves spontaneously oVomiting oNausea oPain oDiarrhea • Sources oEggs and poultry oPet reptiles Salmonellosis • Clinical −Self-limited −Can cause bacteremia • Endocarditis • Osteomyelitis • Mycotic aneurysm −Recommended management for patients who have non-severe Salmonella infection and are otherwise healthy is NO TREATMENT −High risk condition that predispose to bacteremia, and those with severe diarrhea, fever, systemic toxicity or positive blood cultures – treat with Levofloxacin, 500 mg q day for 7-10 days (or another FQ in an equivalent dosage). Salmonellosis

• Typhoid via fecal-oral contamination, rare in US • Constipation and rash early, then diarrhea and pain • Diagnosis • Culture from blood or stool • Treat: Fluoroquinolone • Vaccine available E. coli 0157:H7 (EHEC)

• Sporadic and large outbreaks oProduces Shiga toxin oDiagnose with culture oClinical • Dysentery • Striking abdominal pain • Usually no fever E. coli 0157:H7 (EHEC)

• Complication oHemolytic uremic syndrome • Check serum Cr • Source oContaminated meat • Treatment oSupportive oAntibiotic NOT indicated Foodborne Illness Summary

Pathogen (top 5 domestically acquired foodborne Percent illnesses) Norovirus 58 Salmonella (nontyphoidal) 11 Clostridium perfringens 10 Campylobacter spp 9 Staphylococcus aureus 3

CDC 2011 Estimates: www.cdc.gov/foodborneburden/2011-foodborne-estimates.html Last updated June 21, 2013 Amebiasis

• 5% reported US carriage rate • E. histolytica mostly o Fecal-oral spread o Abdominal cramps o Chills, fever o Liquid BMs with bloody mucus • Diagnosis o Sigmoidoscopy o O&P o Stool/serum antigen o Serology • Treatment o Metronidazole etc. Giardiasis

• Common oMostly from contaminated water • Symptoms oAbdominal cramps oMalabsorption oNausea and vomiting oWatery diarrhea • Diagnosis oO&P oGiardia antigen assay • Treatment oMetronidazole 6. Of the following antibiotics, which is the agent recommended for treatment of pseudomembranous enterocolitis in an individual over the age of 60 with a temp of 38.7C and a wbc count of 19.8K?

A. Amoxicillin B. Ciprofloxacin C. Vancomycin D. Metronidazole Pseudomembranous Enterocolitis

• Common in “post antibiotic” setting o Amoxicillin is most common offending antibiotic. o Occurs with most antibiotics • Etiology o Toxin from Clostridium difficile • Diagnosis o Cytotoxin assays o Immunoassays to toxin • Treatment o Stop antibiotic – use Vancomycin o Fluids • Relapse and carrier rates are possible (10-25%) Traveler's Diarrhea • Multiple causes o Enterotoxigenic E. coli (most common), Campylobacter jejuni, Shigella spp, Salmonella spp • Prophylaxis o NOT recommended by CDC o Routine prophylaxis increases the traveler’s risk for adverse reactions and for infections with resistant organisms. • Strict adherence to preventive measures • Handwashing (alcohol-based hand sanitizer also effective) has been shown to reduce the risk by 30% • Avoiding street vendor foods, tap water, ice, and raw foods has NOT been shown to reduce the risk • Usually self-limited Traveler’s Diarrhea (TD) If Treatment Is Needed…

• Travelers who develop > 3 loose stools in an 8-hour period – especially if associated with nausea, vomiting, abdominal cramps, fever, or blood in stools • Antibiotics* o Fluoroquinolones are drugs of choice when needed single dose or 1 day (increasing resistance) o Alternative: Azithromycin (500 mg q day for 1-3 days) o NO trimethoprim-sulfamethoxazole or doxycycline because of high levels of resistance • Bismuth subsalicylate may also be used for treatment. o One fluid oz or two 262 mg tablets q 30 minutes for up to eight doses in a 24-hour period • The antimotility agent loperamide is a well-established antidiarrheal agent. o Its effective and safe use as an adjunct to antibiotics in the treatment of TD has been demonstrated in several studies. No other nonantibiotic treatment for TD has significant guideline or clinical trial support.

* CDC Health Information for International Travel 2012. New York: Oxford University Press; 2012. Vibrio Cholerae

• In the developing world, especially sub-Saharan Africa and Asia, cholera is a common cause of gastroenteritis. o Contaminated water or food • In U.S., generally associated with travel o Asia o China o South/Central America −OR consumption of contaminated seafood −OR recent consumption of contaminated imported foods • Treatment o Vigorous rehydration o Doxycycline Key Learning Points: Diarrhea

• Rotavirus is the leading cause of infectious diarrhea in children in the U.S. • Norovirus is the leading cause of foodborne disease in U.S. and the leading cause of gastroenteritis in U.S. adults. • Salmonalla is the most common cause of bacterial diarrhea in adults in the U.S. • Antibiotics are not indicated for treatment of E. coli 0157:H7. • Amoxicillin is most common offending antibiotic for pseudomembranous enterocolitis. • Prophylaxis for traveler’s diarrhea is NOT recommended. Diverticular Disease

• Symptoms o 90% asymptomatic o Intermittent LLQ abdominal pain o Irregular defecation • Exam o Tender LLQ o (−) rectal exam without occult blood • Diagnosis Source: Wikipedia o Flexible sigmoidoscope and barium enema • Treatment o High-fiber diet (unprocessed bran, hydrophilic bulk laxatives) Diverticulitis

• Clinical presentation oAcute lower abdominal pain oFever (usually below 102º F) oTachycardia oPhysical findings • Tender lower abdomen, possibly with rebound ―Tenderness only in the LLQ significantly increases the likelihood of diagnosis ([+] LR = 10.4) • Acute abdomen is possible Diverticulitis Diagnostic Studies • CBC: Leukocytosis with “left shift” o 55% will have leukocytosis • BMP o Assess electrolytes and renal function. • Consider C-reactive protein o LLQ tenderness AND a CRP > 50 mg/L, in the absence of vomiting, likelihood of acute diverticulitis significantly increased ([+] LR = 18). • UA: Sometimes WBC and RBC • Plain films: Sometimes free air • US: Sometimes abscess • CT: Evolving as preferred method o Quite a bit of controversy with CT scan regarding the use of contrast agents: Intravenous, oral, or rectal contrast agents versus giving no contrast agents at all, CT KUB. • AVOID endoscopy and BE in acute setting. o Colonoscopy 4-6 weeks post-resolution of symptoms in patients with complicated disease Diverticulitis Treatment • General −Depends on severity −May require only clear liquids and oral antibiotics • Can be done outpatient with follow-up in 2-3 days • Ciprofloxacin and/or metronidazole −OR MAY NEED (hospitalization) • NPO • NG suction • IV fluids • IV antibiotics • Ampicillin + aminoglycoside + metronidazole OR • Imipenem/cilastatin OR • Piperacillin/tazobactam Diverticulitis Treatment • Surgery ‾ 15-30% admitted for acute diverticulitis will need surgical intervention during the admission. ‾ For peritonitis, perforation, unresolved obstruction, and colovesical fistula ‾ Avoid for uncomplicated diverticulitis • Bleeding (Diverticulosis) ‾ 15-40% ‾ Profuse, painless ‾ Generally self-limited Source: Wikipedia SORT: Key Recommendations for Practice

Clinical Recommendation Evidence Rating Antibiotics may not be necessary in patients with B uncomplicated diverticulitis who are being treated in the outpatient setting. There is NO clear evidence that avoiding nuts, corn, or B popcorn decreases the risk of diverticulosis or diverticular complications, such as diverticulitis.

Wilkins T, Embry K, and George R. Diagnosis and Management of Acute Diverticulitis. Am Fam Physician. 2013;87(9):612-20. Cancer of Small Intestine

• Rare oMost commonly seen in Crohn’s • Adenocarcinoma: 46% oOthers: Lymphoma, carcinoid • Diagnosis oUsually imaging study • Treatment oUsually surgery

Source: Henry W. Schmitt/Wikipedia Cancer of Large Intestine

• Most frequent internal neoplasm in the US o5-6% lifetime risk (1 in 17) oThird most common cause of cancer and cancer- related deaths in men and women in the US oMore common in Western nations oEqual frequency in men and women oAfrican Americans and Caucasians equally affected ▪ African Americans have a higher mortality Cancer of Large Intestine • Histology ‾ 95% Adenocarcinoma • Progression from adenoma (adenomatous polyp) to carcinoma – may take 10 years • Polyps • < 1 cm: < 1% chance of CA ‾ 1-2 cm: 10−20% chance of CA ‾ > 2 cm: 30−50% likelihood ‾ Detecting and removing polyps early CAN PREVENT much colon cancer • Early Detection of CRC – decreased mortality Source: [email protected] Risk Factors

• Nonmodifiable • Modifiable o Family or personal history o Smoking of CRC or advanced o Obesity adenomas o Inactivity o Personal history of IBD o Heavy Alcohol Use o Personal history of o Red meat consumption hereditary polyposis (500 g/week) syndromes

CA Cancer J Clin. 2014;64(1):9-29. Gastroenterol Clin North Am. 2002;31(4):925-943. Diagnosis of Cancer of the Large Intestine

• Symptoms: Variable and • Endoscopy nonspecific oFlexible sigmoidoscopy o Rectal bleeding oColonoscopy o Lower abdominal pain • Imaging o Change in bowel habits oBarium enema • Physical findings oCT o Abdominal mass oRectal ultrasound o Enlarged liver • Lab o Stool for occult blood 7. A 54 yo male sees you for a health maintenance visit. He inquires about the options for colorectal cancer screening. He has not had any screening tests performed in the past and has no personal or family history of colon cancer. You explain to him that there are several alternatives, but according to the U.S. Preventive Services Task Force, recommendations regarding the optimal screening intervals vary by test. He opts for fecal occult blood testing. You recommend he repeat this test at which one of the following intervals? A. Yearly B. Every 3 years C. Every 5 years D. Every 10 years Recommendation of the USPSTF on Screening for CRC June, 2016 Population (Adult Age) Recommendation 50-75* Screen with high sensitivity fecal occult blood testing (FOBT), sigmoidoscopy, or colonoscopy (GRADE A) 76-85 Do not screen routinely (GRADE C); individual decision, taking into account the patient’s overall health and prior screening history. Adults in this age group who have never been screened for colorectal cancer are more likely to benefit. > 85 Do not screen • Screening tests – equally acceptable • 2016 recommendation focuses on BEING SCREENED as opposed to screening test to be used * American College of Gastroenterology recommends starting at age 45 in blacks Stool-Based Tests http://www.uspreventiveservicestaskforce.org/Page/Document/ RecommendationStatementFinal/colorectal-cancer-screening2

Screening Frequency Evidence of Efficacy Other Considerations Method gFOBT Every year RCTs with mortality end points: Does not require bowel preparation, High-sensitivity versions (eg, Hemoccult SENSA) anesthesia, or transportation to and from the have superior test performance characteristics screening examination (test is performed at than older tests (eg, Hemoccult II) home) FIT Every year Test characteristic studies: Does not require bowel preparation, Improved accuracy compared with gFOBT anesthesia, or transportation to and from the Can be done with a single specimen screening examination (test is performed at home) FIT-DNA Every 1 or 3 y Test characteristic studies: There is insufficient evidence about Specificity is lower than for FIT, resulting in more appropriate longitudinal follow-up of abnormal false-positive results, more diagnostic findings after a negative diagnostic colonoscopies, and more associated adverse colonoscopy; may potentially lead to overly events per screening test intensive surveillance due to provider and Improved sensitivity compared with FIT per single patient concerns over the genetic component screening test of the test Direct Visualization Tests http://www.uspreventiveservicestaskforce.org/Page/Document/ RecommendationStatementFinal/colorectal-cancer-screening2

Screening Frequency Evidence of Efficacy Other Considerations Method Colonoscopy Every 10 y Prospective cohort study with Requires less frequent screening. Screening and mortality end point diagnostic follow-up of positive results can be performed during the same examination. CT Every 5 y Test characteristic studies: There is insufficient evidence about the potential colonography harms of associated extracolonic findings, which are common Flexible Every 5 y RCTs with mortality end points: Test availability has declined in the United States sigmoidoscopy Modeling suggests it provides less benefit than when combined with FIT or compared with other strategies Flexible Flexible RCT with mortality end point Test availability has declined in the United States sigmoidoscopy sigmoidoscopy (subgroup analysis) Potentially attractive option for patients who want with FIT every 10 y plus endoscopic screening but want to limit exposure to FIT every year colonoscopy USPSTF COLORECTAL CANCER SCREENING USPSTF COLORECTAL CANCER SCREENING Colonoscopy Screening Recommendations Based on Risk Factors Risk Factor Age to Initiate Screening Interval if normal (years) Single first-degree relative with CRC or an 50 years (may start at 45 years in blacks) 10 advanced adenoma diagnosed at > 60 years of age Single first-degree relative with CRC or an 40 years or 10 years younger than affected 5 advanced adenoma diagnosed at <60 relative’s age when diagnosed, whichever years of age is earlier Two first-degree relatives CRC or an 40 years or 10 years younger 5 advanced adenoma diagnosed at any than the youngest affected relative’s age age when diagnosed, whichever is earlier * An advanced adenoma is defined as an adenoma that is 10 mm or larger, has villous elements, or has high-grade dysplasia. Am Fam Physician. 2015;91(2):93-100. AGA

• Do not repeat colorectal cancer screening (by any method) for 10 years after a high-quality colonoscopy that does not detect neoplasia. 8. One week after a complete and adequate baseline screening colonoscopy, a 51 yo female with no history of previous health problems visits you to review the pathology report on the biopsy specimen obtained from the solitary 8-mm polyp discovered in her sigmoid colon. The report confirms that this was a hyperplastic polyp. Her family history is negative for colon cancer. Which one of the following is the most appropriate interval for follow-up colonoscopy in this patient? A. 1 year B. 3 years C. 5 years D. 10 years Br J Surg. 2002;89 (7):845-860. Gastroenterology. 1990;98(2):371-379. Polyps Gastroenterology. 2012;143(3):844-857. Gastroenterology. 2010;139(5):1497-1502. Polyp Risk Follow-up Adenomatous Malignant potential See next slide • Tubular adenoma 4.8% malignant transformation rate (most common) • Tubulovillous 19% malignant transformation rate adenoma 38.4% malignant transformation rate • Villous adenoma Hyperplastic No increased risk for CRC Routine surveillance (50% of polyps found) guidelines Serrated Principle precursor of hypermethylated See next slide gene cancers; 20-30% of CRCs from this pathway; difficult to detect during colonoscopy as flat and indiscrete Guidelines for Follow-up Surveillance Colonoscopy

Initial Colonoscopy Findings Follow-up Interval Normal – No polyps or normal biopsy results 10 years Hyperplastic polyps – small (<10 mm) hyperplastic polyps in rectum or 10 years sigmoid Low-risk polyps • 1 or 2 small (<10 mm) tubular adenomas 5-10 years • Small sessile serrated polyp (<10 mm) without dysplasia 5 years High-risk polyps 3 years • 3-10 tubular adenomas • Tubular adenoma or serrated polyp > 10 mm • Adenoma with villous features or high-grade dysplasia • Sessile serrated polyp with cytologic dysplasia • Traditional serrated adenoma Am Fam Physician. 2015;91(2):93-100. AGA

• Do not repeat colonoscopy for at least five years for patients who have one or two small (<1cm) adenomatous polyps, without high-grade dysplasia or villous histology, completely removed via a high-quality colonoscopy. Algorithm for CRC Screening Diagnostic AGA, 2008 Men and women Symptomatic work-up Volume 134, Issue 5; 1570-1595, May 2008 *HNPCC=hereditary nonpolyposis colorectal cancer & Asymptomatic FAP=familial adenomatous polyposis **either colorectal cancer or adenomatous polyp Age < 50 years Age ≥ 50 Years

Negative family history Positive family history Negative family history

No screening Avg. risk screening

2 or more first-degree relatives affected* 1 first-degree relative affected Or 1 first-degree relative HNPCC* or FAP at age ≥ 60 years affected at age < 60 years

Genetic counseling Colonoscopy beginning age 40 years or Average-risk screening, And special screening 10 years earlier than the youngest diagnosis** beginning at age 50 years in the family, whichever comes first Treatment of Cancer of the Large Intestine • Surgical excision with 5 cm margin • Clearing colonoscopy at time of diagnosis; thereafter, q 3-5 years • 40-50% of patients have long-term survival after resection • Chemotherapy with 5-FU produces partial tumor remission in 15-20% • New agents: Irinotecan and oxaliplatin • Radiation therapy useful for symptomatic metastases Key Recommendations CRC Screening Recommendation SOR Colorectal cancer screening should begin at 50 years of age in average-risk A individuals The American College of Gastroenterology recommends that colorectal cancer C screening begin at 45 years of age in black patients Average-risk patients with normal findings on colonoscopy should have repeat C colonoscopy in 10 years Patients with small, distal hyperplastic polyps are considered to have a normal C colonoscopy result and should have repeat colonoscopy in 10 years Repeat surveillance colonoscopy in 5 to 10 years for low-risk polyps C Repeat surveillance colonoscopy in 3 years for high-risk polyps C THANK YOU Malabsorption • Defined −Impaired absorption of nutrients • Clinical features −Symptoms (consistent across types) • Weight loss • Diarrhea • Bloating and flatulence • Malnutrition Classification of Malabsorptive Disorders

• Luminal disorders • Wall disease −Hepatobiliary disease Regional enteritis −Pancreatic insufficiency Amyloid disease −Altered bacterial flora • Vascular disease Mesenteric artery disease • Jejunal diverticulosis Cardiac failure • Blind-loop syndrome • Metabolic disorders • Scleroderma Pancreatic adenoma • Mucosal abnormalities Carcinoid −“Structural” Hypopituitarism • Celiac disease (sprue) Carcinoma of the bronchus • Tropical sprue • Lymphatic abnormalities • Radiation Enteritis Whipple’s disease • Agammaglobulinemia Lymphangiectasia −“Biochemical” Lymphoma • Abetalipoproteinemia • Iatrogenic causes Surgery and drugs • Amino acid absorptive disorders

Rigas B, Spiro H. Clinical Gastroenterology, 4th ed. McGraw Hill, 1995. Malabsorption Physical Findings • Pallor, anemia • Amenorrhea • Muscle wasting • Paresthesias • Hair loss • Glossitis • Edema • Cheilitis • Pagophagia (ice pica) • Bruising Malabsorption Diagnostic Tests

• Decrease in serum carotene, cholesterol, albumin • Quantitative or qualitative fecal fat • Carbon 14 triolein breath test

−Decrease CO2 fat malabsorption • Small intestine films and biopsy • Cultures from small intestine • Breath hydrogen tests (for bacterial overgrowth) ✔General therapy for malabsorption is nutritional. Common Syndromes Maldigestive and Malabsorptive • Exocrine pancreatic insufficiency −Dx: Steatorrhea + normal D-xylose (no proximal small bowel dysfunction) −Tx: Pancreatic enzyme replacement • Bile acid deficiency – short gut • Parasitic diseases −Giardiasis −Cryptosporidium • Immunodeficiency states • Lactase deficiency −Dx: Breath hydrogen lactose challenge −Tx: Diet Answers 1. B 2. C 3. D 4. B 5. A 6. C 7. A 8. D References

1. Ghosh S et al. Ulcerative colitis. BMJ. 2000;320(7242):1119-1123. 2. Infliximab (Remicade) for Crohn’s disease. The Medical Letter. 2-26-99,41:19-20. 3. Imperiale et al. Risk of advanced proximal neoplasm in asymptomatic adults for colorectal cancer. N Engl J Med. 2000;343:169-174. 4. Johnson S et al. Epidemics of diarrhea caused by a clindamycin-resistant strain of Clostridium difficile in four hospitals. N Engl J Med. 1999;341:1645-1651. 5. Kornbluth A and Sachar DB. Ulcerative colitis practice guidelines in adults. AJG. 1997;92(2):204-211. 6. Leiberman et al. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. N Engl J Med. 2000;343:162-168. 7. Rex DK et al. Colorectal cancer prevention 2000: Screening recommendations of the American College of Gastroenterology. Am J Gastroenterol. 2000;95:868-877. 8. Rockey DC et al. Relative frequency of upper gastrointestinal and colonic lesions in patients with positive fecal occult- blood test. N Engl J Med. 1998;339:153-159. 9. Sharma VK and Howden CW. Colorectal cancer screening: How are we doing and how can we improve? Oncology Spectrums. 2001;2(1):25-31. References

10 Rex DK, Johnson DA, Anderson JC, et. al. American College of Gastroenterology Guidelines for Colorectal Cancer Screening 2008. Am J Gastroenterol online: http://www.medicine.nevada.edu/residency/lasvegas/internalmed/documents/coloncaGuideline.pdf 11 Wilkins T, Jarvis K, and Patel J. Diagnosis and Management of Crohn’s Disease. Am Fam Physician. 2011;84(12):1365-1375. 12 Wilkins T, Embry K, and George R. Diagnosis and Management of Acute Diverticulitis. Am Fam Physician. 2013;87(9):612-20. 13 National Cancer Institute. Red meat consumption; Last Updated: March 2015. Available from: http://progressreport.cancer.gov/prevention/red_meat 14 Sanford C, McConnell A, Osborn J: The pretravel consultation. Am Fam Physician 2016;94(8):620-627. 15 Chen LH, Hochberg NS, Magill AJ: The pretravel consultation. Centers for Disease Control and Prevention, 2017. Supplemental Slides Constipation

• A symptom, not a disease −Unsatisfactory defecation: Difficult, infrequent, incomplete −95% of people have at least three BMs per week. • 2% of people report chronic constipation (M:F 1:3). −Most common digestive complaint in general population • Etiologies Constipation

• History • Etiologies* ‾ Beware of constipation of ‾ Diet recent origin. ‾ Drugs ‾ Stool pattern changes or ‾ Lack of adequate fluid intake alarm signs/symptoms: Rule ‾ Lack of exercise out CANCER. ‾ Irritable bowel syndrome ‾ Depression ‾ Hypothyroidism ‾ Pelvic floor dysfunction ‾ Spinal cord injury

* Best Practice 1993;3(1) Constipation

• Diagnostic studies • Physical findings ‾ Insufficient evidence to support ‾ Rectal exam: Fissures, routine use of blood tests, hemorrhoids, sphincter radiography, or endoscopy in abnormalities, anal/rectal workup without alarm prolapse, impaction signs/symptoms (CBC, FOBT, ‾ Abdominal exam: Check for TSH) abdominal mass. ‾ Endoscopy: Flexible ‾ Check for signs of sigmoidoscopy or colonoscopy hypothyroidism. ‾ Imaging: Barium enema, ultrasound, CT, colonic transit studies, rectal manometry Constipation Treatment

• Depends on etiology −Empiric treatment without diagnostic testing can be considered when alarm features are absent. −Acute • Enemas, suppositories, osmotic laxatives −Patient education: Lifestyle, exercise, hydration, bowel training −Diet: High fiber (psyllium, methylcellulose, bran, polycarbophil) −Laxatives: Mineral oil, lactulose, polyethylene glycol −Rule out fecal impaction. −Treat depression, if present. Cancer of the Anus

• Uncommon −Only 2%-3% as frequent as colon CA −50%-60% squamous cell CA • Associated with chronic inflammation of anus, especially inflammatory bowel disease −Diagnosis: Biopsy −Treatment: Excision and radiation © Dr Noorali Bharwani, nbharwani.com Hemorrhoids • Pathogenesis −Dilated sinusoids within anal canal and distal rectum −External vs internal • Determined by origin: Above/below the dentate line • History −Usually bleeding is the symptom; can experience anal itching (external) or mild pain (internal); severe pain only with thrombosed hemorrhoids. • Physical exam −Visual exam and digital exam Source: Mikael Häggström/ Wikipedia −Anoscopy and sigmoidoscopy Hemorrhoids

• Treatment oHigh-fiber diet oStool softeners oHot sitz baths oTopical agents oLigation oInfrared ablation oSurgery Other Common Anal Problems

• Pruritus ani • Anal fissure Other Common Anal Problems • Pruritus ani −Severe itching around anus • Worse with anxiety −Many causes • Fissure, fistula, hemorrhoid, dermatitis • Diabetes, STDs, premalignant lesions • Parasites, functional −Diagnosis: Rule out causes above. −Treatment • Improve anal hygiene. • Treat constipation and diarrhea. • 0.25% hydrocortisone cream Anal Fissure

• Tear in anal mucosa • Severe pain with defecation • Diagnosis oAnoscopy • Treatment

Source: Wikipedia Treatment

• Botulinum toxin injection • Warm sitz baths • Surgery • Anesthetic ointments ‾ Disrupting to internal sphincter • Soften stool. • 30% have problem controlling flatus. • Sclerotherapy • 20% with minor fecal • Topical nitrates or CCBs incontinence © 2020 American Academy of Family Physicians. All rights reserved.

