Diarrhea, “Answers”

Acute gastrointestinal disorders are some of the most frequent problems evaluated by ED physicians.  Complaints of diarrhea account for almost 5% of visits to the emergency departments (Bitterman, 1988).  Although the disease entity is extremely prevalent and current evidence on the subject is nothing short of “voluminous,” practice differences among ED physicians in its evaluation and management are as varied and inconsistent as the stools themselves.

1. When do you send stool cultures, stool ovum and parasites, and/or fecal WBC? How do you use the results in diagnosis and management?

EML Diarrhea Answers

Stool evaluation of fecal leukocytes (WBC) and occult blood is sent in many ED’s as a positive result has traditionally been thought to be predictive of either an inflammatory or infectious etiology of the diarrhea. Fecal WBC’s and RBC’s are generally found in stool infected with invasive bacterial pathogens such as Salmonella, Shigella, Campylobacter, Enteroinvasive E-coli, Enterohemorrhagic E-col( E-coli 0157-H7), but also in stools of patients with inflammatory disorders such as Crohn’s disease, Ulcerative Colitis, and pseudomembranous colitis. Studies show a sensitivity for predicting bacterial infection for fecal WBC ranging from 40% (Chitkara, 1996) to 73% (Thielman, 2004). Fecal WBC testing also appears to have a specificity of approximately 85% (Thielman, 2004) for bacterial pathogens.

Many studies have demonstrated that fecal occult blood testing (FOBT) is nearly equivalent in sensitivity to fecal WBC in predicting the presence of an invasive bacterial pathogen. One large, well-designed study of 1040 patients with acute diarrhea found that a negative FOBT had a negative predictive value of 87% for invasive bacterial pathogens (McNeely, 1996). Another large study of 446 children demonstrated an 88% sensitivity for the combination of bloody diarrhea by history, positive fecal WBC and positive FOBT for predicting a bacterial pathogen  (Huicho, 1993).

Underpinning the problems inherent in many of these studies is that the gold standard for determining sensitivities, specificities and predictive values was often stool cultures, which themselves have not been shown to be the greatest of tests (as we will discuss). What do we do with these results then, you ask? Well, there is no consensus on when to order fecal WBC or occult RBC’s, however, guidelines by the Infectious Disease Society of America (IDSA) and the American Association of Gastroenterology (AAG) recommend a selective approach since most run-of-the-mill cases of infectious diarrhea are viral in etiology, self-limiting and do not require any testing. They recommend testing patients at high risk for invasive bacterial pathogens (fever > 101.3, severe, or persistent diarrhea (> 7 days), severe abdominal pain, bloody diarrhea, the immunocompromised, elderly or systemically ill patients) (Guerrant, 2001).

Stool cultures, though frequently ordered in the ED, are notoriously poor at identifying bacterial pathogens as a result of their relatively low yield. In six studies conducted between 1980 and 1997 only 1.5%-5.6% of cases grew positive stool cultures. This results in a cost of about $1000 for each positive culture (Guerrant, 2001). Similar low yields have been duplicated by other studies as well. Most people are also unaware that routine stool cultures in most laboratories don’t test for ALL possible pathogens, but primarily identify Shigella, Campylobacter, and Salmonella only.  All other bacteria, including E-coli O157-H7 usually require special requests. As a result, most guidelines also recommend only sending stool cultures in high-risk patients (as denoted above), plus those with positive fecal WBC/occult blood, or those patients being admitted for their diarrhea. The vast majority of patients will not require stool cultures (Dupont, 2014).

Lastly, in developed countries, routine use of stool ova and parasite testing is rarely indicated (Siegel, 1990). Primarily it is used to help identify diarrhea caused by parasites including Giardia, EntamoebaCyclospora and Cryptosporidium. As these pathogens are relatively rare in the US, only consider sending these tests in travelers recently returning from Russia (Giardia and Cryptosporidium) or the mountainous regions of North America (Giardia), in AIDS-associated diarrhea (Cryptosporidium), those exposed to infants at a daycare center (Giardia and Cryptosporidium), or longstanding diarrhea not responsive to antibiotic therapy. If you clinically suspect any of these pathogens be sure to send multiple samples for stool ova and parasites to improve the yield, as parasite excretion may be intermittent.