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Renal Disease II: Chronic Kidney Disease

Gary I. Levine, MD, FAAFP Associate Professor Department of Family Medicine The Brody School of Medicine at East Carolina University Greenville, North Carolina Disclosure Statement

All individuals in a position to control content for this session have indicated they have no relevant financial relationships to disclose. Learning Objectives

1. State the major points of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) for chronic kidney disease (CKD). 2. Accurately identify, screen, evaluate, and classify patients who are at risk of, or have the diagnosis of, CKD. 3. Reduce the risk for progression of CKD to end-stage renal disease (ESRD) by applying appropriate, proven therapeutic interventions early in the disease process. 4. Describe the management strategies for anemia, bone disease, malnutrition, and electrolyte abnormalities in the later stages of CKD. Chronic Kidney Disease (CKD) CKD

• 27 million adults in the United States • 14% of adult Americans • 44% of persons > 65 y/o • > 650,000 Americans were treated for end-stage renal disease in 2015 • Incidence and prevalence of CKD among US adults has declined since 2006 CKD

• Patients with CKD • Have significantly increased risks of cardiovascular disease and stroke • More likely to die of cardiovascular disease than to require dialysis CKD—Risk Factors

• Autoimmune disease • Diabetes • Exposure to certain chemicals and environmental conditions - Lead, cadmium, arsenic, mercury, uranium • Exposure to certain drugs • Family history of CKD • Hypertension • Low birth weight • Low income or education • Lower urinary tract obstruction CKD—Risk Factors • Minority status (eg, blacks, American Indians, Asians, Pacific Islanders) • Neoplasia • Nephrolithiasis • Older age • Recovery from acute kidney injury • Reduction in kidney mass • Systemic infections • Urinary tract infections CKD—Etiology

• Diabetic kidney disease {ADA term} (39%) ‒ Type 2 diabetes 33% ‒ Type 1 diabetes 6% CKD—Etiology • Nondiabetic kidney disease (61%) ‒ Vascular diseases 25% • Hypertension, ischemic renal disease ‒ Glomerular diseases 18% • Primary: lupus nephritis, vasculitis, membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, immunoglobulin A nephropathy • Secondary: infections (eg, hepatitis B and C, human immunodeficiency virus–associated bacterial endocarditis), amyloidosis, heroin use, malignancy (eg, leukemia, Hodgkin lymphoma, carcinoma) ‒ Cystic diseases 7% • Polycystic kidney disease ‒ Tubulointerstitial disease 4% • Urinary tract infections, nephrolithiasis, obstruction, sarcoidosis, multiple myeloma, drug toxicity (eg, proton pump inhibitors, lithium, NSAIDs) Causes of CKD That Lead to ESRD and Transplant

• Diabetic kidney disease • HTN nephropathy •~ 25% of cases • Chronic glomerulonephritis • Polycystic kidney disease • Chronic pyelonephritis • Renal calculi 1. Stage 4 chronic kidney disease is defined as an estimated GFR of?

A. 60-90 B. 30-60 C. 15-30 D. < 15 Definition of CKD (KDOQI) •Kidney damage for > 3 mo •Structural or functional abnormalities • With or without decreased GFR • Pathological abnormalities or • Markers of kidney damage, including abnormal blood, urine, or imaging tests • Persistent albuminuria •GFR < 60 mL/min/1.73 for > 3 mo • With or without kidney damage Chronic Kidney Disease—Stages • Stage 1 ‒ Normal GFR > 90 mL/min with kidney damage • Stage 2 ‒ GFR between 60 to 89 mL/min with kidney damage • Stage 3 ‒ 3a—GFR between 45 and 59 mL/min (new) ‒ 3b—GFR between 30 and 44 mL/min (new) • Stage 4 ‒ GFR between 15 and 29 mL/min • Stage 5 = end-stage renal disease (ESRD) ‒ GFR < 15 mL/min Chronic Kidney Disease—Albuminuria (Albumin/creatinine) • A1 < 30 mg/g • Normal to mildly increased • A2 30 to 300 mg/g • Moderately increased - Microalbuminuria • A3 > 300 mg/g • Severely increased- Macroalbuminuria Chronic Kidney Disease—Evaluation

• Laboratory evaluation • GFR assessment • Protein excretion • Radiology evaluation • Kidney biopsy Baseline Laboratory Evaluation for CKD • UA with microscopic exam • Random or 24-hour urine creatinine clearance/estimated GFR • Random or 24-hour urine protein excretion • CBC • CMP • Serum calcium & phosphorous • Serum uric acid Additional Laboratory Evaluation for CKD • Serum protein electrophoresis (SPEP) • HepBsAg, Hepatitis C antibody, HIV • ANA • C3, C4, & CH50 • ANCA • Anti-GBM antibody Radiology Evaluation for CKD

• Renal ultrasound • CT scan of the kidneys and liver • MRI of the kidneys • Renal angiogram • Voiding cystourethrogram Renal Biopsy—Indications • Persistent hematuria with a low GFR or proteinuria • Nephrotic range proteinuria • CKD of unknown cause ‒ Normal or large kidneys on US 2. Nephrogenic systemic fibrosis most often occurs as the result of which of the following?

A. Chemotherapy with alkylating agent B. Hemodialysis C. Peritoneal dialysis D. MRI with gadolinium contrast Nephrogenic Systemic Fibrosis (NSF)

• Patients with stage 4-5 CKD (GFR < 30 mL/min), on dialysis, or with AKI, are at risk of developing NSF if gadolinium (Gd3+)-based contrast agents (Gd-CA) are used for MR imaging • Gd3+ attaches to endogenous anions (phosphate, hydroxide, carbonate, citrate), forming insoluble salts that deposit in tissues and initiate fibrosis • Risk may be as high as 18% Nephrogenic Systemic Fibrosis (NSF) • NSF is characterized by: ‒ Discolored skin plaques • Can be itchy and painful ‒ Contractures of joints • Potential for complete loss of range of motion ‒ Potentially widespread fibrosis • Liver, lungs, muscles, and heart • NSF may be more likely in patients with recent inflammatory event ‒ Surgical intervention, infection, or thrombotic event • No specific treatment, dialysis doesn’t help much • Avoid gadolinium contrast if GFR < 15 Chronic Kidney Disease—Management • Specific therapy, based on diagnosis • Slowing the loss of kidney function • Evaluation and management of comorbid conditions • Cardiovascular disease • Prevention and treatment of complications of decreased kidney function • Preparation for ESRD and kidney replacement Rx • Replacement of ESRD by dialysis and transplantation, if signs and Sxs of uremia are present Chronic Kidney Disease Management by Stage • Stage I GFR > 90 • Dx and Tx of comorbid conditions, slowing progression, CV risk reduction • Stage II GFR 60-90 • Dx and Tx of comorbid conditions, slowing progression, CV risk reduction • Stage III GFR 30-60 • Evaluating and Tx of complications- III b • Stage IV GFR 15-30 • Prep for kidney replacement • Nephrology referral • Stage V GFR < 15 (ESRD) • Replacement/dialysis Chronic Kidney Disease Self-Management

• Self-management strategies should be key components of a multifaceted treatment plan with attention to multiple behaviors: (C) ‒ Monitoring and treatment of hyperglycemia ‒ Blood pressure ‒ Nutrition ‒ Smoking cessation ‒ Exercise ‒ Adherence to medicines Monitoring CKD

• eGFR should be obtained at least yearly • More often in patients with: –GFR < 60 mL/min/1.73 m2 –Risk factors for faster progression Chronic Kidney Disease Medication Review • Review medications at all visits • Dosage adjustment based on level of CKD • Detection of potentially adverse effects on renal function or complications of CKD Chronic Kidney Disease Management - Key Components • Hypertension • Anemia • Acidosis • Hyperkalemia • Metabolic bone disease • Cardiovascular disease 3. Which of the following statements are true about CKD and hypertension?

A. Most patients with hypertension and elevated creatinine levels can be treated safely with ACE-I or ARB B. JNC-8 recommends a target BP of 130/90 C. ACC/AHA recommends a target BP of 140/90 in patients with albumin/creat > 300 mg/g D. HTN in patients with CKD is typically not responsive to diuretic therapy JNC-8 Guidelines (2/14)—BP Targets • General population ‒ > 60 y/o = 150/90 ‒ < 60 y/o = 140/90 • CKD ‒ 140/90 • DM ‒ 140/90 JNC-8 Guidelines—Initial Rx

• CKD ‒ ACE-I or ARB • African American ‒ Thiazide diuretic or CCB • Caucasian ‒ Thiazide diuretic, CCB, ACE-I, or ARB ACC/AHA Guidelines (11/17) BP Definitions

• Normal BP = <120 systolic and < 80 diastolic • Elevated BP = 120-129 systolic and < 80 diastolic • Stage 1 Hypertension = 130-139 systolic or 80-89 diastolic • Stage 2 Hypertension = >140 systolic or > 90 diastolic ACC/AHA Guidelines (11/17) BP Treatment Thresholds • General population ‒ No Clinical CVD and 10 yr ASCVD risk < 10% • 140/90 ‒ Clinical CVD or 10 yr ASCVD risk > 10% • 130/80 ‒ > 65 ambulatory/non-institutionalized • 130 systolic •CKD ‒ 130/80 • DM ‒ 130/80 ACC/AHA Guidelines (11/17) BP Treatment Target Goal (Based on SPRINT trial) • < 130/80 - For everyone ACC/AHA Guidelines (11/17) BP Treatment in CKD • CKD with macroalbuminuria (> 300 mg/g creatinine) ‒ ACE-I • Use ARB if ACE-I intolerant • CKD without macroalbuminuria (< 300 mg/g creatinine) ‒ Usual 1st line anti-hypertensives • Diuretic, ACE-I, ARB, or CCB KDOQI—Hypertension Guidelines (12/12) • Target BP for CVD risk reduction in CKD should be - < 140/90 mm Hg for patients with A/C < 30 mg/g - < 130/80 mm Hg for patients with A/C > 30 mg/g (B) KDOQI—Hypertension Guidelines • Antihypertensive agents in CKD should be prescribed as follows, when possible: - ACE or ARB if has DM or proteinuria (A) - Diuretics should be included in the antihypertensive regimen in most patients (A). - Choose additional agents based on cardiovascular disease-specific indications to achieve therapeutic and preventive targets and to avoid side effects and interactions (B). KDOQI—Hypertension Guidelines

• Long-acting agents should be used when possible (B). • Two agents may be considered as initial therapy for SBP > 20 mm Hg above goal (C). KDOQI—Hypertension Guidelines

• ACE-I or ARB ‒ Patients with diabetic kidney disease • Albumin/creat > 30 mg/g or eGFR < 60 • With or without hypertension ‒ Patients with non-diabetic kidney disease • Albumin/creat ≥ 300 mg/g (or urinary albumin > 300 mg/24 hrs) • With or without hypertension KDOQI—Hypertension Guidelines

• ACE-I & ARBs can be used safely in most patients with CKD. ‒ Patients should be monitored for dec BP, dec GFR, & hyperkalemia (A) ‒ ACE-I or ARB can be continued if: • GFR decline over 4 months is < 30% from baseline value (B); • Serum potassium is ≤ 5.5 mEq/L (B). • ACE-I & ARBs should be used at mod to high dose (A). • ACE-I & ARBs can be used as alternatives to each other (B) ‒ ACE-I & ARBs should not be used together KDOQI—Hypertension Guidelines

• Most patients with CKD should be treated with a diuretic (A) ‒ Use thiazide diuretics if GFR ≥ 30 mL/min (CKD 1-3) (A) ‒ Use loop diuretics if GFR < 30 mL/min (CKD 4-5) (A) • Loop diuretics in combination with thiazides can be used for patients with ECF volume expansion/edema (A) • Potassium-sparing diuretics should be used with caution: ‒ GFR < 30 mL/min (CKD Stages 4-5) (A) ‒ With ACE-I or ARBs (A) ‒ Risk factors for hyperkalemia (A) KDOQI Hypertension Nutrition Guidelines • Dietary sodium intake of less than 2.4 g/d should be recommended in most adults with CKD and hypertension (A). 4. Which of the following is true regarding anemia in CKD?

A. Packed red cell transfusion is indicated for Hb < 10 B. Target Hb for patients with CKD-4 receiving EPO is 13 g/dL for women and 14 g/dL for men C. Most anemia in patients with CKD is due to iron deficiency D. Therapy with erythropoiesis-stimulating agents is associated an with increased risk of MI and thromboembolic events KDOQI—Anemia Guidelines

• Hb testing should be carried out annually in all patients with CKD • Dx of anemia should be made and further evaluation should be undertaken if Hb ‒ < 13.5 g/dL in adult males ‒ < 12.0 g/dL in adult females KDOQI—Anemia Guidelines

• Initial assessment of anemia should include the following tests: ‒ CBC ‒ Absolute reticulocyte count ‒ Serum ferritin ‒ Serum transferrin saturation • Serum iron/TIBC Anemia

•Anemia of Chronic •Iron Deficiency Disease Anemia

Ferritin normal Ferritin low Serum Iron low Serum Iron low TIBC low TIBC high Fe/TIBC > 15% (normal) Fe/TIBC < 15% (low) Anemia of Chronic Disease

• Chronic kidney disease • Chronic infections • Chronic inflammatory disorders • Malignancy • Malnutrition Anemia of Chronic Disease—Rx

• Treat underlying cause of the ACD • Erythropoiesis-stimulating agent ‒ Continuing symptomatic anemia despite Rx of underlying cause • Red cell transfusion ‒ If continue to have symptomatic anemia despite • Treatment of the underlying cause • Use of an erythropoiesis-stimulating agent Erythropoietin (EPO)

• Glycoprotein growth factor • 90% produced by the kidney • Decreased O2 delivery ‒ Primary stimulus to erythropoietin release ‒ Due to anemia or hypoxemia Erythropoiesis-Stimulating Agents (ESAs) • Darbepoetin alfa (Aranesp) • Epoetin alfa (Epogen, Procrit, Retacrit) • Epoetin beta (Mircera) • Equally effective • Supplemental iron - Maintain transferrin saturation ≥ 20% - Maintain serum ferritin ≥ 100 ng/mL Erythropoiesis-Stimulating Agents (ESAs) • CKD ‒ Consider use if Hb < 11 • < 10 in dialysis patients • Black box warnings ‒ Increased mortality and serious CV events in CKD • MI, CVA, CHF ‒ Increased mortality and tumor progression in cancer patients ‒ Increased thromboembolic events in surgery patients • Contraindicated in uncontrolled hypertension KDOQI—Anemia Guidelines • Red blood cell transfusions should be used judiciously in patients with CKD - Potential development of sensitivity affecting future kidney transplantation • No specific Hb trigger requires transfusion • Target Hb for EPO is not a transfusion trigger 5. The most common acid base abnormality seen in patients with CKD is:

A. Metabolic acidosis B. Metabolic alkalosis C. Respiratory acidosis D. Respiratory alkalosis Metabolic Acidosis—Increased AG {MUDPILES} • Renal failure (uremia) • DKA • Alcoholic ketoacidosis • Lactic Acidosis • Glycols • Salicylates Metabolic Acidosis and CKD

• Due to decreased hydrogen ion excretion • HCO3 < 22 associated with ‒ Increased progression of CKD ‒ Increased overall mortality KDOQI—Metabolic Acidosis Guidelines • In CKD Stages 3, 4, and 5

- Serum levels of total CO2 should be maintained at ≥ 22 mEq/L Treatment of Acidosis in CKD

• Na bicarbonate ‒ 0.5-1 mEq/kg/day ‒ 1-3 grams/day • Na citrate (eg, Shohl’s solution) ‒ Metabolized to bicarbonate ‒ Less bloating ‒ Do not use with aluminum antacids • Enhances intestinal aluminum absorption • Ca citrate • Ca acetate (PhosLo, Eliphos, Phoslyra) • Ca carbonate (Tums) 6. Which of the following patterns is commonly found in patients with CKD?

A. High Ca++, low PO4, high PTH B. Low Ca++, high PO4, high PTH C. High Ca++, high PO4, low PTH D. Low Ca++, high PO4, low PTH CKD-MBD • Chronic kidney disease-mineral and bone disorder (CKD-MBD) • Renal osteodystrophy ‒ Older term, used to define bone pathology observed on biopsy • Characterized by ‒ Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism ‒ Abnormalities in bone turnover, mineralization, volume linear growth, or strength, and/or ‒ Extraskeletal calcification CKD-MBD • Secondary hyperparathyroidism ‒ Encompasses most of the biochemical abnormalities that characterize CKD-MBD • Low Ca++, high PO4, high PTH • Causes of secondary hyperparathyroidism ‒ Phosphate retention due to decreased GFR ‒ Decreased free Ca++ ‒ Decreased 1,25-dihydroxyvitamin D KDOQI—MBD Guidelines (2017 update) • Measure serum calcium, PO4, intact PTH in all patients with GFR < 60 mL/min (CKD-3,4 &5) • Lower elevated serum PO4 toward the normal range KDOQI—MBD Guidelines

• Dietary phosphorus should be restricted to 800 to 1,000 mg/day when serum PO4 levels are elevated • Use PO4 binders if PO4 or intact PTH levels cannot be controlled despite dietary phosphorus restriction Treatment of Hyperphosphatemia

• Non-calcium-containing binders ‒ Now 1st line agents ‒ Better with normal or high Ca++ ‒ On Vit D supplementation •Non-calcium binders ‒ Sevelamer (Renegel, Renleva) 800-1600 mg TID ‒ Lanthanum (Fosrenol) 1500-3000 mg/day Treatment of Hyperphosphatemia

• Calcium-containing binders ‒ Restrict their dose/use per KDIGO ‒ Usually cheaper • Calcium-containing binders ‒ Calcium carbonate ‒ Calcium acetate (PhosLo, Eliphos, Phoslyra) • 1300-2600 mg with each meal • Avoid aluminum hydroxide ‒ May cause aluminum toxicity KDOQI—MBD Guidelines

•In patients with risk factors for osteoporosis, BMD testing (DEXA) may be used to assess fracture risk if results will alter therapy •Bone x-rays are not indicated for the assessment of bone disease of CKD Calciphylaxis

•Calcific uremic arteriolopathy •Calcium deposits in small vessels in skin/fat •Mostly occurs in CKD5 on dialysis •Extremity pain, non healing ulcers, infection •Rx- sodium thiosulfate •Poor prognosis – high 1 yr mortality Diabetic Kidney Disease • CKD develops in 20-40% of diabetics • Diabetic kidney disease is the leading cause of ESRD • Persistent microalbuminuria (30-300 mg/24h) is a marker for the development of diabetic kidney disease in type 2 diabetics • Progression to macroalbuminuria (> 300 mg/24h) predicts progression to ESRD Diabetic Kidney Disease

• Screening for albuminuria should be initiated at time of diagnosis of type 2 diabetes as ~7% already have microalbuminuria • Screen type 1 diabetics 1-5 years from initial diagnosis • If absent, continue to screen annually • Abnormal results should be confirmed with 2 out of 3 samples over 3-6 months due to variability in urine albumin excretion (UAE) Diabetic Kidney Disease

• Random spot urine for albumin-to-creatinine ratio is preferred ‒ Normal: < 30 mg/g creatinine ‒ Microalbuminuria: 30-299 mg/g ‒ Macroalbuminuria: >300 mg/g Diabetic Kidney Disease

• Progression from micro- to macroalbuminuria can be delayed with intensive blood glucose and blood pressure control • ACE inhibitors and ARBs are first-line therapy in presence of albuminuria, even if blood pressure is normal • Anti-proteinuric effect of ACE/ARB is independent of blood pressure lowering KDOQI—Diabetes & CKD

• Use ACE-I or an ARB in normotensive patients with diabetes and albuminuria levels > 30 mg/g who are at high risk of CKD or its progression. (2C) • Do not use ACE-I or ARB for the primary prevention of CKD in normotensive normoalbuminuric patients with diabetes and normal renal function. (1A) ACE/ARB Who Should Receive Them • Diabetes ‒ CKD • Albuminuria > 30 mg/g • GFR < 60 ‒ Hypertension • Non-diabetic CKD ‒ Albuminuria > 300 mg/g ‒ Hypertension Diabetic Kidney Disease

• Reduction of dietary protein intake to 0.8- 1.0 g/kg/d in earlier stages and to 0.8 g/kg/d in later stages of CKD may improve renal function and is recommended (B) CKD- Immunizations •GFR < 30 ml/min (CKD4 & 5) - Influenza • annually - Pneumococcal vaccine • PCV 13 initially • PPV -23 > 8 wks later • then again 5 yrs later • then again > 65 (> 5 yr interval) - Hep B series 7. Indications for nephrology referral in patients with CKD include which of the following? A. GFR < 30 mL/min B. BP > 130/80 despite treatment with an ACE-I and diuretic C. Presence of a new recently trained, highly indebted nephrologist in town D. Diabetes and a urine microalbumin/creatinine ratio of 30 - 300 mg/g CKD: Indications for Nephrology Referral • Acute, complex, or severe cardiovascular disease • Anemia of CKD • Bone and mineral disorder of CKD • Difficult to manage adverse effects of medications • Hyperkalemia • K+ > 5.5 mEq/L (despite treatment) CKD: Indications for Nephrology Referral • Refractory proteinuria ‒ Urinary microalbumin/creatinine ratio > 300 mg/g • Resistant hypertension ‒ Target blood pressure not achieved with use of at least three BP drugs • Stage 4 CKD ‒ GFR < 30 mL/minute • Unexplained decrease in GFR > 30% over 4 months CKD—Evidence-Based Guidelines

• ACE inhibitor or an angiotensin II receptor blocker ‒ Non-diabetic kidney disease with random urine microalbumin/creatinine ratio > 300 mg/g or hypertension ‒ Diabetes with microalbumin/creatinine > 30 mg/g, CKD or hypertension (A) • Concurrent use of ACE inhibitors and ARBs ‒ Should be avoided because of symptomatic hypotension and worsening kidney function (A) • Erythropoiesis-stimulating agents ‒ Hb goal should not exceed 11 g/dL Answers

1. C 2. D 3. A 4. D 5. A 6. B 7. A Thank you! Supplemental Slides- Hyponatremia Hyponatremia

•Normal Na+ = 135 - 145 •Hyponatremia −< 135 −< 125 = severe Hyponatremia - Symptoms

•Acute hyponatremia −Na = 125-130 • Nausea, malaise −Na < 115-120 • HA, lethargy, obtundation, seizures, coma, apnea 84 •Chronic hyponatremia • Fatigue, nausea, dizziness, confusion, lethargy, gait dysfunction, muscle cramps Hyponatremia

•Volume status −Hypovolemic −Euvolemic

85 −Hypervolemic Hyponatremia

•Hypovolemic −Dehydration • vomiting • diarrhea • diuretic use • adrenal insuffiency Hyponatremia

•Euvolemic −SIADH −Primary polydipsia Hyponatremia

•Hypervolemic −HF −Nephrotic syndome −Cirrhosis Hyponatremia - Dx

•Differentiate between hypovolemic, euvolemic, or hypervolemic (SOR C) −History −Extravascular fluid volume assessment on physical exam −Spot urine Na −Urine specific gravity Hyponatremia - Dx

•Euvolemic (hypo-osmolar) hyponatremia −Urine osmolarity −Serum osmolaity −Urine osm > serum osm • SIADH −Urine osm < serum osm • Excess H2O intake/primary polydipsia Hyponatremia - Rx

•Hypovolemic −Dehydration - Hydration • Vomiting/diarrhea - Antiemetic/antidiarrheal agents • Diuretics - Stop diuretics −Adrenal insufficiency • Hydrocortisone/solu-medrol Hyponatremia - Rx

•Euvolemic −SIADH • Treat underlying problem if identified • Fluid restriction • 1,000 – 1,500 ml/24 hrs • Avoid hypotonic fluids • If IV needed, use 0.9% NS • 3% saline if • Na < 120 & severely symptomatic • 100 ml or 1 ml/kg bolus Hyponatremia - Rx •Euvolemic −SIADH • Loop diuretic • Vasopressin receptor antagonists - tolvaptan ➢Oral, selective for the V2 receptor - conivaptan ➢IV, blocks both V2 and V1a receptors −Primary polydipsia • Fluid restriction Hyponatremia

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No part of the materials/content may be copied, duplicated, distributed or retransmitted

in any form or medium without the prior permission of the applicable copyright owner.