Bottom line: It is prudent to order fecal WBCs as a screening test in high risk patients (denoted above), as it may help you determine the presence of an invasive bacterial pathogen, but in these patients an FOBT may be easier, cheaper, and just as good.  Stool cultures should be sent if fecal WBC/RBC testing is positive, or if patients are being admitted for their diarrhea. Stool O&P is rarely indicated or cost-effective in the US except for very few special circumstances (denoted above).  


2. When do you get bloodwork? When do you pursue imaging?

Most patients who present to the ED with acute diarrhea will have a self-limited disease course. However, many physicians often reflexively order a set of basic labs in these patients to check for any “electrolyte disturbances” from the presumed water loss. Many studies have shown that routine blood work in these patients is unnecessary. In a study by Olshaker, et al., 281 adult patients with acute gastroenteritis were retrospectively reviewed and only 1% of patients were found to have a clinically significant electrolyte abnormality that required treatment or affected disposition. None of the patients with acute gastroenteritis alone had electrolyte abnormalities. They also found that the time spent in the ED was 3-4 times longer for those patients who had electrolytes ordered (Olshaker, 1989).

Routine CBC is also unnecessary in most patients with acute diarrhea as an elevated WBC is non-specific. A hemoglobin level may be appropriate in cases of large amounts of bloody diarrhea. A platelet count may be helpful in children with bloody diarrhea in which you are concerned about Hemolytic Uremic Syndrome (HUS) as a further complication, but otherwise these tests are largely unhelpful.

So does this mean we should never order routine lab work on anyone with acute diarrhea? Not necessarily. The above description and evidence is primarily true for cases with a self-limited diarrhea that is likely due to a viral or non-invasive bacterial pathogen (the majority of patients seen in the ED). In the smaller subgroup of patients with risk-factors for invasive bacteria (i.e., high fever, severe or persistent diarrhea (> 7 days), severe abdominal pain, bloody diarrhea, positive fecal WBC or fecal occult blood, the immunocompromised, elderly, or systemically ill/toxic appearing patients), obtain at least a CBC and BMP to assist with your evaluation and treat any electrolyte abnormalities that may be present (Dupont, 2014).

Similarly, most patients seen in the ED with acute diarrhea do not need any imaging to be performed.  It is important, however, to expand your differential diagnosis outside of infectious etiologies of diarrhea to identify the subset of patients at risk for other pathologies for whom further imaging may be warranted.

For example, patients with appendicitis may also present with diarrhea.  Usually vomiting and diarrhea precede abdominal pain in infectious diarrhea, whereas vomiting often follows abdominal pain in patients with appendicitis.  In a study of 181 children < 13yrs old who were eventually discovered to have appendicitis, 27% were initially misdiagnosed, and many of those children presented with diarrhea as an initial symptom (Rothrock, 1991).  Ischemic bowel disease should also be on the differential diagnosis in elderly patients with severe abdominal pain and a history of vascular disease as these patients may also present with occasional diarrhea and bloating (Tabrez, 2001).  If ischemic bowel disease is being considered, a contrasted CT of the abdomen and pelvis should be ordered.  Furthermore, small bowel obstruction and diverticulitis can often present with diarrhea, but may not be diagnosed unless formal imaging is obtained.

Be extra cautious in evaluating elderly patients with diarrhea and abdominal pain as these patients tend to have more serious, often surgical, illnesses that present atypically or go unrecognized longer (Hendrickson, 2003).

Bottom line: most patients seen in the ED with acute diarrhea require no routine blood work unless the patient has high-risk features. Imaging is also usually not necessary unless you are considering other diagnoses including appendicitis, mesenteric ischemia, small bowel obstruction, and diverticulitis.  