Maternity Care, Part 1

David G. Weismiller, MD, ScM, FAAFP Department of Family and Community Medicine University of Nevada, Las Vegas School of Medicine Disclosure Statement

All individuals in a position to control content for this session have indicated they have no relevant financial relationships to disclose. Learning Objectives

1. Cite the content and sequence of routine prenatal care. 2. Recall the laboratory and imaging tests commonly used in prenatal care. 3. Define the diagnosis of diabetes in pregnancy.

1. Nausea and vomiting in early pregnancy is very common. Although often called “morning sickness,” it can be any time of the day. Which one of the following is considered first-line pharmacotherapy?

A. Diphenhydramine, 25–50 mg orally every 4–6 hours B. Ondansetron, 4 mg orally every 8 hours

C. Vitamin B6, 10–25 mg orally in combination with Doxylamine, 12.5 mg orally every 6 to 8 hours D. Methylprednisolone, 16 mg orally every 8 hours Nausea and Vomiting of Pregnancy

• Etiology – Unknown • Prevalence – Nausea 50-80% – Vomiting and retching 50% • Recurrence 15-81% • Typically starts within four to eight weeks of gestation and is expected to subside between 13 and 14 weeks – Perception of the severity of her symptoms, her desire for treatment, and the potential effect of treatment on her fetus all influence clinical decision making • Early treatment of nausea and vomiting of pregnancy may be beneficial to prevent progression to hyperemesis gravidarum Nonpharmacologic Therapy • Dietary measures – Eating frequent small meals and avoid smells and food that cause nausea – Bland food, high in carbs, low in fat (salty foods can be tolerated in the morning, sour and tart liquids are tolerated better than water) • Emotional support – Although not strongly associated with psychologic illness, some may become depressed or have other affective changes Management

• Convert prenatal vitamin to folic acid 1 supplement only

• Ginger capsules 250 mg QID 1 Persistent symptoms

• Consider P6 acupressure with wrist bands 1 Pharmacologic Options

• Vitamin B6 (pyridoxine) 10-25 mg po (alone or in combination with Doxylamine 12.5 mg po), TID to QID. Adjust schedule/dose according to severity of patient’s symptoms OR – Doxylamine is available as the active ingredient in some OTC sleep aids; one half of a scored 25-mg tablet can be used to provide a 12.5-mg dose of doxylamine.

• Vitamin B6 10 mg/Doxylamine 10 mg combination product, two tablets po at bedtime initially, up to four tablets per day (one tablet in the morning, one tablet in midafternoon, and two tablets hs) OR

• Vitamin B6 20 mg/Doxylamine 20 mg combination product, one tablet po at bedtime initially, up to two tablets per day (one tablet in the morning and one tablet hs.) 2. Which one of the following tests is recommended in routine prenatal care?

A. Serologic testing for herpes simplex virus infection B. Pap cytology in each pregnancy C. Cystic fibrosis carrier screening before conception D. Screening for asymptomatic bacteriuria by urine culture Initial Prenatal Visit Lab Tests

• Blood group/Rh • Urine culture (11-16 weeks EGA) • Antibody screen − Asymptomatic bacteriuria • H/H (Screening for anemia) • Sickle cell screen • Rubella antibody titer − African American or Caribbean − 2001 – CDC. Interval to 1 month descent for pregnancy after rubella vaccine • HIV screening • Syphilis screen • Varicella screening − CDC and USPSTF – three times if • +/− CF screening high risk • GDM screening • Hepatitis B virus surface antigen − Intake for Type 2 DM (if increased • Cervical cytology (if needed) risk) ??? • STI − Routine 24-28 weeks − GC/chlamydia Anemia in Pregnancy ACOG Practice Bulletin – July 2008 • Iron supplementation decreases the prevalence of anemia at delivery (Level A) • Iron deficiency anemia during pregnancy has been associated with an increased risk of (Level B) − LBW − Preterm delivery − Perinatal mortality • All pregnant women should be screened for anemia (Level C) − (+) iron deficiency anemia (Hgb < 11 mg/dL (first trimester), < 10.5 (second), < 11 (third): treat with supplemental iron, in addition to prenatal vitamin. Obstetrics and Gynecology. 2008;112(1) 201-207. (Affirmed 2015) USPSTF – 2015

• The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for iron deficiency anemia in pregnant women to prevent adverse maternal health and birth outcomes. • The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of routine iron supplementation for pregnant women to prevent adverse maternal health and birth outcomes. USPSTF Recommendations for STI Screening in Pregnancy • Hepatitis B, Syphilis, HIV − All women HIV Testing

• CDC 2006, 2008; ACOG 2008; USPSTF 2005, 2019 − All pregnant women offered HIV testing at the first prenatal visit and in the third trimester • Routine opt-out HIV testing • Decreased maternal-fetal transmission with detection and treatment • Rapid testing in labor − if undocumented HIV status − Positive test − initiate antiretroviral prophylaxis (with consent) without waiting for confirmatory test.

Centers for Disease Control and Prevention. US Public Health Service Task Force’s Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States, July 2008. CDC. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health care settings. MMWR. 2006;55(RR-14):1-17. USPSTF. Screening for HIV: Recommendation statement. Ann Intern Med. 2005; 143:32-37. ACOG Committee Opinion Number 418, September 2008. USPSTF Recommendations for STI Screening in Pregnancy • Hepatitis B, Syphilis, HIV − All women • Chlamydia§ and Gonorrhea − < 25 years of age − Engaging in high-risk sexual behaviors • Multiple sex partners • Incarcerated • Illicit drug use • Does not recommend routine screening for chlamydia in pregnant women not at increased risk; it notes that individual circumstances may support screening. • No recommendation made about screening for gonorrhea in pregnant women not at increased risk (Category I)

§CDC recommends universal testing for chlamydia in pregnancy Asymptomatic Bacteriuria

• Defined − > 100,000 cfu/mL of a single bacterial species • E. coli is most commonly isolated. • Lactobaccilli and Staphylococcus species (other than S. saprophyticus) may be presumed to be contaminants. • Present in 2-7% of pregnant women − Higher preterm delivery rate than women without bacteriuria • Culture at first prenatal visit − Unusual for women who do not have Asx bacteriuria at initial visit to develop later in pregnancy − Exception? Sickle cell trait • q trimester urine screen 3. Which of the following antibiotics should be used in the empiric treatment of asymptomatic bacteriuria?

A. Ampicillin B. Clindamycin C. Cephalexin D. Ciprofloxacin Treatment • Seven-day course − e.g., cephalexin, 250 mg po QID • Single-dose regimens not widely studied in pregnancy • Ampicillin should not be used − high rates of resistance. • Urine culture after therapy to ensure cure − Culture will also identify patients with persistent or recurrent bacteriuria. • Consider antibiotic suppressive dose (once daily antibiotic dosing) until delivery Antibiotics in Pregnancy

• Considered Safe • Typically Avoid • Amoxicillin • Tetracyclines • Ampicillin • Nitrofurantoin* • Clindamycin • Sulfonamides* • Erythromycin • Penicillin • Cephalosporins * Prescribing sulfonamides or nitrofurantoin in the first trimester is still considered appropriate when no other suitable alternative antibiotics are available. During the second and third trimesters, sulfonamides and nitrofurantoin may be used as first-line agents for infections.

ACOG Committee Opinion #494: Sulfonamides, Nitrofurantoin, and Risk of Birth Defects. Obstet Gynecol. 2011;117(6):1484-1485. Treatment of Asymptomatic Bacteriuria

Antibiotic treatment Outcome compared to placebo RR NNT (95% CI) Clearing asymptomatic 0.25 (0.14-0.48) 1.6 bacteriuria Incidence of pyelonephritis 0.23 (0.13-0.41) 6.7 Incidence of low 0.66 (0.49-0.89) − birthweight babies Incidence of preterm − 20 delivery Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database of Systematic Reviews. 2001;(2):CD000490. Herpes

• All patients and their partners should be asked about a history of genital and orolabial HSV infection. • Rates of vertical transmission at delivery − Primary HSV infection 50% − Non-primary – first episode 33% − Recurrent 0-3% • Genital herpes acquired during pregnancy does not seem to increase rates of neonatal illness or congenital HSV infection as long as HSV seroconversion has completed by time labor begins. Suppressive Therapy > 36 Weeks ACOG 2007 • Women with active recurrent genital herpes should be offered suppressive viral therapy at or beyond 36 weeks of gestation (Level B).

Suppressive treatment after 36 weeks Decreased Risk of recurrent genital herpes at delivery 75% Rate of C/S for recurrent genital herpes 40% Viral detection at delivery using culture or PCR 90%

Indication Acyclovir Valacyclovir Daily suppression 400 mg po TID daily from 36 500 mg po BID daily from 36 weeks until delivery weeks until delivery Evidence of Immunity to Varicella

• Screening for Varicella in pregnancy (CDC 2006) − Recommend routine screening for varicella through history − If negative/unsure history, obtain varicella titer. − Recommend offering vaccination postpartum, if varicella is nonimmune. Cystic Fibrosis Recommendations

• Information about CF screening made available to all couples − Reasonable to offer carrier screening to all couples regardless of race or ethnicity as alternate to selective screening • CF carrier screening should be offered before conception or early in pregnancy − both partners are of Caucasian, European, or Ashkenazi Jewish ethnicity. − May elect to use either sequential or concurrent carrier screening

ACOG Committee Opinion No. 325. Update on Carrier Screening for Cystic Fibrosis. Obstet Gynecol. 2005;106:1465-1468. No Routine Screening

• Hepatitis C − CDC – screen women at increased risk • HPV − Per USPSTF guidelines • < 30 – reflex (ASCUS) q 3 years • > 30 – routine with Pap q 5 years • Parvovirus B-19 Parvovirus B-19 • Embryotoxic, not teratogenic − Infection 1st trimester – miscarriage − Peaks early 2nd trimester – fetal anemia, hydrops fetalis, and stillbirth • Fetus at greatest risk 3-6 weeks after maternal infection − Screening: Maternal IgG and IgM • Fetal monitoring: Weekly U/S and middle cerebral artery Doppler − If hydrops and anemia are present, RBC transfusion may be needed Intimate Partner Violence USPSTF – October 2018

• Screen all women of childbearing age for intimate partner violence regardless of whether symptoms are present. Grade: B recommendation −For women who screen positive, physicians should provide or refer them to intervention services. −Note: Men and women with a h/o IPV are at risk for depression (SOR B) Intimate Partner Violence • Risk assessment during pregnancy should universally include identification of women who are victims of domestic violence • May involve threatened or actual −Physical −Sexual −Verbal −Psychologic Screen at 8, 24, and Screening Questions 32 weeks EGA

Within the last year, have you been hit, slapped, kicked, or otherwise physically hurt by someone?

Since you have been pregnant, have you been hit, slapped, kicked, or otherwise physically hurt by someone?

Within the last year, has anyone forced you to have sexual activities?

If the screen is (+), follow appropriate medical/legal mandates for reporting requirements for state/branch of service. 4. Per ACOG 2013, at 24 weeks gestation you perform a 1-hour glucose tolerance test, which is elevated at 166 mg/dL. You would next:

A. Repeat the 1-hour glucose tolerance in one week. B. Have the patient see the dietician for diabetic diet information. C. Order a 3-hour glucose tolerance test. D. Start low-dose metformin. Gestational Diabetes

• Condition is increasing as obesity and older age at pregnancy become more common. • Increased risk − Gestational hypertension − Preeclampsia − Cesarean delivery − 7-fold increased risk of developing diabetes later in life Detection of GDM

Organization Recommendation Comments ACOG (2018) • Use a 2-step method at 24-28 weeks (Level Use a blood glucose level of either 135 B). or 140 mg/dL with factors such as • Screen for undiagnosed type 2 diabetes at community prevalence rates of GD the first prenatal visit in those with risk factors determining the cutoff. USPSTF (2014) • Screen asymptomatic women after 24 weeks Goal was not to look at the performance (Grade B). or whether one method was better than another for screening. • Current evidence is insufficient to assess the Found treating can significantly reduce balance of benefits and harms of screening the risk of preeclampsia, macrosomia, for GD in asymptomatic pregnant women shoulder dystocia. before 24 weeks of gestation (Grade I). ADA (2014) • Screen for undiagnosed type 2 diabetes at Updated Guidelines: Use either: the first prenatal visit in those with risk factors 1. 1-step method (75g OGTT) • Screen at 24-28 weeks if not previously 2. 2-step method known to have diabetes. RISK FACTORS (Screen early) … ACOG, NIDDK,ADA • Patient is overweight with BMI of 25 (23 in Asian Americans), and ONE of the following: −Physical inactivity −Known impaired glucose metabolism −Previous pregnancy history of • GDM • Macrosomia (>4000 g) • Stillbirth −Hypertension (140/90 or being treated) −HDL cholesterol < 35 mg/dL −Fasting TG > 250 −PCOS, acanthosis nigricans, nonalcoholic steatohepatitis, morbid obesity and OTHER conditions associated with insulin resistance −HgbA1C>5.7%, impaired glucose tolerance or impaired fasting glucose −ASCVD −High risk ethnicity ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol. 2018;131(2):e49-e64. Two-Step Approach in USA ACOG 2018, ADA 2014 • 24-28 weeks (routine) • Initial screening: 50 g oral glucose load (glucose challenge test) • > 135 or > 140 mg/dL* ➔ 3-hour OGTT • Note: > 190, > 90% abnormal 3-hour • 3-hour OGTT ± ➔ 2 or more abnormal values = (+) GDM • Overnight fast, 100 g glucose polymer • Abnormal plasma blood glucose: > fasting 95 mg/dL, 1h 180, 2h 155, 3h 140 *Either threshold acceptable, ACOG 2018 (Level C). ± Can also be used as a 1-step method for high-risk women or in areas in which the prevalence of insulin resistance is 5% or higher (eg, southwestern and southeastern US). Screening Later in Pregnancy

• Open neural tube defects − Maternal serum alpha fetoprotein • Aneuploidy − Quad screen • Screening sonogram • Anemia • Group B Streptococcus Summary MSAFP and Quad Screen • Maternal blood sample (Calculated risk) − High MSAFP: Open neural tube defect − Low • Trisomy 21 • Low MSAFP, high hCG, low estriol, high DIA • Trisomy 18 • Low levels of all four analytes • Most accurate when performed between 16 and 18 weeks EGA • Most common reason for false positive is incorrect assignment of EGA Detection Rates Test* Markers Term risk Sensitivity Specificity Positive cutoff (%) (%) Predictive Value (%) First Nuchal translucency, free 1 in 325 83 95 4 Trimester β-hCG, PAPP-A§, Screening maternal age Quadruple Unconjugated estriol; α- 1 in 385 77 95 2 Screening fetoprotein, free β-hCG, (Second Inhibin A, maternal age trimester) Integrated Nuchal translucency, free 1 in 200 87 98 10 Screening β-hCG, PAPP-A, maternal (First and age, Unconjugated estriol; Second α-fetoprotein, free β-hCG, trimesters) Inhibin A, maternal age * All screening tests have a positive rate of ~5% (most of which are false positives) and a detection rate of 69-87%. §PAPP-A: pregnancy-associated plasma protein A Comparison of Traditional and Cell-Free Screening Tests Traditional Aneuploidy Screening Cell-free DNA Screening Recommended for primary screening Primary or secondary screening modality • ACOG and SMFM recommend as first-line • As primary screening, may be more screening for low-risk pregnancies appropriate for high-risk pregnancies • Should not be performed concurrently with, or • May be offered as a secondary screening test after, cell free DNA screening if traditional screening is abnormal Detection rate 80% for trisomy 21 and trisomy 18 Detection rate 99% for trisomy 21, 96% for with EITHER first-or second-trimester screening. trisomy 18, and approximately 90% for trisomy Detection rate about 94% for Trisomy 21 and 13 and monosomy X 93% for trisomy 18 with integrated screening. Accurate GA assessment is essential for Gestational age is not used to calculate results calculating the screening result, and screening Screening may be performed at any point must be performed within specific GA. beyond 9–10 wk of gestation US minor markers (soft signs) are often used to Ultrasound minor markers (soft signs) are not modify the aneuploidy risk. used to modify the aneuploidy risk 5. According to the CDC, all women of childbearing age should consume how much folic acid on a daily basis?

A. 4 mg B. 0.4 mg C. 1 mg D. 0.8 mg Folic Acid Supplementation

• All women of childbearing age: 0.4 mg/day (1992 CDC) − Periconceptional use: Estimated to reduce risk of NTD by 70- 80% • History NTD: 4 mg/day • 1-3 months before, continue through first 3 months of pregnancy. • Note: IOM recommends 600 mcg/day for adult women aged 19 and older and 800 mcg daily for adolescents aged 14-18 years.

Wald et al. Quantifying the effect of folic acid. Lancet. 2001;358:2069-73. Folic Acid Supplementation With Epilepsy • 4 mg/day − Valproate − Carbamazepine • 800 μg/day − Other AEDs • 1-3 months prior to conception and continue through first trimester. ✔Low serum folate levels in women with epilepsy are independently associated with an increased risk of major fetal malformations. ✔Not conclusively determined if folic acid supplementation prevents NTDs in women receiving antiepileptic drugs (AEDs). 6. According to ACOG, which of the following statements best characterizes the use of sonography in pregnancy?

A. It has the ability to diagnose minor fetal anomalies. B. It is best carried out at 12 weeks estimated gestational age. C. It is an accurate method of determining placental location. D. Routine use is recommended. Screening Ultrasound Defined

• Sonographic assessment of the pregnant abdomen between 16 and 20 weeks EGA (second trimester), in the absence of specific indications for a second- trimester ultrasound. Screening Ultrasound The basic sonographic examination should provide the following information: • Fetal number • Fetal presentation • Documentation of fetal life • Placental location • Fetal biometry • Assessment of amniotic fluid volume • Assessment of gestational age • Survey of fetal anatomy for gross malformations • Evaluation for maternal pelvic masses Ultrasound in Pregnancy Summary – ACOG February 2009 • US examination is an accurate method of determining GA, fetal number, viability, and placental location (Level A). • Ability to diagnose major fetal anomalies established (Level A) • Specific indications are the best basis for use in pregnancy. ACOG − Optimal timing in the absence of specific indications is at 18- ACR 20 weeks. AIUM ACOG Practice Bulletin No. 101. Ultrasopnography in Pregnancy. Obstet Gynecol. 2009;113:451-61. 7. An 18 yo G1 P0 at 40 5/7 weeks presents stating that she thinks her water broke 18 hours ago. An exam confirms ROM. The patient is afebrile with a non-tender uterus; FHR tracing reassuring. She is NOT contracting. A GBS culture obtained 4 weeks ago was (−). Patient with NKDA. In addition to induction of labor, which one of the following is the most appropriate management for this patient?

A. No antibiotic prophylaxis for the fetus B. Ampicillin, 2 g IV initially, then 1 g IV q 4 h until delivery C. Clindamycin, 900 mg IV q 8 h until delivery D. Vancomycin, 1 g IV q 12 h until delivery Group B Streptococcus

• Universal screening culture recommended 36-0/7 and 37-6/7 weeks (NEW July 2019 ACOG and AAP) − Provides a five-week window for valid culture results that includes births that occur up to a gestational age of at least 41-0/7 weeks − Swab lower (2 cm) vaginal (introitus) followed by rectum (insert swab into anus 1 cm) using same swab • Two groups DO NOT get screened − Previous infant with early onset GBS Sepsis − GBS bacteriuria (any culture, any number of cfu/mL) during pregnancy • Order susceptibility testing on isolates (if PCN allergic) • Women who present in labor with unknown GBS status but who had known GBS colonization during a previous pregnancy are now candidates for GBS intrapartum prophylaxis. (NEW July 2019 ACOG and AAP) − Rationale for change – women who were GBS-colonized during a previous pregnancy have a 50% chance of GBS carriage in the current pregnancy • Women with negative GBS cultures within 5 weeks of delivery do not require antibiotics even if risk factors develop ✔Delivery at < 37 weeks of gestation ✔Amniotic membrane rupture > 18 hours ✔Intrapartum temperature > 100.4°F (> 38.0°C) Prevention of Group B Streptococcal Early-Onset Disease in Newborns. ACOG Committee Opinion Summary No.782. Obstet Gynecol. 2019;134(1):206-210 Prevention of Group B Streptococcal Early-Onset Disease in Newborns: ACOG Committee Opinion Summary, Number 782. Obstetrics & Gynecology. 134(1):206-210, July 2019. DOI: 10.1097/AOG.0000000000003335

• Two hours of antibiotics exposure has been shown to reduce GBS vaginal colony counts and decrease the frequency of a clinical neonatal sepsis diagnosis • Shorter duration of recommended intrapartum antibiotics is less effective than four or more hours of prophylaxis

[ Figure 3]. Determination of Antibiotic Regimen for Group B Streptococcus Prophylaxis in Labor. Abbreviations: GBS, group B streptococcus; IV, intravenous. *Individuals with a history of any of the following: a non-urticarial maculopapular (morbilliform) rash without systemic symptoms; family history of penicillin allergy but no personal history; nonspecific symptoms such as nausea, diarrhea, yeast vaginitis; patient reports history but has no recollection of symptoms or treatment. +Individuals with a history of any of the following after administration of a penicillin: urticarial rash (hives), intense pruritis, anaphylaxis, angioedema, laryngeal edema, respiratory distress, hypotension, immediate flushing or rare delayed reactions, such as eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Individuals with recurrent reactions, reactions to multiple beta-lactam antibiotics, or those with positive skin testing also are considered high risk. Modified from Verani JR, McGee L, Schrag SJ. Prevention of perinatal group B streptococcal disease: revised guidelines from CDC, 2010. Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). MMWR Recomm Rep 2010;59(RR-10):1-36. (This Committee Opinion, including Table 1, Box 2, and Figures 1-3, updates and replaces the obstetric components of the CDC 2010 guidelines, "Prevention of Perinatal Group B Streptococcal Disease: Revised Guidelines From CDC, 2010.")

3 8. A 26 yo female presents with lower abdominal pain and vaginal bleeding. Her last menstrual period was 7 weeks ago. A urine pregnancy test is positive, and a quantitative β-hCG level is 2500 mIU/mL. Transvaginal ultrasonography shows no evidence of an intrauterine gestational sac. Baseline laboratory tests, including a CBC, liver function tests, and renal function tests, are all normal. She is treated with a single dose of IM methotrexate at 50 mg/m2 of body surface. Four days later the patient presents for reevaluation, and her quantitative β-hCG level is found to be 3800 mIU/mL. 7 days later the quantitative β-hCG level is found to be 4400 mIU/mL. Which of the following is the most appropriate next step?

A. A repeat dose of methotrexate, 50 mg/m2 of body surface B. Repeat transvaginal ultrasonography to evaluate for a viable intrauterine pregnancy. C. Laparoscopy with salpingostomy D. Expectant management Ectopic Pregnancy

• Ruptured ectopic pregnancy accounts for ~10% of all maternal deaths • Most strongly associated risk factors with ectopic pregnancy ✔Previous tubal surgery ✔Sterilization ✔Prior ectopic pregnancy • Early diagnosis critical ✔Linear salpingostomy is a tube-saving procedure. ✔Pregnancy outcomes with methotrexate are comparable to those with surgery Ectopic Risk Factors

Risk Factor Odds Ratio Previous tubal surgery 21.0 Sterilization 9.3 Prior ectopic pregnancy 8.3 Current use of IUD 5.0 History of PID 3.4 Infertility > 2 years 2.7 Advanced maternal age • > 40 years 2.9 • 35-39 years 1.4 Smoking • > 1ppd 3.9 • 10-19 cigarettes 3.1 • < ½ ppd 1.7 • Prior smoker 1.5 Diagnosis

• Present with abdominal pain and vaginal bleeding; typically ~7 weeks after LNMP • Ultrasound: Diagnostic test of choice − Suspect ectopic: No intrauterine gestational sac and: ✔Transabdominal US: β-hCG > 3500 mIU/mL ✔Transvaginal US: β-hCG > 1800 mIU/mL • β-hCG − Normal IUP – increases by 53% q 48 hours (“doubles”) − Cannot alone differentiate between an ectopic and IUP • Chorionic villi (diagnostic curettage) − If not detected, ectopic pregnancy should be suspected. − Only considered when β-hCG levels are falling or when levels are elevated and US does not show intrauterine pregnancy Change in β-hCG Level Over 48 Hours Evaluation of Possible Ectopic Pregnancy

Change in β-hCG Level Percentage of cases in which the change occurs

Intrauterine Pregnancy • Appropriate increase (>50%) 99 • Inappropriate increase (<50%) 1 Ectopic Pregnancy • Inappropriate increase or decrease 71 • Rate of increase similar to viable IUP (>50%) 21 • Rate of increase similar to SAB (<50%) 8 Spontaneous Abortion • Appropriate decrease (>35%) 90 • Inappropriate decrease (<35%) 10 Adapted from Apgar and from Speroff. Villi Absent on D&C

Decreasing hCG Rising or stable hCG Rising or stable Mass > 4 cm hCG Mass < 4 cm

Follow hCG titers Laparoscopy Medical or laparotomy Treatment Serum Progesterone Levels

• Can detect pregnancy failure and identify patients at risk for ectopic pregnancy • Not diagnostic of ectopic pregnancy − Sensitivity is 15%. − Therefore, 85% of patients with ectopic pregnancy will have normal serum progesterone levels. • Algorithms for diagnosing ectopic pregnancy that include progesterone levels miss more ectopic pregnancies and require more surgeries than do algorithms without progesterone. Treatment

• Hemodynamically unstable patient − Laparotomy • Early diagnosis and patient stable − Laparoscopic salpingostomy • Most cost-effective treatment − Medical management with Methotrexate (MTX) in a single or multi- dose regimen • Multi-dose more effective than surgery, but more expensive • Single-dose has a higher failure rate than laparoscopic salpingostomy, especially in patients with higher β-hCG levels. Absolute Contraindications to Single-Dose MTX

• Breastfeeding • Overt or lab evidence of immunodeficiency • Alcoholism, alcoholic liver disease, or other chronic liver disease • Preexisting blood dyscrasias, such as bone marrow hypoplasia, leucopenia, thrombocytopenia, or significant anemia • Known hypersensitivity for methotrexate • Acute pulmonary disease • Peptic ulcer disease • Hepatic, renal, or hematologic dysfunction, and several metabolic diseases Methotrexate

• Agent most commonly used for medical treatment of ectopic • Folic acid antagonist that inhibits DNA synthesis and cell replication • Mechanism of action oSelectively kill cytotrophoblasts (rapidly dividing cells at fallopian tube implantation site) oBody spontaneously resorbs Monitoring MTX Therapy for Ectopic Pregnancy Obtain a CBC with differential and liver and renal function tests before starting any regimen

Regimen Surveillance Single dose* ⮚Measure β-hCG level on days 4 and 7 MTX, 50mg/m2 IM • If difference >15% decrease (between day 4 and 7), repeat weekly until undetectable(typically 5-7 weeks) • If difference < 15% decrease (between day 4 and 7), REPEAT MTX dose and begin new Day 1 ⮚If fetal cardiac activity present on Day 7, repeat MTX dose and begin new Day 1 ⮚Refer for surgical treatment if β-hCG level is NOT decreasing or fetal cardiac activity persists after 3 MTX doses Adapted from Seeber BE, et al. Obstet Gynecol. 2006 and Little SH, et al. J Fam Prac. 2012;61(11):684 Single-Dose MTX

• Easier to administer and monitor • Best prognostic indicator of successful treatment is initial β-hCG level. − Lower initial level the higher the success rate. • Contraindications: − Ectopic pregnancy > 4.0 cm and fetal cardiac activity Surgery

• Salpingectomy or Salpingostomy • Salpingostomy may result in inadequate evacuation of the products of conception oThus, recurrence of symptoms oCheck β-hCG level weekly to ensure it reaches zero Ectopic Expectant Management • Criteria oLow and decreasing (β-hCG < 1000) oAdnexal mass not detected (via US) oNo embryonic heartbeat oMinimal pain or bleeding oReliable follow-up Opting for a trial of expectant management?

• Extensive counseling on risk of tubal rupture, need for close surveillance • β-hCG q 48 hours to confirm decrease; then, weekly until they reach zero oNo specific rate of decrease = normal. Expectant management continues if patient is asymptomatic and decrease continues (even if gradual) or temporarily plateaus SORT: Key Recommendations for Practice

Clinical Recommendation Evidence Rating Serial measurements of β-hCG levels should be performed in patients with possible ectopic pregnancy. Most viable intrauterine pregnancies (99%) have β-hCG values that increase by about 50% in 48 hour. C

When deciding between surgical and medical treatment of ectopic pregnancy, the choice should be based on the patient’s preference after discussing the risks, benefits, and monitoring requirements of C both approaches. The patient’s absolute β-hCG level should be considered when deciding whether an ectopic pregnancy C can be treated with methotrexate, because the success rate is lower with higher β-hCG levels. Treatment failure may be assumed if the patient’s β-hCG level does not decrease by at least 15% from day 4 to day 7 after methotrexate injection, or if it plateaus or increases after the first week of treatment. C In such cases, additional methotrexate administration or surgical intervention is required. Expectant management should be considered for patients who have low and decreasing β-hCG levels, no evidence of an ectopic mass visualized by transvaginal ultrasonography, and minimal symptoms. B

Barash et al., Diagnosis and Management of Ectopic Pregnancy. Am Fam Phys. 2014;90(1):34-40 Diagnosis of Ectopic Summary

• Failure of β-hCG to double in 48-72 hours • Ultrasound (transvaginal) − IUP rules out ectopic − No gestational sac + β-hCG > 1800 highly suggestive − Gestational sac/embryo outside of uterus confirms ectopic. − Pitfalls: Pseudogestational sac, ruptured corpus luteum • Laparoscopy: Gold standard First-Trimester Bleeding • Differential diagnosis • Ectopic pregnancy • Spontaneous pregnancy loss ✔ Chromosomal abnormalities are causative ~50% of the time. ✔ No bed rest or drug therapy including progestogens will correct the common etiologies (Cochrane 2004). • Idiopathic bleeding in a viable pregnancy • Cervical abnormalities • Infection of the vagina or cervix • Subchorionic hemorrhage • Vaginal trauma • Molar pregnancy Criteria for Diagnosing Early Pregnancy Failure Society of Radiologists in Ultrasound

• Definitive pregnancy failure can be diagnosed in a woman with an IUP of uncertain viability when TVUS reveals any of the following: o Embryonic crown-rump length > 7 mm and no heartbeat o Mean gestational sac diameter > 25 mm and no embryo present o No embryo with heartbeat > 2 weeks after TVUS showed a gestational sac without a yolk sac o No embryo with heartbeat > 11 days after TVUS showed a gestational sac with a yolk sac

N Engl J Med. 2013 October 10;369:1443. (http://dx.doi.org/10.1056/NEJMra1302417) 9. For which one of the following conditions is there good evidence (Level A) for the routine administration of anti-D immune globulin (RhoGAM) to an unsensitized, D-negative patient?

A. After a first-trimester pregnancy loss B. Abdominal trauma C. Second- or third-trimester antenatal bleeding D. Attempting an external cephalic version Anti-D Immune Globulin Unsensitized, D-negative patient, if she has had one of the following conditions or procedures: • Level A Evidence ✔At approximately 28 weeks gestation, unless the father of the baby is also known to be Rh D negative ✔Within 72 hours after the delivery of an Rh D-positive infant ✔After a first-trimester pregnancy loss ✔After invasive procedures such as chorionic villus sampling, amniocentesis, or fetal blood sampling • Level C Evidence ✔Threatened abortion ✔Second- or third-trimester antenatal bleeding ✔External cephalic versionAbdominal trauma

Prevention of Rh D Alloimmunization. ACOG Practice Bulletin #4, Obstet Gynecol. 1999;93(5). Reaffirmed 2013 THANK YOU Answers

1. C 2. D 3. C 4. C 5. B 6. C 7. A 8. C 9. A 10. A Supplemental Slides 10. A 22 yo G1 female at 9 weeks gestation sees you for follow-up after an episode of vaginal bleeding. Her β-hCG levels are rising, and ultrasonography confirms a viable 8-week IUP with no apparent source of bleeding. Appropriate information and advice for this patient would include which of the following? A. She is at increased risk for miscarriage. B. She should remain at bed rest for 1 week beyond the end of the bleeding episode. C. She should take prenatal vitamins to reduce the risk of miscarriage. D. She should take a progestogen to reduce the risk of miscarriage. Pregnancy Loss

• Spontaneous pregnancy loss (loss of a pregnancy without outside intervention < 20 wks gestation) − Threatened − Inevitable − Incomplete − Missed − Ectopic − Complete − Recurrent spontaneous (habitual) • Ultrasonography is very helpful in the diagnosis. • Chromosomal abnormalities are causative ~50% of the time. Pregnancy Loss

• 20% of pregnant women will have some bleeding < 20 wks gestation. − ~50% will end in a spontaneous pregnancy loss. • 20% of recognized pregnancies will end in miscarriage or loss. • No bed rest or drug therapy including progestogens will correct the common etiologies (Cochrane 2004). • At the time of onset of the bleeding, viability is most likely already determined. First-Trimester Bleeding

• Laboratory tests should include − KOH and wet prep of vaginal secretions − CBC − ABO and Rh testing − Quantitative hCG − GC and Chlamydia testing • Ultrasonography − Crucial in identifying status of the pregnancy − Location of the pregnancy − Transvaginal with hCG > 1,800 mIU/mL (should see IUP) − Transabdominal with hCG > 3,500 mIU/mL (should see IUP) CDC - “High-Risk” Sexual Behaviors

• Previous STDs • New or multiple sex partners • Inconsistent condom use • Engage in commercial sex work and drug use • Those living in communities with a high prevalence of disease Pregnancy Loss

• Biochemical predictors of “Successful Outcomes” − “Doubling” of the β-hCG level in 48 hours − Serum progesterone level > 25 ng/mL • Predictors of “Failure of Successful Outcomes” − Subchorionic hemorrhage on US • If present, continuation rate of pregnancy is decreased even if heartbeat is present. − Serum progesterone level < 5 ng/mL − Failure of the β-hCG to double at 48 hrs First-Trimester Bleeding and Preterm Delivery

• Compared with controls, women presenting with first-trimester bleeding or threatened pregnancy loss were more likely to deliver prematurely. • Bleeding group rate was 11.9%. − Most likely between 34-37 wks gestation • Control group rate was 5.6%. © 2020 American Academy of Family Physicians. All rights reserved.

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Managing Common Cutaneous Problems

Gary I Levine, MD, FAAFP Associate Professor Department of Family Medicine The Brody School of Medicine at East Carolina University Greenville, North Carolina Disclosure Statement

All individuals in a position to control content for this session have indicated they have no relevant financial relationships to disclose. Learning Objectives

1. Summarize the AAFP Core Educational Guidelines – Conditions of the Skin. 2. Recognize many of the dermatologic entities included in the curriculum guide, including but not limited to: psoriasis, tinea corporis, ichthyosis, lichen planus, bullous pemphigoid, tinea versicolor, herpes zoster, rhus dermatitis, contact dermatitis, scabies, atopic dermatitis, folliculitis, furunculosis, pseudofolliculitis barbae, acne vulgaris, rosacea, seborrheic dermatitis, perioral dermatitis, discoid lupus, pityriasis alba, vitiligo, erythrasma, alopecia areata, tinea capitis, pediculosis capitis, erythema migrans, and melasma. Learning Objectives

3. Recognize many of the dermatologic entities included in the curriculum guide, including but not limited to: molluscum contagiosum, genital warts, common warts, genital herpes, basal cell carcinoma, sebaceous hyperplasia, keratoacanthoma, seborrheic keratosis, malignant melanoma, actinic keratosis, squamous cell carcinoma, dermatosis papulosa nigra, acrochordon, Bowen’s disease, impetigo, erysipelas, epidermal cyst, keloid, neurofibroma, and xanthelasma. References

• Charles M. Phillips, MD - Dept. of Medicine, Brody School of Medicine • Richard P. Usatine, MD - Dept. of Family Medicine, UTHSCSA • Clinical Dermatology - Thomas Habif • 6th Edition, July 2015 • Centers for Disease Control & Prevention - Sexually Transmitted Diseases Division • Jefferson Medical College Image Bank AAFP Core Educational Guidelines – Conditions of the Skin

•American Family Physician. Vol 60 #4 Sept. 15, 1999 •Curriculum guide for dermatologic entities with which family physicians should be familiar

•http://www.aafp.org/afp/1999/0915/p1258.html Primary Lesion Types

• Macules

• Papules

• Nodules

• Plaques

• Pustules

• Vesicles/Bullae

• Wheals

• Scales

• Crusts

• Erosions/Ulcers

• Fissures/Atrophy

• Scars

A 45 yo male presents with a chronic rash that is present over his knees and elbows.

B. Psoriasis

C. Mycosis fungoids

D. Bowen’s disease Psoriasis

•Psoriasis •Cutaneous T-cell •Chronic cutaneous lymphoma (mycosis (discoid) lupus fungoids) •Tinea corporis •Pityriasis rosea •Paget’s disease •Secondary syphilis •Lichen planus •Ichthyosis •Bowen’s disease Tinea Corporis

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Psoriasis

• Oval, erythematous, plaque-like lesions • Can develop at sites of trauma • Often involves extensor surfaces - Elbows, knees, & scalp • Pitting fingernails • Associated with asymmetric polyarthritis Psoriasis—Types

• Chronic plaque psoriasis • Guttate psoriasis • Pustular psoriasis • Erythrodermic psoriasis Psoriasis—Treatment •< 5% of body involved - Topical corticosteroids - Calcipotriene (Dovonex) • Vitamin D3 analog - Calcitriol (Vectical) - Tazarotene (Tazorac) - Anthralin - Salicylic acid - Localized UVB phototherapy - Tacrolimus, Pimecrolimus Psoriasis—Treatment

• > 5% of body involved (phototherapy) - UVB • Broad band, narrow band (II-III, B-C) • +/- topical, systemic, biologic agents - Narrow band UVB - Excimer laser (IIB) Psoriasis—Treatment • Severe recalcitrant disabling (FDA-approved) - Methotrexate (IIB) • Gold standard - Acitretin (eg, Soriatane) (IIB) • Plaque type - Cyclosporine (eg, Sandimmune) (IIB) - Apremilast (eg, Otezla) • Anti-TNF agents - Infliximab, etanercept, adalimumab, ustekinumab, apremilast Case # 2

A 65 yo woman presented with this painful rash on her face

A. Prednisone

B. Valacyclovir (eg, Valtrex)

C. Silver sulfadiazine (eg, Silvadene)

D. Gabapentin (eg, Neurontin) Herpes Zoster

•Herpes simplex •Pemphigus vulgaris •Herpes zoster •Erythema multiforme •Impetigo •Porphyria cutanea tarda •Dermatitis herpetiformis •Fixed drug eruptions •Burns •Bullous pemphigoid Bullous Pemphigoid

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Herpes Zoster (Shingles)

• Varicella-zoster virus • Reactivation of latent infection • 10-20% lifetime incidence • Generally involves skin of a single dermatome • Pre-eruptive pain, itching, burning (4-5 days) • Fever, headache, malaise Herpes Zoster (Shingles)

• Vesicles, of varying size, on erythematous base • Successive crops over 7 days • Crust lasts 2-3 weeks • Postherpetic neuralgia - Increases with age of patient - Increases with pain during eruptive phase - Incidence = 20% at 1 month Herpes Zoster—Treatment

•Analgesics •Wet compresses (Burow’s solution – aluminum acetate) •Antiviral therapy - Acyclovir (eg, Zovirax) • 800 mg 5x/day x 7 days - Famciclovir • 500 mg TID x 7 days - Valacyclovir (eg, Valtrex) • 1 g TID x 7 days Herpes Zoster—Treatment

• Oral corticosteroids (eg, Prednisone) - May decrease pain initially during acute phase - Does not reduce subsequent postherpetic neuralgia - May increase the risk of secondary bacterial infection Postherpetic Neuralgia—Treatment

• Anticonvulsants - Pregabalin (Lyrica) - Gabapentin (eg, Neurontin) • Tricyclics • Opioid analgesics • Sympathetic nerve blocks - Bupivacaine - Must be given within 2 months of onset to be effective Herpes Zoster Vaccine (Shingrix) • Recombinant zoster vaccine • 2 doses, given IM, 2-6 months apart • Approved by FDA /CDC for persons 50 years of age and older • Preferred vaccine per CDC • 90% effective at preventing shingles and PHN • Regardless of past Hx of varicella, zoster, or Zostavax Rx - Do not need to check titer • Do not give if pregnant or breastfeeding Herpes Zoster Vaccine (Zostavax)

• Contains the same live attenuated varicella virus as Varivax but at a much higher titer of vaccine virus • Approved by FDA for persons 50 years of age and older • Recommended by CDC for > 60 y/o • 50% effective at preventing shingles and 67% for PHN • Regardless of past Hx of varicella or zoster • Do not use if immunosuppressed, immunodeficient, pregnant, TB, or allergic to neomycin/gelatin • Administered by the subcutaneous route Case # 3

•A 25 yo male with known HIV infection who lives in substandard housing presents with a generalized pruritic rash 3. Which of the following represents the best treatment for this condition? A. Prednisone B. Hydroxyzine C. Permethrin 5% (eg, Elimite) D. Abacavir (Ziagen) Scabies

• Miliaria rubra • Atopic dermatitis • Urticaria • Insect bites • Scabies • Pruritic papular eruption (HIV) • Pruritic urticarial papules and plaques of pregnancy (PUPPP) Atopic Dermatitis

• Hypersensitivity reaction to Sarcoptes scabiei - Eggs, fecal pellets (scybala) • Nocturnal pruritus - Scratching spreads mites to other areas • Curved or linear burrows • Vesicles or small papules • Pustules indicate secondary infection Scabies • Location of lesions - Finger webs - Wrists - Elbows - Knees - Buttocks - Axilla - Waist - Breasts - Genitals Scabies Burrow

• Locate burrow with felt-tip pen ink • Scrape with #15 curved scalpel blade • View under mineral oil or KOH • Look for mites, eggs, feces (scybala) Sarcoptes Scabiei

• Overwhelming infestation • Crusted lesions • Not particularly pruritic • Seen mostly in immunocompromised patients Scabies—Treatment

• Launder all bedding and clothes worn within 48 hrs in hot water, or dry clean or place in plastic bag x 3 days • Treat patient, intimate contacts, and family members in same household Scabies—Treatment

• 5% Permethrin cream - Drug of choice - Apply below the neck, may repeat in 1 week • Ivermectin (Stromectol) 200 micrograms/kg PO, repeat in 1-2 wks - Effective for Norwegian scabies • Benzyl benzoate 25% ointment • Crotamiton (Eurax) • 6% precipitated sulfur in petrolatum Rhus Dermatitis

• Caused by contact with urushiol (from sap) • Found in plants from Anacardiaceae family, Rhus (Toxicodendron) genus - Poison ivy - Poison oak - Poison sumac - Cashew - Mango - Ginkgo - Japanese lacquer tree Rhus Dermatitis

• Linear lesions • Vesicles - Fluid does not contain resin and won’t spread rash • Erythema • May occur within 8 hrs or up to a week after exposure Rhus Dermatitis—Treatment

• Decontamination within 10 min after exposure - Not helpful after 1 hr • Wet compresses, calamine lotion • Topical corticosteroids – high potency • Systemic corticosteroids - Prednisone 60 mg (1 mg/kg) tapered over 14 days (preferred) - Prednisone 20 mg BID x 7 days - Triamcinolone acetonide suspension 40 mg IM once Contact Dermatitis Contact dermatitis - nickel

A 55 yo male congressman c/o new rash (a few localized lesions on his chest) after returning from a business trip with a female lobbyist. He admitted to spending an inordinate amount of time having meaningful conversations with her in a hot tub.