3. Which patients do you treat with antibiotics?

Whether or not to prescribe antibiotics and to which patients is one of the most controversial and most discussed aspects of the management of diarrhea. Analyzing all the evidence currently available is enough to cause one to have diarrhea in and of itself, but fear not. Let’s break it down in pieces . . .

Why give antibiotics in the first place, you ask, if many of these disease processes are self-limited?  In various studies, antibiotics appear to decrease the length of the diarrhea symptoms by about 24-48 hrs regardless of whether the diarrhea was guiac positive, fecal WBC positive, or had positive stool cultures  (Guerrant, 2001; Dryden, 1996Wistrom 1992).  The moderately to severely ill seem to benefit more from antibiotics.  Why would antibiotics decrease symptoms in culture negative stools? Some believe the antibiotics are eradicating bacterial pathogens that stool cultures were unable to detect. Traditionally it was thought that antibiotics may not be beneficial in mild-moderate diarrhea, due to their tendency to prolong the carrier state, especially amongst those infected with Salmonella.  However, newer studies show and that carrier rates are approximately equivalent in those treated with or without antibiotics (Dryden, 1996).

So now that we understand why we may give antibiotics, the question becomes who we should give them to? Many experts argue that most patients, regardless of symptoms and lab test results, don’t need antibiotics since most acute diarrheal illnesses are self-limited.  Additionally, further prescription of antibiotics will lead to increased drug resistance and side-effects. Other guidelines, including those from the IDSA and AAG, provide a more conservative approach. They state patients should receive antibiotics if they are presenting with symptoms of traveler’s diarrhea, as immediate treatment can reduce symptom duration by 2-3 days (Guerrant, 2001).  They further recommend antibiotic therapy in those patients with high fever (>101.3), history suspicious of a moderate-severe bacterial infection, guiac positive stools or positive fecal WBC (Guerrant, 2001).  Some criticize the IDSA guidelines for relying too heavily on stool testing to decide whether or not to give antibiotics.

Just as important as knowing which patient to give antibiotics to is knowing which patients to be cautious about giving antibiotics. In general, antibiotics are not advised for the treatment of diarrhea in most pediatric patients.  The cornerstone of treatment in pediatric patients is fluid replacement. Inadequate fluid replacement leads to the 9% of hospitalizations in children < 5 yrs of age caused by diarrhea (Cicirello, 1994).  Caution is also advised in prescribing antibiotics in patients with grossly bloody diarrhea.  This is because one of the common causes of grossly bloody diarrhea is Enterohemorrhagic E-coli (AKA E-coli 0157-H7).  Various studies (including one published in the New England Journal of Medicine in 2000) demonstrated higher risk of HUS in pediatric patients with EHEC who were treated with antibiotics (Wong, 2000).  There is also concern that elderly patients with EHEC may develop TTP if treated with antibiotics.

If you decide to give antibiotics to a patient with an acute diarrheal illness, which antibiotics should you give? Most studies and current guidelines recommend ciprofloxacin to help eradicate acute bacterial pathogens. Two basic regimens exist, either a one-time dose of ciprofloxacin 1gm or a regimen of ciprofloxacin 500mg twice/day x 3 days.  Some regimens use macrolides, as fluoroquinolones will not be effective in cases of Campylobacter (Dupont, 2014).

Bottom line: In most cases of watery diarrhea, no antibiotics are needed as the disease is usually self-limiting. When there is concern for invasive disease (positive fecal WBCs or RBCs, or young, adult, healthy patients with grossly bloody stools), it may be reasonable to prescribe ciprofloxacin 500mg BID x 3 days to help reduce symptoms by 24-48 hours (although many sources argue that this is unnecessary)Also, be cautious in giving antibiotics to pediatric and elderly patients with grossly bloody diarrhea as HUS and TTP are concerns.      