© Dr. Richard Usatine 4. Which one of the following would you recommend for the management of this condition? A. Oral cephalexin B. No pharmacologic therapy, but stay out of hot tubs C. Oral TMP-SMX D. Topical clotrimazole

• Folliculitis - Superficial bacterial infection of the hair follicles - Purulent material in the epidermis • Furuncle (boil) - Deep infection of the hair follicle in which purulent material extends through the dermis into the subcutaneous tissue • Carbuncle - Coalescence of several furuncles into a single inflammatory mass - Purulent drainage from multiple follicles Furunculosis

Source: Amrith Raj/Wikipedia Sycosis Barbae

Source: George Henry Fox/Wikipedia Folliculitis

• Etiologic agents - Usually attributable to Staph. aureus - Pseudomonas, aeromonas, and other gram negatives • Hot tubs, whirlpools, swimming pools - Candida species • Broad-spectrum antibiotics • Immunocompromised • Steroid Rx - Non-TB mycobacteria Folliculitis—Rx

• Lesions may resolve spontaneously - With or without drainage • More extensive involvement or lesions lasting x 2-3 weeks are usually treated with antibiotics • Warm compresses may be applied three times daily • Shaving should be avoided in involved areas Folliculitis—Rx

• Hot tub folliculitis - Avoid exposure to the source of contaminated water - Most cases – no further Rx needed - Can use acetic acid 5% compresses 2-4x/day - Severe cases – can treat with ciprofloxacin Folliculitis—Rx

• Staph folliculitis - Mild – topical mupirocin - Severe or persistent lesions • Not MRSA – dicloxacillin, cephalexin • MRSA – Bactrim, clindamycin, doxycycline • Topical antifungals (azoles) - Suspected fungal etiology Pseudofolliculitis Barbae

Source: Army Medical Department Impetigo

© Dr. Richard Usatine Impetigo • Contagious superficial bacterial infection • Most common in children ages 2-5 y/o • Primary - Direct bacterial invasion of previously normal skin • Secondary - Infection at sites of minor skin trauma • Abrasions, minor trauma, and insect bites - Infection at sites of underlying conditions • Eczema Impetigo • Types - Nonbullous impetigo • Most common form • Lesions begin as papules, surrounded by erythema, that progress to pustules • Pustules enlarge and form thick crusts with a characteristic golden appearance • Principal pathogen is now S. aureus - Beta-hemolytic streptococci accounts for a minority of cases Impetigo • Types - Bullous impetigo • Vesicles enlarge to form flaccid bullae with clear yellow fluid • Become darker, turbid • Ruptured bullae leave a brown crust • Usually due to Staph. aureus Impetigo

• Streptococcal impetigo can very rarely be associated with development of - Poststreptococcal glomerulonephritis Impetigo—Treatment

• Topical therapy - Limited number of lesions without bullae - Mupirocin 2% (Bactroban)- TID - Retapamulin 1% (Altabax) - BID • Oral antibiotics - Dicloxacillin, cephalexin, clindamycin - If suspect MRSA, or PCN allergic • Clindamycin • TMP-SMX • Linezolid (Zyvox) Erysipelas

Source: CDC Case # 5

•A 16 yo female would like to be treated for this facial rash, which has not responded to OTC cleansing preparations. Her high school prom is 3 © Dr. Richard Usatine months away. She is not sexually active. 5. Which one of the following would you recommend for the management of this condition?

A. Topical retinoid alone

B. Topical clindamycin alone

C. Topical retinoid + topical benzoyl peroxide + oral doxycycline

D. Isotretinoin Acne Vulgaris

Source: Army Medical Department Acne Vulgaris

• Androgen-mediated disorder of pilosebaceous units - Androgens stimulate sebum production and proliferation of keratinocytes - Keratin plug obstructs follicle os - Propionibacterium acnes proliferates in plugged follicle - Cutibacterium acnes (was P. acnes) growth produces inflammation Acne Vulgaris—Lesions

• Closed comedones (whiteheads) • Open comedones (blackheads) • Nodules or papules • Pustules (“cysts”) • Scars: ice pick, rolling, boxcar, atrophic macules, hypertrophic, depressed, sinus tracts Acne Vulgaris

Source: Henryart Acne Vulgaris

Source: James Heilman, MD/Wikipedia Acne Vulgaris—Lesions

• Most common areas affected: - Areas of greatest concentration of sebaceous glands • Face • Chest • Back • Upper arms Acne Vulgaris—Treatment

• Comedonal acne - Keratinolytic agent • Mild inflammatory acne - Keratinolytic agent, or BP, or BP +/- Keratinolytic agent +/- topical antibiotic • Moderate inflammatory acne - Keratinolytic agent + BP/topical antibiotic +/- systemic antibiotic • Severe (nodulocystic) acne - Isotretinoin Acne Vulgaris—Treatment

• Topical keratinolytics - Tretinoin (eg, Retin-A) • Start with lowest concentration of cream and advance as tolerated • Apply hs after washing • May cause an initial flare of lesions • Side effects include erythema, dryness, scaling - Adapalene (eg, Differin) • Apply hs after washing • Better tolerated than tretinoin and equally effective • Can be combined with benzoyl peroxide. Acne Vulgaris—Treatment • Topical keratinolytics - Tazarotene (Tazorac) • Binds to nuclear retinoic acid receptors • Side effects similar to tretinoin, not as well tolerated • Teratogenic - Azelaic acid (Azelex, Finacea) • Apply BID • Keratinolytic, anti-inflammatory, and antibacterial • Can cause hypopigmentation Acne Vulgaris—Treatment

• Topical antibacterials - Benzoyl peroxide • Apply thin film 1-2x/day • No known resistance • May cause skin irritation and bleach clothes - Benzoyl peroxide/erythromycin • Apply once daily • Must be refrigerated - Benzoyl peroxide/clindamycin Acne Vulgaris—Treatment

• Topical antibacterials (DO NOT USE AS MONOTHERAPY) - Erythromycin (eg, A/T/S, Emgel) • Increasing P. acnes resistance - Clindamycin (eg, Cleocin T) • Apply BID - Tetracycline – 0.22% solution • Apply BID • May cause skin to fluoresce in black lights - Metronidazole (Metrogel, Metrocream) • Apply once daily - Dapsone (Aczone) – 5% gel, apply BID • Adult females with inflammatory acne Acne Vulgaris—Treatment

• Systemic antibiotics - Limit to 12 wks therapy - Tetracycline • 500-1,000 mg daily • Begin at high dose, and taper in 2-4 weeks if patient responds • Do not use in children < 8 years old • May cause photosensitivity • Not as effective as minocycline, doxycycline Acne Vulgaris—Treatment • Systemic antibiotics Minocycline (Minocin) - 50-200 mg daily - Less photosensitivity than tetracycline, but other side effects include vertigo, autoimmune hepatitis, and lupus-like syndrome Doxycycline (Vibramycin) - 50-200 mg daily - Generally preferred PO antibiotic for acne - Can take with food, but higher incidence of photosensitivity Wood’s Lamp

Source: Kallemax/Wikipedia Acne Vulgaris—Treatment

•Systemic antibiotics - Erythromycin • 500-1000 mg daily • GI side effects are commonly seen • Resistance in P. acnes may limit effectiveness - Azithromycin • 500 mg initially then 250 mg x 4 days - Sulfamethoxazole-trimethoprim (Bactrim) • 1 DS tablet once or twice daily • Used for gram-negative folliculitis or resistance to tetracycline and erythromycin Acne Vulgaris—Treatment

• Use oral or topical antibiotics for 3 months - Stop if inflammatory lesions resolve • Can switch abruptly from oral to topical without taper • Generally don’t use topical and oral antibiotics together • Can use BP + oral antibiotic Acne Vulgaris—Treatment • Oral contraceptives (FDA-approved for acne) - Ethinyl estradiol + • Drospirenone (eg, Yaz, Yasmin) • Drospirenone/levomefolate (eg, Beyaz, Safyral) • Norgestimate (eg, Ortho Tri-Cyclen) • Norethindrone (eg, Estrostep) • Spironolactone (eg, Aldactone) - Only use in women - Not FDA approved for acne Acne Vulgaris—Treatment

• Isotretinoin - 60-90% cure rate - Given for 12-20 weeks - Side effects • Cheilitis, hyperlipidemia, pseudotumor - Highly teratogenic • Patient and provider must register with iPLEDGE program • www.ipledgeprogram.com Acne Vulgaris—Treatment • Light-based treatments - Ultraviolet A/Ultraviolet B (UVA/UVB), blue or blue/red light, pulse dye laser, KTP laser, infrared laser - Photodynamic therapy for 30–60 minutes with 5-aminolevulinic acid × 3 sessions is effective for inflammatory lesions - Limited evidence of effectiveness for most light therapies - Greatest utility when used as adjunct to medications or in patient who can’t tolerate medications Acne Vulgaris—Surgical Treatment

• Comedo extraction after incising the layer of epithelium over closed comedo • Incision and drainage for abscesses • Inject large cystic lesions - 0.05-0.3 mL triamcinolone (Kenalog 2-5 mg/mL) - Use 30-g needle to inject and slightly distend cyst Acne Vulgaris—Treatment

• Topical tea tree oil - Is effective, slow onset

Franz Eugen Köhler, Köhler's Medizinal-Pflanzen Acne Vulgaris—Referral

• Consider referral/consultation to dermatologist - Refractory lesions despite appropriate therapy - Consideration of isotretinoin therapy - Management of acne scars Rosacea

Source: M. Sand, D. Sand, C. Thrandorf, V. Paech, P. Altmeyer, F. G. Bechara: Cutaneous lesions of the nose. In: Head & face medicine Band 6, 2010, S. 7, ISSN 1746-160X Rosacea

• Prevalence = 15 million in US • Most common in Celtic ethnicity • Most common after age 30 • More common in women • Unknown etiology • Chronic, intermittent • Involves forehead, cheeks, nose, ocular area Rosacea

• Primary features - Erythema • Transient symmetric flushing: Accentuated by hot liquids and alcohol • Nontransient - Papules and pustules - Telangiectasia Rhinophyma

M. Sand, D. Sand, C. Thrandorf, V. Paech, P. Altmeyer, F. G. Bechara: Cutaneous lesions of the nose. In: Head & face medicine Band 6, 2010, S. 7

George Grantham Bain Collection Google Images Rosacea—Triggers for Flushing

• Extremes of temperature • Sunlight • Spicy foods • Alcohol • Exercise • Acute psychological stressors • Medications • Menopausal hot flashes Rosacea—Treatment • Topical antibiotics- for papules/pustular - 0.75% metronidazole (Metrogel) – BID - 1% metronidazole (Noritate) – daily - Azelaic acid 15% (Azelex) – BID - Benzoyl peroxide 5% – BID • +/- erythromycin or clindamycin - Clindamycin cream – less effective • Other topical agents - Brimonidine 0.33% gel (Mirvaso) – daily – alpha 2 adrenergic agent – for erythema - Ivermectin 1% cream daily •Others - Carvedilol PO – effective for flushing Rosacea—Treatment • Oral antibiotics - Doxycycline (Vibramycin) 100-200 mg/day - Tetracycline 1 gram/day - Erythromycin 1 gram/day - Minocycline (Minocin) 100-200 mg/day - Metronidazole (Flagyl) 250 mg BID - Azithromycin (Zithromax) 500 mg, then 250 mg x 4 days • Retinoids - Isotretinoin 0.5 mg/kg/day x 20 weeks for severe resistant cases Seborrheic Dermatitis

Source: Roymishali/Wikipedia Seborrheic Dermatitis • Biphasic incidence - Infants between the ages of 2 weeks and 12 months - During adolescence and adulthood • Increased among individuals with HIV - Prevalence = 35% with early HIV infection - 85% among patients with AIDS • Increased in Parkinson’s disease - May improve with L-dopa therapy Seborrheic Dermatitis—Treatment

• Face - Low-potency topical corticosteroid cream - Topical antifungal – BID until better • Ketoconazole 2% • Ciclopirox 0.77% cream/gel (Loprox) • Pimecrolimus & tacrolimus Seborrheic Dermatitis—Treatment

• Scalp - Antifungal shampoos • Selenium sulfide 2.5% • Ketoconazole 2% • Ciclopirox 1% Perioral Dermatitis

• Mild involvement - Topical pimecrolimus 1% BID - Topical metronidazole 0.75-1% gel or cream daily • More than mild involvement - Tetracycline • 250-500 mg BID - Doxycycline (preferred) • 50-100 mg BID - Minocycline • 50-100 mg BID Lupus Erythematosus (Systemic)

•Chronic cutaneous LE (scarring, discoid LE ) •Subacute cutaneous LE (SCLE) •Acute cutaneous LE (ALE) (systemic) Lupus Erythematosus

• Most patients have mucocutaneous lesions at some time during the course of the illness • Butterfly rash - Most common lesion - Erythema over the cheeks and nose - Spares the nasolabial folds - Appears after sun exposure Discoid Lupus Erythematosus

© Dr. Richard Usatine Discoid Lupus Erythematosus— Treatment • Photoprotection • Avoidance of aggravating drugs • Smoking cessation • Topical corticosteroid (group 1 or 2) – BID - Clobetasol (Temovate) • Topical calcineurin inhibitors - Pimecrolimus 1% cream (Elidel) - Tacrolimus 0.03% cream or 0.1% ointment (Protopic) •Systemic antimalarials- if no response to topical Rx - Hydroxychloroquine - Quinacrine Case # 6

A. Benzathine penicillin G B. Pimecrolimus (Elidel) C. Oral fluconazole (Diflucan) D. Prednisone Tinea Versicolor

• Pityriasis alba • Vitiligo • Tinea versicolor • Postinflammatory hypopigmentation • Leprosy • Halo nevus • Chemical induced • Phytophotodermatitis Pityriasis Alba

This is not an adult © Dr. Richard Usatine Vitiligo

• Caused by Pityrosporum ( Malassezia) species • Lesions result from conversion from budding to mycelial form • Occurs with heat, humidity, pregnancy, steroids, immunosuppression • More common at ages associated with high sebaceous activity Tinea Versicolor

• Lesions begin as circular macules that enlarge • Occur as tan, dark brown, or hypopigmented lesions • Have a powdery scale that is noted with scraping • Usually occur on upper trunk, neck, abdomen • Pale yellow fluorescence with Wood’s lamp Tinea Versicolor—Treatment

• Topical – for limited disease - Ketoconazole 2% shampoo (Nizoral) x 3 days - Selenium sulfide 2.5% x 7 days or q week x 4 - Terbinafine 1% solution (Lamisil) BID x 1 week - Traditional topical antifungals BID x 2-4 weeks - Zinc pyrithione (Selsun Blue) 1% shampoo daily x 2 weeks Tinea Versicolor—Treatment

• Oral – for extensive disease or non-responders - Itraconazole (Sporanox) 200 mg daily x 5-7 days - Fluconazole (Diflucan) 300 mg single dose, repeat in 1 week - Avoid oral ketoconazole • Concern about hepatotoxicity • Prophylaxis - Ketoconazole 2% shampoo (Nizoral) q week - Itraconazole (Sporanox) 200 mg PO BID q month x 6 months The Tinea Family • Tinea - Means fungal infection • By site - Tinea capitis - Tinea corporis - Tinea pedis • Other - Tinea versicolor - Tinea gladiatorum - Tinea incognito Tinea Corporis

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Erythrasma •Bacterial infection - Corynebacterium minutissimum •Less inflammatory than tinea •Coral pink fluorescence with Woods lamp •Rx – Mild - Topical clindamycin, erythromycin - Topical clotrimazole- works, despite lack of fungal involvement •Rx – Mod - severe - PO erythromycin, clarithromycin Tinea Capitis

Sources: Grook Da Oger(L) and Normak Purvis Walker Tinea Capitis—Rx • Griseofulvin - 20 to 25 mg/kg/day (microsize formulation) for - 6 to 12 weeks - 10 to 15 mg/kg/day (ultramicrosize formulation) for - 6 to 12 weeks • Terbinafine - 10 to 20 kg: 62.5 mg daily for 2 to 4 weeks - 20 to 40 kg: 125 mg daily for 2 to 4 weeks - Above 40 kg: 250 mg daily for 2 to 4 weeks Tinea Capitis—Rx • Itraconazole - 3 to 5 mg/kg daily for 4 to 6 weeks • Fluconazole - 6 mg/kg/day for 3 to 6 weeks • Kerion - Consider addition of systemic glucocorticoid therapy • May improve discomfort, no data on improved healing • Consider treating household contacts with antifungal shampoo - Selenium sulfide 2.5% - Ketoconazole 2% - Apply for 5 min 3x/wk Traction Alopecia

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Androgenic Alopecia

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Alopecia Areata

• Autoimmune etiology Association with thyroiditis and vitiligo • Exclamation point hairs - At edges of patches - Short broken hairs - Proximal end is narrower than the distal end - Can be extracted with minimal traction • Rarely may see - Complete loss of scalp hair • Alopecia totalis - Complete loss of all scalp and body hair • Alopecia universalis Alopecia Areata—Rx • Corticosteroids - Intralesional injections with triamcinolone Q 4-6 wks - Topical - Systemic (short-term) • Topical minoxidil 5% • Topical immunotherapy - Alopecia totalis • Anthralin 0.5-1% short contact therapy • Wigs Alopecia Areata—Prognosis

• 50% with limited patchy hair loss - Recover within a year • May persist for several years • 10% do not regrow hair Pediculosis Capitis

Source L & R: Wikipedia © Dr Richard Usatine Head Louse (Pediculus humanus capitis)

Source: Wikipedia Pediculosis Capitis—Rx

• Pyrethroids - 1st line Rx • Malathion 0.5% lotion • Benzyl alcohol 5% • Spinosad (Natroba) 0.9% topical • Topical ivermectin 0.5% lotion • Oral ivermectin 200 micrograms/kg for resistant lice • Permethrin + oral TMP-SMX Pediculosis Capitis—Rx • Children with pediculosis capitis do not need to be excluded from school once treatment has started https://www.cdc.gov/parasites/lice/head/schools.html • Household members and close contacts should be examined for infestation • Individuals who share bedding with the affected person should be treated prophylactically Melasma

Courtesy of the CDC Case # 7

This 26 yo male dermatology resident presented to your office concerned about a new patch of “warts” on his penis.

Picture courtesy of the CDC Case # 7

•“Funny that you should ask, my girlfriend has some of these “umbilicated papules” on her bottom, as well.”

Picture courtesy of the CDC 7. The most likely cause of his lesions is:

A. Treponema pallidum B. Herpes simplex virus C. Human papilloma virus D. Molluscum contagiosum virus Molluscum Contagiosum Courtesy of G Levine, MD Genital Warts

Courtesy of the CDC Wart

• Due to infection with HPV (Human Papillomavirus) - 150 types - HPV type 1 – plantar warts - HPV types 6 & 11 – genital warts • Infection with HPV occurs by skin-to-skin contact Genital Wart—Treatment

• Patient administered - Podofilox – 0.5% • BID x 3 days, off 4 days, repeat cycle x 4 - Imiquimod – 5% cream (Aldara) • HS, 3x/week, x 16 wks - Sinecatechins 15% ointment (Veregen) • TID for maximum of 16 wks Genital Wart—Treatment

• Provider-administered - Cryotherapy - BCA/TCA - Surgical or laser removal Common Warts

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Callus

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Duct Tape on Wart

Source: Joel Franusic/Flickr Genital Herpes

Courtesy of the CDC Genital Herpes—Treatment

• Acyclovir (Zovirax) - Primary = 400 mg TID x 7 days, 200 mg 5x/day x 7 days - Recurrent = 400 mg TID x 5 days, 800 mg BID x 5 days, 800 mg TID x 2 days - Suppression = 400 mg BID

• Famciclovir - Primary = 250 mg TID x 7 days - Recurrent=125 mg BID x 5 days,1 g BID x 1 day, 500 mg then 250 mg BID x 2 days - Suppression = 250 mg BID Genital Herpes—Treatment • Valacyclovir (Valtrex) - Primary = 1 g BID x 7 days - Recurrent = 1 g daily x 5 days, 500 mg BID x 3 days - Suppression = 500 mg or 1 g daily Molluscum Contagiosum

© Dr. Richard Usatine Molluscum Contagiosum • Caused by double-stranded DNA poxvirus • Spread by skin-to-skin contact and autoinoculation • Umbilicated, firm, flesh-colored, dome-shaped papules • Children - Lesions anywhere except palms & soles - Treatment is optional • Adults - Lesions mostly in genital area - Should be treated to avoid sexual transmission Molluscum Contagiosum— Treatment • Benign Neglect - may spontaneously resolve in 6 months - 4 yrs • Cryosurgery • Curettage - May cause scarring • Cantharidin (non genital) • Imiquimod 5% cream (Aldara) - TID x 5 days/wk x 1 month • Podofilox (adults) • KOH 5% • Topical retinoids • Salicylic acid • Laser Case # 8

•A 68 yo male was sent in by his daughter who was concerned about a small growth on her father’s scalp.

A. Keratoacanthoma B. Dermatofibroma C. Sebaceous hyperplasia D. Basal cell carcinoma Basal Cell Carcinoma

•Basal cell carcinoma •Squamous cell carcinoma •Keratoacanthoma •Sebaceous hyperplasia •Melanoma •Neurofibroma •Hemangioma •Prurigo nodularis Sebaceous Hyperplasia

• Most common skin cancer • Male > female • Mostly in age > 40 • 85% occur in head/neck • Clinical course is unpredictable - Can remain small for years or develop in growth spurts • Diagnosis by biopsy Basal Cell Carcinoma—Subtypes • Nodular - Most common - Less aggressive • Superficial - Plaque-like • Sclerosing - Rare • Pigmented Basal Cell Carcinoma (Nodular)

Source: John Hendrix, MD Basal Cell Carcinoma

Source: Klaus D. Peter, Gummersbach, Germany Basal Cell Carcinoma (Superficial)

• Excisional biopsy - Often adequate for small lesions • Electrodesiccation/curettage, cryotherapy - Nodular & superficial • < 6 mm in size, < 3 mm in depth Basal Cell Carcinoma—Treatment

• Mohs micrographic surgery - Sclerosing - Other BCCs with poorly defined margins - High-recurrence areas • Nose, eyelid - Large (> 2 cm) primary or recurrent BCCs - Lesions where conservation of tissue is important Basal Cell Carcinoma—Treatment

• Radiation - Non-surgical candidates • Imiquimod 5% cream (Aldara) • 5-Fluorouracil 5% (Efudex) - BID x 12 weeks •Vismodegib 150 mg daily PO - FDA approved for advanced or metastatic BCC Actinic Keratosis

Source: Timpo/Wikipedia Actinic Keratosis • Prevalence - Increases with age • Risk factors - Men > women - Fair-skinned, blue-eyed - Sun exposure • Location - Epidermis on sun-exposed areas of the body - Head, neck, forearms, and hands Actinic Keratosis

• Rough scaly patches - Normal skin tone to reddish brown - Circumscribed - 1 mm to 2.5 cm • Often multiple • Generally asymptomatic - Can see pruritus or a burning sensation Actinic Keratosis

• Most common premalignant lesions seen by dermatologists (???? intraepidermal SCC) • Potential to progress to squamous cell carcinomas - Most actinic keratoses do not progress to cancer - 26% regress spontaneously - 60% of cutaneous squamous cell carcinomas arise from AKs Actinic Keratosis—Rx

• Cryotherapy - 20-sec freeze is 80% effective • Curettage - Best for hyperkeratotic lesions • Photodynamic therapy - Aminolevulinic acid - Methyl aminolevulinate Actinic Keratosis—Rx • Topical - Fluorouracil • 5% cream BID x 2-4 wks • 0.5% cream – may have fewer side effects - Imiquimod • 5% cream daily 2-3x/wk x 16 wks • 50% response, min progression to SCC - Diclofenac • 3% gel daily x 3 months - Ingenol mebutate • 0.015% gel daily x 3 days Bowen Disease

Source:Watplay/Wikipedia Keratoacanthoma

Source: Jmarchn/Wikipedia Squamous Cell Carcinoma

Source: National Cancer Institute Cutaneous Squamous Cell Carcinoma • Precursors - Actinic keratosis • Same disease process as SSC but at different stage of evolution - ? Keratoacanthoma - Cutaneous horn - Bowen’s disease - Erythroplasia of Queyrat • Risk factors - Chronically diseased or injured skin • Ulcers, sinus tracts - Exposure to iodizing or UV radiation • Use of any tanning device may increase the risk of squamous cell carcinoma by 2.5-fold - Immunosuppression Cutaneous Squamous Cell Carcinoma—Dx • Shave technique - If the lesion is raised • 2- to 4-mm punch biopsy - Of the most abnormal-appearing skin Cutaneous Squamous Cell Carcinoma—Rx • Surgical excision - Typically recommended as first-line treatment • Mohs micrographic surgery • Electrodesiccation/curettage or cryotherapy - Smaller, low-risk lesions • Radiotherapy - Tumors in high-risk, surgically difficult areas - Usually is not considered for patients younger than 55 years Case # 9

•A 55 yo male is found to have these skin lesions at the time of a routine exam.