4. What other medications do you use? Loperamide, Lomotil, Pepto? What about probiotics?

Loperamide (Imodium) is a peripheral opioid receptor agonist that acts on the mu-opioid receptors in the myenteric plexus of the large intestine without affecting the mu-receptors in the CNS. It works by slowing gastrointestinal motility, thereby allowing more time for fluid and electrolytes to be absorbed from the fecal material. Loperamide is generally considered to be safe in most acute infectious diarrhea in patients who are afebrile and have non-bloody diarrhea and those individuals with chronic diarrhea from inflammatory bowel disease (Gore, 2003).

In those with more severe illnesses (immunocompromised, bloody diarrhea, fever > 101.3), some experts believe the use of Loperamide will allow the invasive bacteria to remain in the gut for a longer period of time and potentially worsen the acute diarrheal illness. However, there is evidence that supports the use of Loperamide in sicker patients in combination with antibiotics. In two studies, one in Thailand on patients with dysentery and another amongst US soldiers with traveler’s diarrhea, the use of Loperamide effectively reduced the number of loose bowel movements compared to placebo when given in adjunct with ciprofloxacin (Petrucelli, 1992; Murphy 1993).

Loperamide may increase the risk of HUS in pediatric patients (Guerrant, 2001Cimolai, 1990) and many guidelines advise against the use of anti-motility agents in pediatric patients.

Lomotil (diphenoxylate/atropine) is a combined opiate-agonist (diphenoxylate) and anticholinergic (atropine) agent that is also available as an adjunct for symptomatic treatment of diarrhea. The diphenoxylate component acts on the mu-receptors of the gut wall in a similar fashion to Loperamide, however, its mu effects are not restricted to the periphery and may cross into the CNS. As a result, atropine is combined in the medication to discourage overdose. From the drug description alone, it can be seen that this medication may be more dangerous and habit-forming than Loperamide in treating the acute symptoms of diarrhea. Diphenoxylate has not been studied in any randomized clinical trials and is not recommended by many experts for symptomatic treatment of acute diarrhea.

Bismuth subsalicylate, sold most commonly under the brand name Pepto-Bismol functions as an anti-secretory, anti motility agent with some weak but present bactericidal properties. As it is a salicylate, its toxicologic considerations, especially in pediatric patients, require extreme caution and likely avoidance in small children out of concern for at home dosing misadventures. Very little rigorous study of Pepto exists, with some volunteer reports of its use in traveler’s diarrhea in military personnel decreasing symptoms subjectively (Putnam, 2006). One double-blinded randomized study of Bangladeshi children aged 4-36 months found a modest improvement in acute diarrheal illness (Chowdhury, 2001). AN open label study in volunteers found loperamide to be faster and more effective than Pepto in adults (Dupont, 1990). Pepto, though, may be particularly useful in cases of norovirus, a common cause of acute diarrhea (Pitz, 2015). If toxicity is avoided in dosing, there is little downside in including this in a patient’s antidiarrheal armamentarium.

Probiotics are live organisms found in a variety of foodstuffs that have been used to help colonize the intestine with “good bacteria” to prevent or treat both infectious and antibiotic associated diarrhea. Lactobacillus is one of the most widely available and studied of these probiotics. In the Cochrane Review of over 23 studies involving over 1900 adults and children, probiotics were found to reduce the overall risk of having diarrhea at 3 days by approximately 35% and reduced the duration of the diarrhea by approximately 30 hours (Allen, 2004). Multiple other studies show similar results while also demonstrating a good safety profile.

In regards to the use of probiotics in the prevention of antibiotic-associated diarrhea, the largest meta-analyses was conducted in 2012 (62 studies, 11,000 patients). A majority of the included studies used Lactobacillus as the probiotic and found a 42% lower risk of developing antibiotic associated diarrhea than control groups (RR 0.58, 95% CI 0.5-0.68) with a number needed to treat (NNT) of 13 to prevent one case of antibiotic associated diarrhea (Hempel, 2012).

Bottom line: Loperamide (Imodium) may be useful and safe in most cases of acute diarrhea, however, some caution should be advised in the severely ill and in and those with bloody diarrhea unless an antibiotic is concurrently prescribed. Loperamide should be avoided in pediatric patients. Lomotil is not recommended for symptomatic relief. Probiotics (specifically Lactobacillusare showing promising evidence for their use in the prevention and treatment of both infectious and antibiotic associated diarrhea.    

Author: Bhandari  Editors: Swaminathan, Bryant


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Diarrhea, Questions

1. When do you send stool cultures, stool ovum and parasites, and/or fecal WBC? How do you use the results in diagnosis and management?
em lyceum diarrhea2. When do you get bloodwork? When do you pursue imaging?
3. Which patients do you treat with antibiotics?
4. What other medications do you use? Loperamide, Pepto, Lomotil? What about probiotics?
Posted in antibiotics, diarrhea, lomotil, loperamide, parasites, pepto | 3 Comments

Status Asthmaticus, “Answers”

1. When do you use NIPPV in status asthmaticus?

The use of NIPPV (non-invasive positive pressure ventilation) for respiratory failure has been proven to be beneficial and widely accepted in practice for multiple indications including COPD exacerbations and pulmonary edema from CHF. As it has been shown to work in these disease processes, there is naturally interest in determining whether NIPPV would be useful as a treatment modality for severe asthma exacerbations or status asthmaticus. By providing external PEEP, NIPPV is proposed to offset the intrinsic PEEP of bronchospasm, which results in alveolar recruitment, improved ventilation-perfusion mismatch, and decreased work of breathing (Lim, 2012). According to the Global Initiative for Asthma (GINA, 2015), a severe asthma exacerbation is clinically defined as a patient who talks in words only (rather than in full sentences), sits hunched forward, agitated, RR >30 breaths/min, accessory muscle usage, pulse rate >120, SpO2 <90% on room air or PEFR </= 50% of predicted. Additionally, after one hour of therapy if PEFR or FEV1 remains <60% of predicted, then the patient is considered as having a severe asthma exacerbation. These patients are the ones in whom we are interested in knowing if NIPPV has any benefit.

EML Status asthmaticus answersThere have been several randomized, controlled trials that directly compare NIPPV to standard medical therapy in severe asthma. Brandao, et al. (2009), randomized 36 patients with an FEV1 <60% of predicted to receive standard therapy, bi-level NIPPV (Inspiratory positive airway pressure = 15cm H2O, Expiratory positive airway pressure = 10cm H2O) or bi-level NIPPV (IPAP= 15 cm H2O, EPAP = 5cm H2O). When they analyzed FVC, FEV1, PEF and FEV25-75% at 30 minutes after initiation of therapy, the low EPAP NIPPV group showed statistically greater improvement in FVC, FEV1, PEF and FEV25-75% when compared to the standard therapy group. Interestingly, the high EPAP group only showed significant difference in improvement in peak-expiratory flow.

Two additional studies, Soroksky, et al. (2003) and Gupta, et al. (2010), reported rates of endotracheal intubation as well as mortality, in addition to objective respiratory parameters. Soroksky, et al. randomized 30 patients with severe asthma (defined by FEV1 <60% of predicted) to receive either nasal bi-level NIPPV or placebo with a sham device providing a pressure of 1cm H2O. This study showed a greater improvement in FEV1 in the NIPPV group compared to the placebo group at both 3 and 4 hours. Additionally, they reported greater improvement from baseline in PEFR, FVC and respiratory rate at both 3 and 4 hours in the NIPPV group. No patients in either group died or were intubated. Finally, in Gupta, et al. 53 patients with severe asthma who were admitted to a pulmonary ICU were randomized to NIPPV or standard asthma therapy. This study showed a trend toward improvement in a number of patients with FEV1>50% improvement from baseline in the NIPPV group, though this trend did not reach statistical significance. Interestingly, there was a statistical advantage in both ICU length of stay and hospital length of stay in the NPPV group with the NIPPV group requiring almost half the amount of time in the ICU (10hr versus 24 hr; p=0.01) and a shorter total hospital stay (38hr versus 54 hr; p= 0.01). There were two patients in the NPPV group who went on to intubation, though the difference was not statistically significant.