A. Treatment with topical 5-fluorouracil B. Observation of lesions C. Excisional biopsy with wide 4 cm margins D. Referral for Mohs micrographic surgery Seborrheic Keratoses

• Intradermal nevus • Melanoma • Seborrheic keratosis • Kaposi’s sarcoma • Cherry angioma • Pigmented basal cell carcinoma Cherry Angiomas

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Pyogenic Granuloma

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Atypical (Dysplastic) Nevus

Source: National Cancer Institute Malignant Melanoma

• Mostly found in non-Hispanic Caucasians • Median age = 57 • Men 1.5x > women • Metastasize widely Malignant Melanoma—Risk Factors

• Large number of atypical nevi • Other skin cancers • Congenital giant nevus • Family history of melanoma • Immunosuppression • UV radiation exposure Malignant Melanoma—Subtypes

• Superficial spreading - Most common - Upper back & legs in 40-50 yo • Nodular - Mostly men in 50-60 yo • Lentigo maligna - Facial location in 60-70 yo • Acral lentiginous - Digits & mucous membranes ABCDEs of Melanoma •A – Asymmetry •B – Border irregularity •C – Color variegation •D – Diameter greater than 6 mm •E – Evolving (changing) •U- Ugly duckling sign - Looks different than other nevi Superficial Spreading Melanoma

• Thickness determines prognosis - AJCC Staging (current) • T1: ≤1 mm = 95% 10 yr survival • T2: 1.01 to 2 mm • T3: 2.01 to 4 mm • T4: >4 mm = 55% 10 yr survival - Breslow microstage (mm) (mostly historical) • Measured depth of tumor invasion - Clark level (historical) • Histologic layer of dermis involvement Seborrheic Keratosis

© Dr. Richard Usatine Seborrheic Keratosis vs. Melanoma—Diagnosis • Melanoma suspected - Full-thickness biopsy • Excision preferred • Very wide excision not necessary - Generally 2 mm is sufficient • Punch if small enough Seborrheic Keratosis—Treatment

• Certain seborrheic keratosis - Destructive treatment • Cryosurgery • Curettage +/- electrodessication • Curettage/shave excision - Observation Seborrheic Keratosis

•Sign of Leser-trélat - Sudden appearance of numerous SKs - Sudden increase in size of existing SKs - Associated with internal malignancy • Gastric adenocarcinoma Dermatosis Papulosa Nigra

Source: Grook Da Oger/ Wikipedia Case # 10

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Case # 10

•A 39 yo female c/o a lump on her back that has gotten bigger and smaller over the past several years, and has occasionally drained some cheesy- looking material.

Jefferson Clinical Images Database. http://jeffline .jefferson.edu/JCI/. 10. You tell her that the material within the lesion is most likely which one of the following?

A. Keratin B. Sebum C. Pus D. Cheese

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Epidermal Cyst

© Dr. Richard Usatine Epidermal Cyst • Also known as - Epidermoid cysts - Epidermal inclusion cysts - Sebaceous cysts • Most common cause of cutaneous cysts • Have characteristic central punctum • Cyst wall produces keratin, not sebum • Lesions may remain stable or progressively enlarge • Spontaneous rupture with inflammation can occur Epidermal Cyst

• Inflamed, uninfected epidermal cysts often resolve spontaneously without therapy - Tend to recur • Injection of triamcinolone - 3 mg/mL for the face - 10 mg/mL for the trunk - Can hasten the resolution of inflammation and may prevent need for I&D Epidermal Cyst—Rx

• Excision - Best accomplished when the lesion is not inflamed - 4-6 weeks after inflammation has resolved • Infected, fluctuant cysts - Larger, more erythematous, and more painful than sterile inflamed cysts - Require I&D - Drain/wick for at least 24 hrs Epidermal Cyst—Rx

• Oral antibiotics - Cellulitis or cysts not responding to I&D - Augmentin - Tetracycline - Erythromycin - Bactrim Lipoma

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Keloid

Source: SKM-Hospital, Nepal Keloid—Rx • Intralesional corticosteroids - 1st line therapy - 70% will improve - Recurrence = 50% at 5 yrs - Complications • Cutaneous atrophy • Hypopigmentation - Triamcinolone 5-40 mg/mL • Inject 0.1-0.5 mL via 30 gauge needle to make keloid blanch • Repeat 1-4 wk intervals Neurofibroma

Jefferson Clinical Images Database. http://jeffline.jefferson.edu/JCI/. Xanthelasma

Source: Peter D. Klaus Answers

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Maternity Care, Part 2

David G. Weismiller, MD, ScM, FAAFP Department of Family and Community Medicine University of Nevada, Las Vegas School of Medicine Disclosure Statement

All individuals in a position to control content for this session have indicated they have no relevant financial relationships to disclose. Learning Objectives

1. Identify appropriate techniques to recognize and manage premature onset of labor. 2. Define the treatment of DM, and the diagnosis and treatment of hypertension in pregnancy. 3. Describe management of induction and augmentation of labor, including post term pregnancy. 4. Recall the recognition and treatment of late pregnancy bleeding including abruptio placentae, placenta previa, and postpartum hemorrhage. 1. A 20 yo female is seen for follow-up 6 weeks after delivery. Her pregnancy was complicated by preeclampsia. Her examination is unremarkable. This patient will be at increased risk for which of the following in midlife?

A. Breast cancer B. Diabetes C. Hypothyroidism D. Ischemic heart disease Definitions

• Gestational hypertension • Nomenclature − > 140/90 mm Hg on 2 − Preeclampsia occasions at least 4 hours − Eclampsia apart • Preeclampsia PLUS Seizure − > 160 mm Hg systolic or − Chronic hypertension > 110 mm Hg diastolic − Chronic hypertension with • Hypertension can be superimposed preeclampsia confirmed within minutes to facilitate timely − Gestational hypertension antihypertensive therapy. • Transient hypertension of pregnancy • Chronic hypertension Epidemiology • Hypertension in pregnancy is the most common medical complication of pregnancy occurring in 5-10% of all cases • 6th leading cause of maternal mortality US 2006-2009, 9.9% of maternal death (CDC)

Condition By the numbers Chronic Hypertension 1-5% of pregnancies Superimposed Preeclampsia on Chronic 25% of chronic HTN Hypertension Gestational Hypertension 3-6% of all pregnancies Preeclampsia 3-5% of all pregnancies Severe Preeclampsia ~ 1/3 of preeclampsia Eclampsia 0.05%-0.2% of all pregnancies Preeclampsia – Eclampsia

Diagnosis • Gestational BP elevation after 20 weeks of gestation in a woman with previously normal BP • Proteinuria > 0.3 g protein in a 24-hour urine specimen − No longer REQUIRED to make the diagnosis of preeclampsia when hypertension occurs with one or more severe features. − When proteinuria IS used among other diagnostic criteria for preeclampsia, a protein:creatinine ratio of at least 0.3 is sufficient. ACOG Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122-1133. Severe Features • SBP > 160 mm Hg; DBP > 110 mm Hg on 2 occasions at least 4 hours apart while the patient is on bed rest (unless antihypertensive therapy is initiated before this time) • Plt count < 100,000/mL • Impaired liver function −Abnormally elevated transaminases (> twice normal) −Severe persistent RUQ pain or epigastric pain unresponsive to medication and not accounted for by alternative diagnosis, or both • Progressive renal insufficiency (serum Cr > 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease) • Pulmonary edema • New-onset cerebral or visual disturbances Preeclampsia – Eclampsia

• Diagnosis −Gestational BP elevation after 20 weeks of gestation in a woman with previously normal BP −Proteinuria > 0.3 g protein in a 24-hour urine specimen • No longer REQUIRED to make the diagnosis of preeclampsia when hypertension occurs with one or more severe features • When proteinuria IS used among other diagnostic criteria for preeclampsia, a protein:creatinine ratio of at least 0.3 is sufficient −Severe features • Patients who have had preeclampsia have a 4X increased risk of hypertension and a 2X increased risk of ischemic heart disease, stroke, and VE. −No association between preeclampsia and cancer

ACOG Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122-1133. Risk Factors for Preeclampsia • Pregnancy-associated factors • Maternal-specific factors – Chromosomal abnormalities – Age < 20 and > 35 – Hydatidiform mole – Black race – Hydrops fetalis – Family history – Multifetal pregnancy – Nulliparity – Oocyte donation or donor insemination – Preeclampsia in previous pregnancy – Structural congenital abnormalities – Medical conditions – Urinary tract infection • Diabetes • Obesity • Paternal-specific factors • Chronic hypertension – First-time father • Renal disease • Thrombophilias – Previously fathered a preeclamptic pregnancy in another woman – Offspring of preeclamptic pregnancy Chronic Hypertension

• Gestational BP elevation before the 20th week of gestation • Hypertension that is diagnosed for the first time during pregnancy and does not resolve postpartum is also classified as chronic hypertension • Chronic hypertension is the most common cause of IUGR • 25% will develop superimposed preeclampsia Typical Laboratory Evaluation

• Uric Acid • CBC • Hemoconcentration and platelet count • Liver Function Tests (AST or ALT) • Protein/Creatinine Ratio • 24-hour Urine Total Protein Management of Chronic Hypertension • Blood pressures persistently above 160/110 should be treated to goals between 120/80 and 160/110 −Labetalol −Nifedipine • Ultrasound screening for fetal growth restriction is appropriate. • Antenatal fetal surveillance* should be performed in women who: −Require antihypertensive therapy −Have superimposed preeclampsia −Have fetal growth restriction

ACOG Practice Bulletin No. 203. Chronic Hypertension in Pregnancy. Obstet Gynecol. 2019;133(1):e26-50. *Fetoplacental assessment: Biophysical profile or modified biophysical profile to include umbilical artery Doppler velocimetry Treatment of Hypertension in Pregnancy and Postpartum ACC/AHA – 2014

• Severe hypertension should be treated (Level A) −Methyldopa, labetalol, nifedipine • Consideration MAY be given to treatment of moderate hypertension given the evidence for POSSIBLY increased stroke at currently defined systolic and diastolic BP cutoffs, as well as evidence for decreased risk for the development of severe hypertension with treatment (although maternal-fetal risk-benefit ratios have NOT been established). (Level B) • After giving birth, continue medications in women with chronic hypertension – dose adjustment to reflect the decrease in the volume of distribution and GFR that occurs after delivery. Monitor for development of postpartum preeclampsia (Level C)

Bushnell C, McCullough LD, Awad IA, et. al. Guidelines for the Prevention of Stroke in Women: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2014;45. Summary of Recommendation and Evidence Low-Dose Aspirin for Prevention of Preeclampsia – September 2014 USPSTF • Recommends the use of low-dose aspirin (81 mg/d) as preventive medication after 12 weeks of gestation in women who are at high risk for preeclampsia. (Grade: B recommendation) • Concludes with moderate certainty that there is a substantial net benefit of daily low-dose aspirin use to reduce the risk for preeclampsia, preterm birth, and IUGR in women at high risk for preeclampsia. Clinical Risk Assessment for Preeclampsia – USPSTF

Risk Level Risk Factor Recommendation High1 • History of preeclampsia, especially when accompanied by an adverse Low-dose aspirin is the outcome patient has > 1 of these risk • Multifetal gestation factors • Chronic hypertension • Type 1 or 2 diabetes • Renal disease • Autoimmune disease (i.e., systemic lupus erythematous, the antiphospholipid syndrome) Moderate2 • Nulliparity Consider low-dose aspirin if • Obesity (body mass index 30 kg/m2) the patient has several of • Family history of preeclampsia (mother or sister) these moderate-risk factors3 • Sociodemographic characteristics (African American race, low socioeconomic status) • Age > 35 y • Personal history factors (e.g., low birthweight or small for gestational age, previous adverse pregnancy outcome, 10-y pregnancy interval) Low Previous uncomplicated full-term delivery No low-dose aspirin 1. Single risk factors that are consistently associated with the greatest risk for preeclampsia. The preeclampsia incidence rate would be approximately 8% in a pregnant woman with 1 of these risk factors 2. A combination of multiple moderate-risk factors may be used by clinicians to identify women at high risk for preeclampsia. These risk factors are independently associated with moderate risk for preeclampsia, some more consistently than others 3. Moderate-risk factors vary in their association with increased risk for preeclampsia Prevention of Preeclampsia ACOG – 2013

• Women with histories of preeclampsia that is recurrent or has previously developed prior to 34 weeks SHOULD be offered daily low-dose aspirin (60-80 mg) commencing at the end of the first trimester • NOT recommended for primary prevention of preeclampsia −Bed rest/restriction of physical activity (not for treatment of POL either) −Vitamin C or E administration −Dietary salt restriction • Calcium may be useful to reduce the severity of preeclampsia in populations with low calcium intake; this finding is NOT relevant to a population with adequate calcium intake, e.g., United States • Bedrest is NOT recommended for prevention OR treatment of preeclampsia Prevention of Preeclampsia ACC/AHA – 2014

• Women with chronic primary or secondary hypertension or previous pregnancy-related hypertension should take low-does aspirin from the 12th week of gestation until delivery (Level A) • Calcium supplementation (of > 1g/d, orally) should be considered for women with low dietary intake of calcium (< 600 mg/d) to prevent preeclampsia (Level A)

Bushnell C, McCullough LD, Awad IA, et. al. Guidelines for the Prevention of Stroke in Women: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2014;45. Prevention of Stroke in Women With a History of Preeclampsia • Increased risk of future hypertension and stroke 1 to 30 years after delivery in women with a history of preeclampsia (Level B) • Consider: −Evaluating all women starting 6 months to 1 year postpartum, as well as those who are past childbearing age, for a history of preeclampsia/eclampsia as a risk factor (Level C) −Evaluate and treat for CV risk factors including hypertension, obesity, smoking, and dyslipidemia (Level C)

• Gestational blood pressure elevation without proteinuria that is detected for the first time after 20 weeks gestation • Two types − Transient hypertension of pregnancy: Preeclampsia has not developed, and BP has returned to normal by 12 weeks postpartum. − Chronic hypertension: BP elevation persists. Timing of Delivery

• Women with gestational hypertension or preeclampsia without severe features should have planned delivery at 37 weeks gestational age (Level B) • Women with chronic hypertension and with no additional maternal or fetal complications supporting earlier delivery (Level B) − If not prescribed maintenance antihypertensive medications, delivery before 38 0/7 weeks of gestation is not recommended. − If prescribed maintenance antihypertensive medications, delivery before 37 0/7 weeks of gestation is not recommended.

ACOG Practice Bulletin No. 202 Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019;133(1):e1-25. ACOG Practice Bulletin No. 203. Chronic Hypertension in Pregnancy. Obstet Gynecol. 2019;133(1):e26-50. 2. 19 yo primigravida at approximately 40 weeks EGA comes to the hospital with painful contractions. She has received no prenatal care. Examination: Cervix is 4 cm dilated and 80% effaced at station -1. Blood pressure is 164/111 mm Hg and a urine dipstick shows 3+ protein. She reports that she has had severe headaches for 3 days and has noticed a lot of swelling in her hands and feet. Moments after her blood is drawn and IV access is obtained, she has a generalized tonic-clonic seizure and fetal heart tones drop to 60 BPM. Which of the following is the most appropriate immediate course of action?

A. Emergency cesarean section B. Lorazepam, 2 mg IV push, repeated in 2 minutes if necessary C. Magnesium sulfate, 4 g loading dose IV, followed by a drip at 2 g/hr D. Terbutaline, 0.25 mg subcutaneously Management

• Anticonvulsive therapy • MgSO4 • Reduces the risk of first or subsequent seizures in women with severe preeclampsia ✔Now ONLY recommended for women with preeclampsia with severe features • Reduces risk of subsequent seizures in women with eclampsia ✔Antidote for toxicity: Calcium gluconate 1 g IV over 3 minutes • Antihypertensive therapy • Vaginal delivery is preferred! ACOG Task Force on Hypertension in Pregnancy.Obstet Gynecol. 2013;122(5):1122-1133. Antihypertensive Therapy Acute Hypertension in Preeclampsia • BP dangerously high or rises suddenly in women with preeclampsia, especially intrapartum. • Antihypertensive medications should not be administered unless BPs are persistently > 160/110 Pharmacologic Agent Dose Arterial vasodilator 5 mg IV over 1-2 minutes, or IM e.g., hydralazine Beta-blocker 20-40 mg IV bolus or 1 mg/kg infusion (maximum e.g., labetalol 220 mg) Calcium antagonists 10 mg po and repeat in 30 minutes, if necessary; oral nifedipine lowered BP e.g., nifedipine more quickly than did IV labetaolol. (Shekhar S et al. Obstet Gynecol. 2013;Nov;122:1057.)

Sodium nitroprusside 0.25 ug/kg/min to a maximum of 5 ug/kg/min Postpartum Management

• In women with gestational hypertension and/or preeclampsia, BP should be monitored for at least 72 hours postpartum and again 7-10 days after delivery. • Greatest risk for postpartum hypertension o Antenatal preeclampsia – particularly with higher urinary protein, serum uric acid, and BUN

ACOG Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122-1133. 3. Gestational diabetes has been associated with all of the following perinatal complications EXCEPT:

A. Increased frequency of maternal hypertensive disorders B. Increased risk of operative delivery C. Increased frequency of neonatal hyperglycemia D. Increased risk of intrauterine fetal death during last 4-8 weeks of gestation Why All the Fuss… Adverse Outcomes Maternal Fetal • Increased frequency • Excessive fetal growth (macrosomia) o Maternal hypertensive disorders o Increased risk for operative delivery o Cesarean delivery o Shoulder dystocia • Increased risk of intrauterine fetal o Birth trauma death during last 4-8 weeks of • Neonatal morbidity gestation o Hypoglycemia o Fasting hyperglycemia o Hypocalcemia (> 105 mg/dL) o Hyperbilirubinemia o Polycythemia The most common cause of neonatal death in children of mothers known to have DM before pregnancy is congenital anomalies. GD Treatment ACOG 2018 • Initial management (Level A) − Nutritional counseling by registered dietician − Advice on moderate exercise program (if possible); minimum of 150 minutes per week • No conclusive evidence for the threshold value at which clinicians should start pharmacologic therapy • Pharmacologic treatment − Insulin is considered first-line treatment in pregnancy (Level A) − Glyburide treatment should NOT be recommended as a first-line pharmacologic treatment because, in most studies, it DOES NOT yield equivalent outcomes to insulin (worse outcome including macrosomia and birth injury (Level B) − In women who decline insulin therapy or if unable to safely administer, metformin is a reasonable second-line choice (Level B) ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol. 2018;131(2):e49-e64. Gestational Diabetes Maternal Surveillance – Glucose Monitoring

• Glucose Target Levels − Fasting or preprandial < 95 mg/dL − 2-hour postprandial BG < 120 mg/dL (1 hour < 140mg/dL) − 1-2 times per week versus daily; review weekly − Pharmacologic Treatment (if on more than 3 occasions) − > 95 mg/dL fasting whole blood glucose or − > 120 mg/dL 2 h postprandial − Daily glucose monitoring Diabetes Timing of Delivery?

• Timing of delivery in women with GDM that is controlled with only diet and exercise (A1GDM) should NOT be before 39 weeks gestation, unless otherwise indicated. Expectant management up to 40 6/7 weeks of gestation in the setting of indicated antepartum testing is generally appropriate (Level C) • GDM well controlled on medications (A2GDM) or Type 2, delivery is recommended at 39 0/7 to 39 6/7 weeks of gestation (Level C)

ACOG – 2018 Diabetes Timing of Delivery?

• Poorly controlled – Expert guidance supports earlier delivery but data lacking regarding precise timing −Delivery between 37 weeks 0 days and 38 weeks 6 days may be justified −Delivery between 34 weeks 0 days and 36 weeks 6 days reserved for (1) failure of in-hospital glycemic control or (2) abnormal fetal testing • Council regarding risks/benefits of scheduled cesarean delivery when EFW > 4500 g (Level C)

ACOG – 2018 Long-Term Considerations

• Increased risk for recurrence of GD − 33-50% likelihood • Increased risk for development of diabetes after pregnancy − Up to 1/3 will have diabetes or impaired glucose metabolism at postpartum screening. − 35% of women 5-10 years after parturition • Offspring – increased risk − Obesity − Glucose intolerance − Diabetes in late adolescence and young adulthood Postpartum

• Reclassification of maternal glycemic status at least 4 weeks after delivery (preferred 4-12 weeks, ACOG 2018) [Level C] − FPG or 2-hr OGTT • Reassessment of glycemia every one (USPSTF) to three years (ADA) [SOR:C], if above normal; yearly assessment (ADA) if impaired fasting glucose or impaired glucose tolerance at 6-12 weeks

ACOG – 2018 Management of Postpartum Screening Results

Gestational diabetes

FPG or 75-g, 2-hr OGTT at 4-12 weeks postpartum

FPG > 125 mg/dL or FPG 100-125 mg/dL or FPG < 100 mg/dL or 2-hr glucose > 199 mg/dL 2-hr glucose 140-199 mg/dL 2-hr glucose <140 mg/dL

Impaired fasting glucose or Diabetes mellitus Normal IGT or both

• Consider referral for management • Assess glycemic status Refer for diabetes • Weight loss and physical activity every 1-3 years. management counseling as needed • Consider metformin if combined • Weight loss and physical impaired fasting glucose and IGT activity counseling as • Medical nutrition therapy needed • Yearly assessment of glycemic status 4. A 26 yo G2P1 presents at 30 weeks gestation with a complaint of severe itching. She has excoriations from scratching in various areas. She says that she had the same problem during the last pregnancy, and her medical records reveal a diagnosis of intrahepatic cholestasis of pregnancy. Elevation of which of the following is most characteristic of this disorder? A. GGT B. Bile acids C. Direct bilirubin D. Prothrombin time Intrahepatic Cholestasis of Pregnancy (ICP)

• Most common pregnancy-related liver disorder • Etiology ambiguous − Abnormalities in the metabolism and disposition of sex hormones and/or bile acids • ? Genetic predisposition • ? Environmental factors Intrahepatic Cholestasis of Pregnancy Diagnosis • Historic − Pruritus at night, pruritus continually (with no rash) and mild jaundice during the 3rd trimester; elevation of serum level of total bile acids • Clinical jaundice in 50% of cases; pruritus worsens with onset of jaundice. − Tends to recur (60-70%); severity varies. − Seldom exhibits before 25 weeks • Hepatitis − More than 20% of women known to be infected with hepatitis C develop ICP, so testing is indicated. • Liver biopsy − Pathologic findings are not specific, and a liver biopsy is rarely indicated. Laboratory Presentation

Parameter Finding Serum alkaline Increased 5-10 fold (hepatic > placental) phosphatase Bilirubin Elevated bilirubin (conjugated, < 5 mg/dL) Serum transaminases Usually normal

Serum bile acids > 3 times upper limit of normal (fasting) GGT Usually normal or modestly elevated – may help to differentiate this condition from other cholestatic liver diseases

PT Usually normal – but if elevated may reflect a vitamin K deficiency from malabsorption Pharmacologic Treatment

• Goal: Decrease maternal symptomatology and enhance fetal outcome. • Main drug prescribed: Most benefit for both mother and infant − ursodeoxycholic acid* − 10 mg/kg q day Pharmacologic Treatment

Drug Action Effect Pregnancy Risk Cholestyramine Anionic exchange resin binding bile Decreased pruritus, no effect on acids in the intestine for excretion fetal outcome; no effect on liver C enzymes Dexamethasone Suppression of fetal production of Alleviate pruritus and liver enzyme estrogen decreasing bile acid levels abnormalities C

Epomediol Terpenoid compound, prevents and Alleviate pruritus; no change in liver reverses cholestasis induced by ethinyl enzyme abnormalities C

Phenobarbital Induces hepatic enzymes to decrease Some benefit to decrease bile acids symptoms; no effect on fetal D outcome Ursodeoxycholic acid, Hydrophilic bile acid that replaces more Decreases pruritus, bile acids; Actigall, and Ursodiol cytotixic bile acids improved fetal outcomes B

Hydroxyzine Antihistamine activity Decreased pruritus C Outcomes – ICP

• Maternal – usually benign o Impaired quality of life o Pruritus and abnormal laboratory tests resolve within 1-2 weeks of delivery, no sequelae. • Fetal – may be serious o Higher bile acid levels and impaired transport of bile acids from the fetus through the uteroplacental circulatory system ✔Preterm labor, preterm delivery ✔Fetal compromise ✔Increased risk of cesarean delivery ✔Meconium-stained amniotic fluid ✔IUFD Bleeding in Late Pregnancy

• Placenta previa • Placenta abruption • Vasa previa • Cervical trauma (e.g., intercourse) • Vaginal infections • “Bloody show” 5. Which of the following statements is true regarding bleeding in late pregnancy?