There was also a 2012 Cochrane Review, which performed a meta-analysis on these and several other studies on the use of NIPPV in acute asthma (Lim, 2012). This analysis also showed no benefit for NIPPV with respect to intubation or mortality, but did show that NIPPV may improve both ICU length of stay as well as total hospital length of stay in the asthmatic patient. The meta-analysis also confirms the difference in respiratory parameters noted in Soroksky and Gupta, namely that patients in a ward setting were more likely to show improvement in pulmonary function parameters with NIPPV than their ICU counterparts indicating that asthma severity requiring admission to an ICU may predict failure of NIPPV.

With respect to pediatrics, several studies have shown a potential benefit in the setting of both moderate and severe asthma. Though multiple observational studies and case reports exist (Akingbola, 2002; Carroll, 2006; Beers, 2010; Williams, 2010) which all support the safety and potential efficacy of NIPPV in pediatrics patients. Basnet, et al. (2012) represents the largest prospective, randomized-controlled trial specifically looking at NIPPV in the setting of pediatric status asthmaticus. Though this study suffers from low numbers with only 20 patients randomized, it does show a statistical benefit in the NIPPV group with regards to clinical asthma scores, respiratory rate, and supplemental oxygen need. In this study, one patient was discontinued from NIPPV for persistent cough.

Bottom Line: NIPPV has not been shown to be superior to standard therapy with respect to mortality or need for intubation, though it does appear to potentially show a benefit with respect for hospital length of stay and other respiratory effort parameters. NIPPV has also been shown to be safe for use in pediatrics with severe asthma.

2. Do you start inhaled corticosteroids on asthma patients who are going to be discharged from the ED?

Inhaled corticosteroids (ICS) are the mainstay of therapy for long-term control of mild to severe-persistent asthma. In its 2015 report on a global strategy for asthma management, the National Heart, Lung and Blood Institute recommends initiation of ICS therapy at ED discharge for patients with an acute asthma exacerbation, citing a known reduction in mortality with daily ICS use in asthmatics (GINA, 2015; Suissa, 2000). This recommendation is specifically for long-term use of ICS, though there has also been some study into the efficacy of ICS use for a shorter period for patients discharged from the emergency department both for the treatment of acute asthma exacerbations as well as for the purpose of chronic asthma management.

Inhaled corticosteroids work by directly targeting the inflamed airways and have the benefit of minimal systemic absorption and, therefore, minimal systemic side-effects. For long term asthma care, this greatly decreases the need for chronic use of systemic corticosteroids.

As initiation of systemic corticosteroids in the setting of an acute asthma exacerbation is recommended by multiple professional societies and is considered standard of care, we won’t go into significant depth into the evidence for ICS use alone for the treatment of asthma in the emergency department and at discharge. It is, however, worthwhile to note that there are multiple studies that support the initiation of ICS in the emergency department. Some research comparing ICS directly to systemic corticosteroids, both IV and PO, has demonstrated shortened time to improvement in respiratory parameters (usually FEV1 as percent of predicted) as well as decreased time to discharge (Scarfone, 1995; Devidayal, 1999; Rodrigo, 2005; Starobin, 2008). When ICS therapy was added to corticosteroid therapy in the ED, multiple studies and a systematic review indicate that ICS therapy decreased rate of admissions, though the reviewers caution that the newest evidence trended toward no difference (Edmonds, 2012).