A. The most serious complications of placental abruption are the result of hypovolemia B. Young maternal age is a risk factor for placenta previa C. Placenta previa typically presents with painful vaginal bleeding D. Placental abruption is diagnosed using ultrasonography Placenta Previa

• Occurs in 0.3-0.6% of all births • Painless vaginal bleeding • Bleeding patterns – first bleeding episode: − Before 30 weeks 33% − Between 30 and 35 weeks 33% − After 36 weeks 33% • Each successive episode of bleeding may be heavier, more unpredictable. Placenta Previa Etiology • Usually none is found • Risks − Prior C/S or history of uterine curettage • ? Damage to myometrium or endometrium − Cocaine − Advanced maternal age − Tobacco • Recurrence rate of 6-12x in subsequent pregnancy • Malpresentation is the result rather than the cause of placenta previa Placenta Previa Diagnosis • Antenatal by ultrasound • Before 24 weeks, only a cautionary significance is attributed to a placenta close to the os. − 90% have moved away from the os at term. − Need to confirm “movement” in 3rd trimester. − In cases where the bulk of the placenta is over the os after 24 weeks, it is less likely to be clear of the os at term. Placental Abruption

• Separation of the placenta from implantation site - Clinical diagnosis (pain and typically vaginal bleeding) • Occurs in approximately 1% of all deliveries − Incidence increases with gestational age. − Most serious complications are due to hypovolemia → acute renal failure. • Etiology − Trauma, cocaine abuse, acute decompression of amniotic fluid, preterm rupture, hypertensive disorders, tobacco use • Risk of recurrence high (20-30x) Placental Abruption Management • Assess fetal viability − Fetal demise – here placental detachment usually > 50% • Deliver the fetus • Prepare to transfuse − Live fetus + rigid uterus – again > 50% detachment • 90% fetal demise - C/S − Live fetus + soft uterus - induction of labor Antepartum Hemorrhage Summary

Symptom/Sign Placenta previa Placental Abruption

Pain Minimal Severe

Contractions Absent or mild Hard, rapid, often tetanic

Blood Bright red Port wine

Coagulation Normal Abnormal

Concealed Almost never > 20% of time hemorrhage Preterm Labor Diagnosis

• Gestation > 24 weeks, < 37 weeks • Contractions and cervical change 6. Which of the following is a risk factor for preterm labor?

A. Prior preterm birth B. Interpregnancy interval < 12 months C. Long cervical length on endovaginal ultrasound (> 25mm) D. Administration of 17-hydroxylprogesterone caproate to expectant mother Risk Factors for Preterm Labor

• Prior preterm birth • Non-Hispanic black race − Recurrence risk of • Interpregnancy interval < 6 17-37% months • Multiple gestation • Tobacco use • Short cervical length on • Infection endovaginal U/S – Bacterial vaginosis − <25 mm at 18-25 weeks – Bacteriuria – Urinary tract infection Preterm Labor Symptomatic Management Intervention Recommendation Bed rest Not effective for the prevention of preterm birth and should NOT be routinely recommended (Level B) Hydration Not effective for the prevention of preterm birth and should NOT be routinely recommended (Level B) Tocolytic agents First line: Beta-adrenergic agonist, calcium channel blockers, NSAID for short-term prolongation of pregnancy; maintenance therapy is INEFFECTIVE for preventing preterm birth and improving neonatal outcomes (Level A) Corticosteroids Single course between 24 and 34 weeks who are at risk of preterm delivery with in 7 days (Level A) (Betamethasone 12 mg q 24hX2 OR dexamethasone 6 mg q 12hX4) Antibiotics Should NOT be used to prolong gestation or improve neonatal outcomes in women with POL and INTACT membranes (Level A) Magnesium Sulfate Reduces the severity and risk of CP in surviving infants if administered when birth is anticipated before 32 weeks of gestation (Level A) Prevention of Preterm Labor

• 17-hydroxyprogesterone caproate (IM) − Trade name: Makena − 250 mg IM weekly from 16-20 weeks through 36 weeks • Only one indication − Pregnant women with a history of at least one spontaneous preterm birth Prevention of Preterm Delivery

• In addition to 17-P −Check cervical length via U/S every 2 weeks from 16-22 weeks −Consider cerclage for cervical length <25 mm • Benefit of 17-P for women with history of preterm delivery −0.31 RR of birth < 34 weeks [CI=0.14-0.69] −0.50 RR of neonatal mortality [CI=0.33-0.75] 7. A 26 yo gravida 3 para 2 with mild chronic hypertension and an uncomplicated pregnancy has just delivered a vigorous female by spontaneous vaginal delivery. She is noted to have heavy vaginal bleeding and a bimanual examination reveals a soft, poorly contracted uterus. Her temperature is 37.1°C (98.8°F), blood pressure 168/97 mm Hg, pulse rate 105 beats/min, and oxygen saturation 95% on room air. Which one of the following uterotonic agents is CONTRAINDICATED in the management of this patient’s postpartum hemorrhage? A. Oxytocin (Pitocin) B. Carboprost tromethamine (Hemabate) C. Misoprostil (Cytotec) D. Methylergonovine Postpartum Hemorrhage (PPH) Definition

• Cumulative blood loss of greater than or equal to 1,000 mL or • Blood loss accompanied by signs or symptoms of hypovolemia −Early (or primary): First 24 hours after delivery −Late (or secondary): After 24 hours but before 6 weeks after delivery

ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists Number 183, October 2017: Postpartum Hemorrhage, Obstetrics and Gynecology 2017;130(4):e168-e186. (Reaffirmed 2019) Early Postpartum Hemorrhage Etiology

• Uterine atony (Tone) • Retained placental − Uterine overdistention fragments (Tissue) • Hydramnios ‒ Including abnormal placentation • Multiple gestation • Accreta • Fetal macrosomia • Increta − Oxytocin use − High parity • Percreta − Rapid or prolonged labor − Intra-amniotic infection − Halogenated anesthetic Early Postpartum Hemorrhage Etiology

• Lacerations of vagina • Coagulopathy (Thrombin) and cervix (Trauma) − Hereditary − Forceps − DIC − Fetal macrosomia • Sepsis − Precipitous labor and • Abruption delivery − Hemolysis, Elevated Liver − Episiotomy Enzymes, Low Platelets • Uterine rupture (HELLP) • Uterine inversion Treatment Approach

• Uterine massage − Bimanual • Oxytocics (medical uterotonic therapy) • Inspect for lacerations • Surgical intervention

Anderson JM and Etches D. Prevention and Management of Postpartum Hemorrhage. Am Fam Physician. 2007;75:875-82. Postpartum Hemorrhage Treatment Medical Uterotonic Therapy • Oxytocin − IV, IM, or intramyometrial

• Misoprostol (Cytotec, PGE1) − Per rectum (400 mcg after placenta and 100 mcg at 4 and 8 hours postpartum, total 800-1000 mcg)* • Methylergonovine − Contraindicated in presence of hypertensive disease state

• 15-methyl PGF2-alpha (Carboprost or Hemabate) − IM or intramyometrial

• Dinoprostone (PGE2) * Caliskan E et al. Am J Obstet Gynecol. 2002; 187:1038-45. Postpartum Hemorrhage Prevention

• Correct anemia • Avoid routine episiotomy • Infant to breast • Routine use of medications after delivery of the placenta *Misoprostol is NOT approved by the U.S. FDA for use in prevention or treatment of PPH Medications for Prevention of PPH Medication Dose Contraindications/ Mechanism of Side Effects Cautions Action First Line Agent Oxytocin 10 IU IM or 5-10 Overdose or Stimulates the Rare IU IV bolus prolonged use upper segment of can cause water the myometrium to intoxication. contract rhythmically, constricting Possible hypotension spiral arteries with IV use decreasing blood following cesarean flow through the section uterus Second Line Agent Misoprostol* 600 mcg oral; Caution in patients with Generalized smooth Nausea, vomiting, Use ONLY when CV Disease muscle contraction diarrhea, pyrexia Prostaglandin E1 oxytocin is NOT available. analog Postpartum Hemorrhage Prevention • Correct anemia • Avoid routine episiotomy • Infant to breast • Routine use of medications after delivery of the placenta • Active management of third stage Third Stage of Labor Management

Expectant Active • Await separation • Oxytocin with shoulder • Leave cord uncut delivery • Spontaneous placental • Cord clamped and cut delivery early (2-3 minutes) • Oxytocin/breast after placental • Controlled cord traction separation

Begley CM, Gyte GM, Devane D, Mcguire W, Weeks A. ActiveVersus Expectant Management for Women in the Third Stageof Labour. Cochrane Database Syst Rev 2011:CD007412. PPH Recommendations (SOR A)

• Active management of the third stage of labor should be utilized to decrease the risk of PPH, postpartum maternal hgb < 9 mg/dL, and the need for manual removal of the placenta. • Delayed cord clamping (one to three minutes) decreases neonatal risk of anemia and does not increase risk of PPH • Oxytocin remains first choice for prevention of PPH because it is as, or more, effective than ergot alkaloids or prostaglandins and has fewer side effects • Misoprostol is less effective for prevention of postpartum hemorrhage than oxytocin and has more side effects Postdates Pregnancy > 42 weeks • Accurately date everyone. − Early sonograms help (Level A) • Antenatal fetal testing between 41 and 42 weeks (Level C) − q 4-7 days depending on method − Most do MBPP q 3-4 days • Induction: Risk of routine induction (C/S) in the era of cervical ripening agents is lower than previously reported − Cervical ripening: Improves success of inductions (Level B) • Bishop score of 8 − Oxytocin − Nonpharmacologic methods of labor induction may be helpful Cervical Ripening Agents (Induction is indicated, cervix is unfavorable) • Total score > 8 (Max score 15); probability of vaginal delivery after labor induction is similar to that after spontaneous labor. Dilatation 0 cm 1-2 cm 3-4 cm > 5 cm (Points) 0 1 2 3 Effacement 0-30% 40-50% 60-70% > 80% (Points) 0 1 2 3 Consistency Firm Medium Soft (Points) 0 1 2 Position Post Mid Anterior (Points) 0 1 2 Station* -3 -2 -1/0 +1/+2 (Points) 0 1 2 3

* Station reflects a -3 to +3 scale. Modified from Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol. 194;24:267. Macrosomia ACOG – > 4500g (Morbidity increases sharply beyond this weight) • Level A − Prediction of birth weight imprecise by US or clinical measurement. For suspected macrosomia, the accuracy of estimated fetal weight using US biometry is no better than that obtained with abdominal palpation − No contraindications – encourage engagement in aerobic and strength conditioning exercises during pregnancy to reduce the risk of macrosomia − Control of maternal hyperglycemia reduces the risk of macrosomia; maternal glucose management recommended for pregnancies complicated by DM • Level B − Suspected fetal macrosomia or large for gestational age is NOT an indication for induction of labor before 39 0/7 weeks of gestation … insufficient evidence that benefits of reducing shoulder dystocia risk would outweigh the harms of early delivery • Level C − Suspected macrosomia is NOT a contraindication to labor after cesarean.

ACOG Practice Bulletin No. 216. Macrosomia,. Obstet Gynecol. 2020;135(1):246-248. Induction

• Level A Evidence − Post term pregnancies with unfavorable cervix can undergo induction OR expectant management. − Prostaglandins (PG) can be used to promote cervical ripening AND induce labor. − Delivery should be effected if there is evidence of fetal compromise or oligohydramnios. • Level C Evidence − Reasonable to initiate fetal monitoring between 41-42 weeks. • Many practitioners use twice weekly. • NST and AFI (MBPP) should be adequate. − Many recommend induction or prompt delivery in patients with a favorable cervix and no other complications. Additional Resource

• Syllabus – Advanced Life Support on Obstetrics −First Trimester Complications −Medical Complications −Preterm Labor/PROM −Vaginal Bleeding in late pregnancy −Intrapartum Fetal Surveillance −Maternal Resuscitation/PPH −Shoulder Dystocia −Labor Dystocia

Answers 1. D 2. C 3. C 4. B 5. A 6. A 7. D 8. A 9. D Supplemental Slides 8. A 26 yo G2P1 at 36 weeks fell off of her bicycle 2 hours ago. She says that she has felt no movement since the fall. She has abrasions on the left forearm and left leg but otherwise appears uninjured. Which one of the following would be the most sensitive indicator of fetal compromise in this patient? A. Continuous electronic fetal monitoring B. Vaginal bleeding C. Uterine ultrasonography D. Kleihauer-Betke Management of the Pregnant Woman After Trauma • Stabilize the pregnant woman using “ABC” protocols • Supplemental oxygen • IV lactated Ringer’s solution in 3:1 ratio based on blood loss • Laboratory studies − CBC − Blood type and Rh − Kleihauer-Betke • Not predictive of fetal outcome − Injuries are severe – consider: • Coagulation studies • Chemistry panel • ABG • Deflect uterus off of great vessels if more than 20 weeks gestation. • Radiologic studies as needed Secondary Survey

• Examine for nonobstetrical injury. − Treat as needed. • Speculum examination to rule out spontaneous rupture of membranes, vaginal bleeding • Check for fetal heart tone.

Fetal heart tone Fetal heart tone ABSENT PRESENT

Maternal treatment only; no fetal Estimate gestational age (history, fundal height, Leopold’s resuscitation maneuvers, ultrasonography < 24 weeks of gestation*

Document fetal heart tone No fetal resuscitation

* Determination of fetal viability varies by institution. Some centers use estimated fetal weight limits typically 500 g; others use a gestational age of 24-26 weeks. > 24 Weeks of Gestation*

YE EFM for 24 hours, intervene Electronic fetal monitoring S if needed for NRFHR tracing. for four hours

• Vaginal bleeding • SROM D/C monitoring and discharge to • FH tone abnormality home, return to L and D: • Uterine contractions for > 4 hours • Vaginal bleeding • High-risk mechanism of injury • Decreased fetal movement NO • Uterine tenderness • Loss of fluid vaginally • Abdominal pain • Repetitive uterine contractions • Maternal anesthesia • Abdominal pain or tenderness 9. Following a prolonged second stage of labor, your primigravid patient at 42 weeks gestation delivers the fetal head, but the anterior shoulder does not release with a normal amount of downward traction. The statement that most accurately is associated with this complication is:

A. A history of shoulder dystocia in a previous pregnancy does not confer any greater risk of the complication in this pregnancy. B. It is important to stop and suction the newborn before attempting to deliver the anterior shoulder in cases where this complication is anticipated C. Routine induction of labor for macrosomia has been proven to improve perinatal outcomes. D. After delivery of the fetal head, pH can be expected to drop by 0.04 per minute due to cord compression. Shoulder Dystocia

• Caused by the impaction of the anterior shoulder above the symphysis pubis • Elective induction of labor or elective cesarean delivery for all women suspected of carrying a fetus with macrosomia is not appropriate (Level B). − Planned C/S to prevent SD may be considered (Level C) • EFW > 5000 g with no DM • EFW > 4500 g with DM Shoulder Dystocia: Complications • Maternal • Fetal − Lacerations Brachial plexus (10%-20%) • Perineum • Erb’s palsy • Vagina • Majority are bruising/stretching; complete • Rectum recovery in 6-12 months (80+ percent) − Hemorrhage Cervical spine • Uterine atony Asphyxia • Lacerations • Cord pH drops 0.04/minute Fractures • Clavicle • Humerus Shoulder Dystocia

• A true obstetric emergency; studies suggest the majority are relieved by maneuvers that are safe for fetus and mother. • Manual maneuvers will facilitate resolution of most of these cases. − Sequence in which maneuvers are performed will depend on the experience/preference of the individual provider. No evidence that one maneuver is superior to another in releasing an impacted shoulder or reducing the chance of injury. • Fundal pressure is counterproductive and not indicated. ACOG Committee Opinion Term Singleton Breech

• Decision regarding mode of delivery should depend on experience of healthcare provider. − Cesarean will be preferred mode for most physicians because of diminishing expertise in vaginal breech delivery. • Offer and perform ECV whenever possible. • Planned vaginal delivery may be reasonable. − Great caution, detailed patient informed consent • Inform woman that the risk of perinatal or neonatal mortality or short-term serious neonatal morbidity may be higher than if cesarean delivery is planned. © 2020 American Academy of Family Physicians. All rights reserved.

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Management of Chronic Pain

Gary I. Levine Associate Professor Department of Family Medicine The Brody School of Medicine at East Carolina University Greenville, North Carolina Disclosure Statement

All individuals in a position to control content for this session have indicated they have no relevant financial relationships to disclose. Learning Objectives

1. Cite the 2016 CDC guidelines for prescribing opioids for chronic pain 2. List several illnesses and conditions associated with chronic pain. 3. Identify mechanisms for quantifying pain. 4. Recognize potential challenges in the management of chronic pain. 5. State the types of behavioral therapies that are effective options for patients with chronic pain 6. Describe pharmacologic therapy of chronic pain, including the rational use of opioids. 7. Describe opiate side effects and withdrawal. 8. Identify the differences between tolerance, physical dependence, addiction, and pseudoaddiction. 9. Identify key facts regarding urine drug testing. 10. List elements of a pain management (informed consent & treatment) agreement as recommended by the Federation of State Medical Boards. References

JAMA The journal of the American Medical Association

•March 15, 2016 •CDC Guideline for Prescribing Opioids for Chronic Pain— United States, 2016 •Deborah Dowell, MD, MPH; Tamara M. Haegerich, PhD; Roger Chou, MD •All 12 recommendations are category A except recommendation 10 (category B) •Apply to all patients outside of active cancer treatment, palliative care, and end-of-life care) CDC Guidelines App CDC Opioid Guidelines

•CDC advises against misapplication of guidelines −1) For adults −2) For chronic non cancer pain −3) No dosage cutoff −4) Avoid abrupt withdrawal/taper from high dose −5) Utilize MAT for opioid use disorder References

• Federation of State Medical Boards. Guidelines for the Chronic use of Opioid Analgesics. April, 2017. References

• Pain Management Best Practices US Dept. of Health & Human Services May 2019 Pain

• “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

• International Association for the Study of Pain (IASP) Classification of Pain Pain

Acute Chronic Injury Postoperative Flare

Neuropathic Mixed Nociceptive Visceral

Diabetic neuropathy (DN) Cancer pain Osteoarthritis IBS Post-herpetic neuralgia (PHN) Low back pain Rheumatoid Pancreatitis Radiculopathy (RADIC) Fibromyalgia arthritis Bladder pain Fibromyalgia Noncardiac chest pain Abdominal pain syndrome Chronic Pain

• Persistent pain, either continuous or recurrent, that affects patients’ well-being, level of function, and quality of life • Lasts > 12 weeks • No functional benefit • Doesn’t resolve with tissue healing Epidemiology of Pain

• Chronic pain affects approximately 10-30% of the US population annually - 30-50% worldwide • Pain is the most common reason patients seek medical attention Prevalence of Pain in Selected Chronic Illnesses

Disease USA Prevalence (Millions)

Back Pain*** 54.6 Arthritis (DJD)*** 43 Chronic Headache*** 40 Osteoporosis 25 Diabetes 15.7 Rheumatoid Arthritis 2.5 Fibromyalgia 2

Arthritis Foundation, American Diabetes Association, National Institute of Neurologic Diseases and Stroke, 1997-1999 1. Which of the following statements is correct? A. Depression is commonly associated with chronic pain B. On a numerical pain scale, 10 usually represents the absence of pain (true happiness) C. The Federation of State Medical Boards now mandates consultation with a pain management specialist for patients receiving chronic opioid therapy for chronic pain D. Allodynia is an elevated pain response to a painful stimulus Chronic Pain • Hyperalgesia - An elevated pain response to painful stimuli • Allodynia - Perception of pain caused by a usually nonpainful stimuli Chronic Pain—Associations

• Depression • Anxiety • Insomnia • Weight loss • Decreased quality of life Barriers to Effective Pain Management

• Inadequate training in pain management • Poor methods of pain assessment • Conflicting clinical guidelines • Provider concerns - Regulation of controlled substances - Fear of causing addiction or being deceived - Management of side effects Assessment of Pain Intensity—Verbal • No pain • Mild pain • Moderate pain • Severe pain • Very severe pain • Worst possible pain Assessment of Pain Intensity— Numerical Scale

‒ 0 ---- No pain ‒ 1 ‒ 2 ‒ 3 ‒ 4 ‒ 5 ---- Moderate pain ‒ 6 ‒ 7 ‒ 8 ‒ 9 ‒ 10 ---- Worst possible pain Assessment of Pain Intensity—Faces Scale 0 3

1 4

2 5 Cultural Aspects of Pain

• Patients from ethnic minorities and cultures different from the health care professionals treating them are at risk of receiving inadequate pain management Federation of State Medical Boards Pain Treatment Guidelines • The Federation of State Medical Boards has written the “Guidelines for the Chronic use of Opioid Analgesics” - Updated April, 2017 - www.fsmb.org • These guidelines are for use by State Medical Boards, with specific recommendations for practicing physicians Federation of State Medical Boards Pain Treatment Guidelines

• Documentation of a relevant history, physical examination, and laboratory evaluation • Assessment of risk of alcohol or medication misuse • Review of the state PDMP • Screening for depression Federation of State Medical Boards Pain Treatment Guidelines

• Documentation of the patient’s treatment plan, including ways to measure treatment response • Documentation of monitoring effectiveness (5 A’s) at each visit Patient Assessment/Reevaluation

• The 5 “A’s” of Chronic Pain Management ‒ Analgesia ‒ Activities of daily living ‒ Adverse effects ‒ Aberrant drug-taking behaviors ‒ Affect Federation of State Medical Boards Pain Treatment Guidelines