Specifically looking at the original question, there are two published studies that report the addition of ICS therapy to systemic steroids at ED discharge for the treatment of acute asthma exacerbations. Rowe, et al. (1999) performed a placebo-controlled, double-blind, randomized trial where they randomized 188 patients to be discharged with a prednisone burst for seven days with placebo or with inhaled budesonide for 21 days. Their primary outcome was relapse after discharge. They report a statistically significant reduction in relapse in 21 days among the budesonide group (12.8% versus 24.5%; P= 0.049) which resulted in a NNT = 9 for the prevention of relapse. The other published study, Brenner, et al. (2000), compared a prednisone burst for 5 days plus placebo or inhaled flunisolide for 24 days Their primary metric was PEFR at 3, 7, 12, 21, and 24 days. They had a fairly high lost to follow-up rate at 28% but were unable to demonstrate any difference in PEFR improvement in the flunisolide group compared to placebo (87% versus 83% at 24 days). While it was not the primary outcome, they reported similar relapse numbers in the groups.

Though these studies represent mixed data with regard to actual treatment of acute exacerbations, there is more robust data to support starting ICS therapy out of the emergency department for the prevention of future exacerbations. In Sin, et al. (2002), they followed 1295 patients who presented to an ED with an acute asthma exacerbation. They determined that if the patients used an ICS medication after discharge from this index visit, they were 45% less likely to have a relapse ED visit within two years (RR, 0.55; 95% CI, 0.44-0.69). Though it was not entirely clear from the study if the ICS medications had been started by the ED providers or by the patient’s PCP, there is also good evidence that PCP’s do not routinely start ICS medications after an ED visit. In a study by Cydulka, et al. (2005), fewer than half of patients who presented to the ED with acute asthma exacerbations were started on ICS therapy as an outpatient by their PCP.

With this in mind, both GINA (2015), and the NIH/National Asthma Education and Prevention Program recommend initiation of long-term (2-month supply) ICS medications at the time of ED discharge. Though long-term ICS use is only recommended for patients with persistent asthma, multiple studies have shown that between 67-85% of patients who present to the ED with an asthma exacerbation have symptoms consistent with persistent asthma (Self, 2009).

Bottom Line: Long-term use of ICS is the standard of care for patients with persistent asthma for the prevention of exacerbations and improvement in mortality. As there is a high rate of patients with persistent asthma among those who present to the ED with an acute asthma exacerbation, and there is inconsistent follow-up initiation of ICS therapy by PCP’s, the ED physician should strongly consider starting long-term ICS therapy on any patient with symptoms of persistent asthma prior to discharge.

3. When, if ever, do you use ketamine for induction or for treatment without intubation?

Ketamine (ketamine hydrochloride) is a dissociative anesthetic that has been used both for primary treatment of bronchospasm and as adjunctive therapy for bronchospasm in the form of an induction agent when intubating a patient with severe asthma. First described in a case report in 1971 (Betts, 1971), ketamine has long been studied in pediatric patients for direct reversal of bronchospasm. The mechanism of action, studied by Gateau, et al. (1989) in human bronchial preparations, is felt to not involve the beta receptor or prostaglandins, but this basic science research did show a direct bronchodilatory effect.

Unfortunately, since these potential effects were first described, there has been a paucity of good studies to support the clinical benefit of ketamine in the asthmatic patient. There are many case reports which describe the observed efficacy of ketamine in the refractory asthmatic patient, particularly among pediatric patients, though only a few observational studies or RCT’s. Petrillo, et al. (2001) performed a prospective, observational study looking at ten pediatric patients who had been unresponsive to standard therapy but had not yet been intubated. In this bolus and continuous infusion therapy model, the authors report an improvement in clinical asthma score as well as improvement in oxygen saturations. Allen, et al. (2005) went further by performing a double-blinded RCT comparing bolus and continuous infusion dose ketamine to placebo for pediatric patients with an acute asthma exacerbation. They did not demonstrate a benefit of ketamine over placebo when using the Pulmonary Index score as their primary outcome.