• Documentation of signed written informed consent and treatment agreement Federation of State Medical Boards Pain Treatment Guidelines • Periodic “random” drug testing - Appropriate action if abnormal!! • An accurate record of all treatments and medications prescribed • Having the patient return at appropriate intervals for evaluation - More frequently during initiation of opioid Rx Federation of State Medical Boards Pain Treatment Guidelines • Seek consultation/referral as needed - Pain, psychiatry, addiction, mental health specialist 2. Which of the following statements regarding pharmacotherapy in chronic pain is true? A. Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain B. Neuroleptic malignant syndrome is a concerning side effect of the combined use of tramadol and cyclobenzaprine C. TCA antidepressants have not been shown to be effective in the treatment of diabetic neuropathy D. SSRIs are effective in treating the pain of postherpetic neuralgia CDC Opioid Guidelines 2016 - #1 • Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain • Consider opioid therapy only if expected benefits for both pain and function > risks • Opioids, if used, should be combined with nonpharmacologic and nonopioid pharmacologic therapy Chronic Pain—Management

• Physical modalities • Nonpharmacologic behavioral therapies • Pharmacologic therapies • Neural blockade • Implantable devices Chronic Pain - Nonpharmacologic Physical Modalities •Acupuncture •Physical therapy •Osteopathic manipulation •Chiropractic •Massage therapy •Ultrasound •Spinal cord stimulation Acupuncture

• Acupuncture may reduce the total amount of medication taken by patients with chronic pain. • Studies that looked at more than 60,000 acupuncture treatments have shown no serious adverse events. • Effective for low back pain, DJD, chronic headache Chronic Pain- Nonpharmacologic Behavioral Rx

• Cognitive behavioral therapy (e.g., for coping with pain) • Relaxation • Meditation • Guided imagery • Hypnosis • Biofeedback • Sleep !!!! Pharmacotherapy Guidelines • Monotherapy if possible - Titrate only 1 drug at a time • Improvement in pain • Improvement in function • Limited side effects • Recognition that each patient is different - Individual variation in response Pharmacologic Agents • Acetaminophen • NSAIDs - Traditional - Cox-2 agents • Adjuvant agents • Tramadol/tapentadol - Schedule IV • Opioids Pharmacologic Agents • Adjuvant agents - TCA - SNRI - Anticonvulsants - Centrally acting alpha-adrenergic agents - Muscle relaxants - Topical anesthetics Antidepressants •TCA - Amitriptyline (Elavil) - Nortriptyline (Pamelor) •SNRI - Duloxetine (Cymbalta) - Milnacipran (Savella) Antidepressants (TCA & SNRI) •Demonstrated benefit in randomized studies

Illness Effect size Diabetic neuropathy 1.7 Postherpetic neuralgia 1.4 Tension type headache 1.1 Migraine 0.8 Atypical facial pain 0.8 Fibromyalgia 0.6 Anticonvulsants

• FDA indication for chronic pain ‒ Carbamazepine (eg, Tegretol) ‒ Divalproex sodium (eg, Depakote) ‒ Gabapentin (eg, Neurontin) ‒ Pregabalin (Lyrica) ‒ Topiramate (eg, Topamax) Centrally Acting Alpha-Adrenergic Agents • Clonidine (eg, Catapres) • Trigeminal neuralgia • Chronic back pain • Chronic headache • Cluster headache • Tension type headache • Spastic torticollis • Neuropathic pain Muscle Relaxants

• Cyclobenzaprine (eg, Flexeril) • Carisoprodol (eg, Soma) - May see withdrawal symptoms • Methocarbamol (eg, Robaxin) • Metaxalone (eg, Skelaxin) • Orphenadrine (eg, Norflex) • Tizanidine (eg, Zanaflex) Tramadol (Ultram)

• Weak mu opioid receptor agonist • NNT for 50% improvement in neuropathic pain = 3.8 • Weak SNRI – has antidepressant properties • May cause serotonin syndrome if taking • Cyclobenzaprine, tricyclics, SSRI • May lower seizure threshold Tapentadol (Nucynta)

•Compared to tramadol - Stronger analgesic effect - Weaker serotonin reuptake inhibition - Same norepinephrine reuptake inhibition Marijuana & Chronic Pain •Cannabis - THC- produces a high - CBD (cannabidiol) • Not intoxicating at typical doses •Established indications for medical cannabis - Epilepsy- Lennox-Gastaut - ChemoRx induced N/V - AIDS associated anorexia/wt loss Marijuana & Chronic Pain • Leung,L. Cannabis and Its Derivatives: Review of Medical Use, JABFM, 2011, 24 (4) http://jabfm.org/content/24/4/452.full • Smoked cannabis • Evidence for clinical benefits in HIV-induced neuropathic pain • Oral extract of cannabis • Evidence of relieving self-reported symptoms of spasticity caused by multiple sclerosis • Oromucosal form of cannabis extract • Efficacious for peripheral and central neuropathic pain, especially that caused by multiple sclerosis. Marijuana & Chronic Pain

•Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. Whiting, P. et all, JAMA, June 2015 - There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity •Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems- A Clinical Review. Hill, K. JAMA, June 2015 - Use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence Medical Marijuana 2019.

https://en.wikipedia.org/wiki/Legality_of_cannabis_by_U.S._jurisdiction 3. Which of the following statements is true?

A. Topical analgesics are not typically associated with systemic side effects and drug interactions B. The dose of topical diclofenac (Voltaren 1% gel) is higher for treating osteoarthritis in the upper extremity than in the lower extremity C. EMLA cream, a mixture of lidocaine and diphenhydramine, is FDA- approved for the topical treatment of pain D. Lidocaine 5% patch (Lidoderm) is effective when applied anywhere on the body, not just over the site of pain Topical Analgesics

• Active within the skin, peripheral nerves • No significant serum levels of drug - Few significant systemic side effects - Relatively free of drug interactions Topical Analgesics • ASA • Diclofenac topical (Voltaren gel) - 2 g QID for upper extremity joints - 4 g QID for lower extremity joints • Capsaicin - Neuropathic pain & DJD - Effectiveness limited by side effects & compliance • Local anesthetics - EMLA • Eutectic mixture of lidocaine & prilocaine • Used as a topical anesthetic prior to skin punctures • Not FDA-approved for pain - Lidocaine patch 5% (Lidoderm) Topical Lidocaine Patch 5% (Lidoderm) • Up to 3 patches at a time over painful site - 12 hrs duration - Can be cut if needed • Side effects - Application site sensitivity - Systemic side effects rare • Mechanical barrier may decrease allodynia • Efficacy demonstrated for postherpetic neuralgia Opioids

Prof. Dr. Otto Wilhelm Thomé ''Flora von Deutschland, Österreich und der Schweiz'' 1885, Gera, Germany 4. Which of the following statements regarding opioids is true? A. Opioids have been shown to be effective for cancer- related pain, but not for neuropathic pain B. A realistic goal of opioid therapy is complete pain relief C. It is unnecessary to identify individuals at risk for substance abuse prior to beginning opioid therapy D. Treatment should begin with short-acting agents, then titrated to optimal effect Opioid Epidemic •399,000 opioid overdose deaths from 1999-2017 •Waves - 1st – 1990’s – prescription opioids - 2nd – 2010 – heroin - 3rd – 2013 – fentanyl Opioid Epidemic •Overdose death rate increase paralleled increase in prescription analgesic drug sales •Drug overdose is now the leading cause of accidental death in US (MVA = #2) - 2016 data (Per CDC) •63,000 lethal drug OD •40,000 OD related to prescription analgesics Efficacy of Opioids for Chronic Pain

• Good evidence for effectiveness in pain from cancer • Cochrane review 2010 - Weak evidence that opioids reduce chronic non- cancer pain in some highly selected patients • Busso & Kamaleldin 2018 - Opiods provide benefit in non-cancer related pain but magnitude of benefit is small Efficacy of Opioids for Chronic Pain •Older Cochrane review - 45% of pts have 50% reduction in pain scores • Osteoarthritis • Neuropathic pain • Back pain • Patients with chronic diffuse centralized pain - HA, fibromyalgia, abdominal pain, pelvic pain - Less likely to benefit from opioids - More likely to be harmed from opioids CDC Opioid Guidelines 2016 - #2 • Before starting opioid therapy for chronic pain • Establish treatment goals with all patients • realistic goals for pain and function • consider how therapy will be discontinued if benefits < risks • Continue opioid therapy only if there is • clinically meaningful improvement in pain & function > risks to patient safety. Opioid Therapy—Realistic Goals • Complete pain relief rarely achieved • Common goals include ‒ Pain reduction ‒ Improvement in selected areas of function ‒ Improved mood ‒ Improved work Prior to Opioid Use

• Focal or treatable pain generators should be identified and treated • Use physical and psychological modalities • Attempt restoration of sleep • Treat mood disorders • Use nonopioid/adjuvant analgesics Initiating Opioid Therapy

• Informed consent & treatment agreement • Opioid therapeutic trial < 90 days • Begin with short-acting agents - Titrate to optimal effect • Aggressively/proactively manage side effects • Drug screening at onset and at least every 12 months • Reassessment - Is the medication improving function? - If not, implement exit strategy. CDC Opioid Guidelines 2016 - #4

• When starting opioid therapy for chronic pain • Prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids CDC Opioid Guidelines 2016 - #9

• Review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data • Receiving opioid dosages or dangerous combinations at high risk for overdose • Review PDMP data when • Starting opioid therapy for chronic pain • Periodically during opioid therapy for chronic pain • ranging from every prescription to every 3 months. Opioid Risk Tool

Female Male Family Hx EtOH 1 3 Family Hx Illicit Drugs 2 3 Family Hx Rx Drugs 4 4 Patient Hx EtOH 3 3 Patient Hx Illicit Drugs 4 4 Patient Hx Rx Drugs 5 5 Age 16-45 1 1 Hx preadolescent sex abuse 3 0 ADHD/OCD/Bipolar/Schizophrenia 2 2 Depression 1 1 0-3 = low risk, 4-7 = mod risk, > 8 = high risk 5. Which of the following statements regarding opioids is true?

A. There are 3 opioid receptors: phi, beta, & kappa B. When prescribing opioids for acute pain, more than 7 days supply will rarely be needed C. Oxycodone is roughly 3x as potent as morphine D. Transdermal fentanyl is indicated for acute and postop pain management Opioid Receptors • Three opioid receptor classes ‒ Mu •Morphine ‒ Kappa •Butorphanol ‒ Delta •Enkephalins CDC Opioid Guidelines 2016 - #5

• When opioids are started, clinicians should prescribe the lowest effective dosage. • Use caution when prescribing opioids at any dosage • Carefully reassess evidence of individual benefits and risks when increasing dosage to > 50 oral morphine milligram equivalents (MME) or more per day • Avoid increasing dosage to 90 oral MME or more per day • Or carefully justify a decision to titrate dosage to this level CDC Opioid Guidelines 2016 - #6

• When opioids are used for acute pain • Prescribe the lowest effective dose of immediate- release opioids • Prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids • 3 days or less will often be sufficient • More than 7 days will rarely be needed Short-Acting Opioids

• Morphine sulfate • Codeine • Hydrocodone (eg, Vicodin, Lortab, Lorcet, Norco, Vicoprofen) • Oxycodone (eg, Percocet, Percodan) • Hydromorphone (eg, Dilaudid) • Oxymorphone (eg, Opana) • Fentanyl (eg, Actiq) Long-Acting Opioids

• Methadone (eg, Dolophine, Methadose) • Sustained-release morphine (eg, MS Contin, Kadian) • Sustained-release oxycodone (eg, Oxycontin) • Sustained-release hydromorphone (Exalgo) • Buprenorphine/naloxone (eg, Suboxone) • Transdermal buprenorphine (Butrans) • Transdermal fentanyl (eg, Duragesic) Long-Acting Opioids • Must be opioid tolerant prior to using: - Transdermal fentanyl - ER hydromorphone - High doses of most long-acting opioids • Opioid tolerant - Taking 60 mg morphine, 25 mcg fentanyl, 30 mg oxycodone, 8 mg hydromorphone, 25 mg oxymorphone per day - Duration > 1 week Long-Acting Opioids

• ER tablets should be swallowed whole ‒ Do Not cut, crush, break • Some ER morphine capsules can be opened and sprinkled on applesauce • Transdermal patches should be used intact ‒ Do Not cut or tear or expose to heat • Improper administration can lead to rapid absorption of high doses of opioids, overdose, respiratory depression, and death Opioid Equianalgesic Doses

Drug Proprietary PO IM ½ life Duration Name (mg) (mg) (hrs) (hrs)

Morphine 30 10 2-3 2-4

Morphine CR MS Contin 30 10 2-3 8-12

Morphine SR Kadian 30 10 2-3 24 Opioid Equianalgesic Doses

Drug Proprietary PO IM (mg) ½ life Duration Name (mg) (hrs) (hrs)

Oxycodone Roxicodone 20 2-3 3-4

Oxycodone CR Oxycontin 20 2-3 12

Oxymorphone Numorphan 10 1 2-3 2-4

Management of cancer pain: Pharmacotherapy. Pain management: The online series, module 11. American Medical Association, 2006 Opioid Equianalgesic Doses

Drug Brand PO (mg) IM (mg) ½ life Duration Name (hrs) (hrs)

Buprenorphine Butrans 0.4 0.3 2-7

Codeine 180 3-4 250 mcg Fentanyl Sublimaze 7-12 IV = 4 mg/hr Fentanyl TTS Duragesic 16-242 48-72 Hydrocodone (+ Lortab, 30 3-4 acetaminophen) Vicodin Opioid Equianalgesic Doses Drug Proprietary Name PO IM ½ life Duration (hrs) (mg) (mg) (hrs)

Hydromorphone Dilaudid 7.5 1.5 2-3 2-4

Levorphanol Levo-dromoran 4 2 12-15 4-6

Meperidine Demerol 300 100 6-8

Methadone **(variable) Dolophine 8 10 12-190 4-12 Tapentadol Nucynta 100 6 Tapentadol ER Nucynta 100 12 Conversion to Long-Acting Opioid • With long term opioid Rx for chronic pain, conversion from a short-acting to a long- acting opioid can be a reasonable choice Long-acting opioids may provide a more stable blood level Fentanyl or Buprenorphine Patch • 25 mcg/hr of the fentanyl patch (Duragesic) is equivalent to 60-135 mg per day of orally administered morphine • Can provide pain control in patients who are unable to swallow medications • Can be applied by the patient, a family member, or other caregiver Fentanyl or Buprenorphine Patch • Contraindications ‒ Not opioid tolerant ‒ Acute pain or pain of short duration ‒ Postop pain ‒ Mild pain ‒ Intermittent pain • Remove fentanyl patch prior to MRI 6. Which of the following is correct?

A. One should avoid prescribing opioids and benzodiazepines concurrently B. Withdrawal symptoms are not seen with cessation of long-acting narcotics, ie, methadone C. Miosis is noted during opioid withdrawal D. Opioid withdrawal precipitated by narcotic antagonists is typically severe and often life threatening CDC Opioid Guidelines 2016 - #7 • Evaluate benefits and harms with patients • Within 1 to 4 weeks of starting opioid therapy for chronic pain • With dose escalation • With continued therapy, at least every 3 months • If benefits do not outweigh harms of continued opioid therapy • Optimize other therapies • Taper opioids to lower dosages • Taper and discontinue opioids Opioid Side Effects

• Constipation • Respiratory depression • Sedation • Nausea/vomiting • Dizziness/orthostatic hypotension • Mental confusion • Itching • Edema • Decreased libido • Opioid-induced hyperalgesia CDC Opioid Guidelines 2016 - #11

• Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible. CDC Opioid Guidelines 2016 - #8 • Before starting and periodically during continuation of opioid therapy • Evaluate risk factors for opioid-related harms • Incorporate strategies to mitigate risk • Consider offering naloxone if increased risk for opioid overdose • history of overdose • history of substance use disorder, • higher opioid dosages (≥50 MME/d) • concurrent benzodiazepine use Naloxone •Medical setting −IV/IM/SC −0.4-2.0 mg q 2-3 min until response •Nasal spray (Narcan) −Single use, single dose −4 mg/actuation •Auto-injector (Evzio) −2 auto-injectors/carton −0.4 mg (old) – 2 mg subcut or IM Opioid Withdrawal

• After cessation of opioid • Use of partial agonists - Buprenorphine (Buprenex) • Use of agonist-antagonists - Pentazocine (Talwin), nalbuphine • Use of antagonist - Naloxone (Narcan) Opioid Withdrawal

• May begin 6 to 12 hours after the last dose of a short- acting opioid - Persist for several days • 24 to 48 hours after cessation of methadone - Persist for several weeks • May begin immediately after reversal with antagonist - Usually mild, but potentially life-threatening in compromised patients • Peak within 24 to 48 hours of onset Opioid Withdrawal • Symptoms ‒ Nausea, vomiting ‒ Abd pain ‒ Diarrhea ‒ Goose bumps ‒ Excessive yawning ‒ Tremors ‒ Myalgias & arthralgias ‒ Rhinorrhea ‒ Lacrimation ‒ Anxiety & restlessness Opioid Withdrawal • Physical findings ‒ Mydriasis ‒ Yawning ‒ Hyperactive bowel sounds ‒ Piloerection ‒ Tachycardia ‒ Hypertension or hypotension ‒ Tachypnea Opioid Withdrawal •Treatment - Naturally occurring withdrawal • Either opioid or nonopioid adjunctive medication • Methadone 10 mg IM or 20 mg PO - Usually sufficient to relieve symptoms of withdrawal without producing intoxication • Clonidine (Catapres) - 0.1-0.3 mg PO every hour • Benzodiazepines • Antiemetics • Antidiarrheals Opioid Withdrawal

• Treatment - Iatrogenic withdrawal (from an opioid antagonist) • Adjunctive medications should be used rather than opioids Opioid-Associated States

• Tolerance • Physical dependence • Addiction • Pseudo-addiction Tolerance

• Continued exposure to a drug induces changes that result in a decrease in drug effects over time Physical Dependence

• State of adaptation manifested by drug class – specific withdrawal syndrome • Precipitated by - Abrupt cessation - Dose reduction - Decreased blood level - Administration of antagonist Addiction (ASAM 2011)

• “Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social and spiritual manifestations. This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors. • Addiction is characterized by inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.” Pseudo-Addiction

•Latrogenic syndrome of behaviors developing as a result of inadequate pain control •Behaviors disappear when pain is adequately controlled, unlike addiction •Controversial –Not recognized in latest Federation of State Medical Boards definition list Aberrant Drug-Related Behaviors— Addiction • Rx forgery • Concurrent use of illicit drugs • Recurrent Rx losses • Selling Rx drugs • Stealing or borrowing drugs • Getting meds from nonmedical sources • Frequent unsanctioned dose escalations CDC Opioid Guidelines 2016 - #12

• For patients with opioid use disorder • Offer or arrange evidence-based treatment • medication-assisted treatment with buprenorphine or methadone • Requires separate DEA registration as a narcotic treatment program and applicable CSAT and federal and state agency approvals • in combination with behavioral therapies 7. Which of the following statements is true?

A. Pain management (informed consent & treatment) agreements have been proven to dramatically decrease the incidence of addiction B. Pain management (informed consent & treatment) agreements are recommended for all chronic opioid-receiving patients by the Federation of State Medical Boards and the CDC C. Pain management (informed consent & treatment) agreements typically mandate regularly scheduled, as opposed to periodic, drug testing D. Synthetic and semisynthetic opioids like oxycodone, fentanyl, and methadone are usually detected in immunoassay-based urine drug testing CDC Opioid Guidelines 2016 - #3

• Before starting and periodically during opioid therapy, discuss with patients • Known risks and realistic benefits of opioid therapy • Patient and clinician responsibilities for managing therapy Pain Management Agreements (Informed Consent & Treatment Agreements) • Frequently recommended by experts in chronic pain management • Recommended by Federation of State Medical Boards and CDC • No studies have demonstrated a reduction in the incidence of addiction or abuse when contracts are used Pain Management Agreements (Informed Consent & Treatment Agreements) • Sample PMA • https://www.nhms.org/content/examples-opioid- informed-consent-agreement • New Hampshire Medical Society • Sample opioid prescribing checklist • https://www.nhms.org/sites/default/files/Pdfs/1-4- 17Opioid_Patient_Checklist_Med_502_Opioid_Prescribin g_Rules.pdf Pain Management Agreements (Informed Consent & Treatment Agreements)

• Potential risks & benefits of opioid Rx • Potential side effects • Likelihood of tolerance/physical dependence • Risk of opioid misuse, addiction, overdose • Risk of drug interactions, oversedation, and impaired motor skills Pain Management Agreements (Informed Consent & Treatment Agreements) • Goals of treatment • Patient responsibility for safe medication use • Patient responsibility to obtain opioids from only one source • Patient agreement to periodic drug testing • Provider’s prescribing policies and expectations • Provider’s responsibility to be available or have coverage for unforeseen problems/scheduled refills • Reasons why therapy may be changed/stopped CDC Opioid Guidelines 2016 - #10 • When prescribing opioids for chronic pain • Use urine drug testing before starting opioid therapy • Consider urine drug testing at least annually • assess for prescribed medications • other controlled prescription drugs • illicit drugs Urine Drug Testing

• Enzyme-linked immunoassay testing of antibodies is usually the first urine drug test done because it is quick and may be used to test for multiple drugs at once • Immunoassay testing is not always accurate for detecting all drugs and there is sometimes cross- reactivity with others • Use gas chromatography/mass spectrometry (GCMS) for specific drug testing Urine Drug Testing • Morphine and codeine usually are detected accurately • Synthetic and semisynthetic opioids like oxycodone, fentanyl, and methadone are not always detected with immunoassay - Can be specifically tested with GC/MS Urine Drug Testing

• Cocaine testing has a low degree of cross-reactivity and is generally a true positive (within 48 hrs of last exposure) • A negative test for benzodiazepines may not be accurate because it sometimes does not detect recent use • Tests for amphetamine/methamphetamine have a high degree of cross-reactivity to other sympathomimetics like ephedrine or pseudoephedrine Continue Opioid Therapy

• If there is ‒ Improvement in ADLs and psychosocial functioning ‒ Effective pain relief ‒ Lack of significant side effects ‒ Lack of aberrant behaviors •If not, consider exit strategy ‒ Tapering off opioids Opioid Exit Strategy

• Discontinue opioids ‒ Test positive for illicit drug use ‒ Threatening behavior to provider/staff ‒ Forgery/diversion ‒ Drug OD/intoxication • Tapering off opioids ‒ Gradual • 10% dose reduction every 1-4 weeks ‒ Rapid • 25% dose reduction every 3-7 days When to Refer to Pain Specialist • > 90 mg/day of morphine (oral) equivalent • History of abuse or drug-related offenses • Failure to improve with multiple trials of medications • Selected patients who could benefit from invasive therapy, ie. steroid epidural injection • Consider psychological evaluation in all patients Answers

1. A 2. A 3. A 4. D 5. B 6. A 7. B Thank you! Supplemental Slides Management of Chronic Pain Chronic Low Back Pain Nonpharmacologic Rx

•Intensive interdisciplinary rehabilitation •Exercise therapy •Acupuncture •Massage therapy •Spinal manipulation •Yoga •Cognitive-behavioral therapy •Progressive relaxation Fibromyalgia – Nonpharmacologic Rx

• Moderate aerobic exercise • Muscle strengthening • EMG biofeedback • Patient education • Hypnosis • Cognitive behavioral therapy • Acupuncture • Chiropractic manipulation • Therapeutic massage • Balneotherapy • Tender point injection • Sleep Osteoarthritis – Nonpharmacologic Rx •Joint protection •Diet/wt loss •Exercise •Temperature modalities •Ultrasound •Hydrotherapy •PT/OT •Patient education Migraine – Nonpharmacologic Rx

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