In adult patients, Howton, et al. (1996) peformed a double-blinded RCT with a bolus and continuous infusion in adult patients, similar to Allen, et al. (2005) In this study, the authors did not find any benefit of ketamine to placebo, however they did have to decrease the bolus dose from 0.2mg/kg to 0.1mg/kg during the study due to a significant number of dysphoric reactions. The dissociative effect of ketamine has also made it of interest to investigators looking at sedation to enable implementation of NPPV therapy for patients who otherwise are not tolerating it. The use of a sedative like ketamine for the purpose of pre-oxygenation (with NPPV or NRB mask) is termed Delayed Sequence Intubation or DSI (Weingart, 2015). As described in the observational prospective study by Weingart, et al. (2015), ketamine was used to sedate agitated patients with respiratory failure requiring intubation in the peri-intubation period for the purpose of better pre-oxygenation.

In contrast, Kiureghian, et al. (2015) describes a case report where ketamine was used for the sole purpose of applying NPPV in a patient with a severe asthma exacerbation. Recognizing the limited evidence to support NPPV for acute asthma exacerbations, it’s not clear how useful this method would be for primary treatment of these patients. DSI for better pre-oxygenation using ketamine may have applications for a certain subset of severe asthmatic patients requiring intubation.

Finally, utilization of ketamine as an induction agent for rapid-sequence intubation in the severely asthmatic patient has also been of interest given the described bronchodilatory properties. L’Hommedieu, et al. (1987) presented a small case-series of five pediatric patients who were intubated using ketamine as the induction agent, with succinylcholine as the paralytic. All patients who had an initial pCO2 measured (one was in respiratory arrest) were noted to be hypercarbic prior to intubation and had improvement in pCO2 values after intubation. Whether this is an effect of the ketamine or of positive pressure ventilation is not clear, as there is no control or standard therapy group to compare the ketamine group to in this tiny case-series. There do not appear to be any additional studies looking at ketamine as an induction agent in severe asthma.

Bottom Line: Ketamine has been shown in laboratory models to have a bronchodilatory effect. The use of ketamine for improved oxygenation though delayed-sequence intubation appears safe and may improve pre-intubation hypoxia. Using ketamine as an induction agent in the severe asthmatic patient has some theoretical advantage and may be considered in a patient without contraindications to ketamine administration.

4. When do you use epinephrine in status asthmaticus and when do you avoid it?

First described in the medical literature by Melland (1910), the use of systemic epinephrine for the reversal of bronchoconstriction was a mainstay of asthma treatment for many years. Epinephrine can be administered through a variety of routes including subcutaneous, inhaled and intravenous administration. It has both alpha and nonselective beta receptor activity, which is in contrast to the beta2 selective agents we more commonly use today. It has been proposed that the alpha receptor stimulation may also have a benefit in acute asthma exacerbations by decreasing bronchial wall congestion and edema (Grandordy, 1995).

Perhaps the first study of epinephrine that demonstrated a measurable improvement in respiratory parameters was by Hurtado, et al. (1934). This small observational study of 5 patients demonstrated an improvement in the vital capacity after administration of subcutaneous epinephrine. In a later study, Rees, et al. (1967) administered subcutaneous epinephrine to nine asthmatic patients and measured FVC and PaO2 both before and after epinephrine administration. This study showed an improvement in both FVC and PaO2 after epinephrine was given. When looking at both dosing of subcutaneous epinephrine as well as timing of administration in reference to peak effect, Gotz, et al. (1988) demonstrated that patients after ephinephrine administration continued to show improvement in peak expiratory flow rates (PEFR) for up to 40 minutes, no matter what the initial dose given was (0.1mg, 0.3mg or 0.5mg). There was also no difference in degree of improvement in PEFR between the different doses.

In the 1970’s, more selective beta2-agonists such as terbutaline began to come into favor with the theory that they would have fewer adverse effects than epinephrine due to their more selective profile. Schwartz, et al. (1976) directly compared subcutaneously injected terbutaline to epinephrine and found that terbutaline improved both FVC and FEV1 by almost double that of epinephrine, indicating that terbutaline may be a superior bronchodilating agent. In Smith, et al. (1977) , 49 patients were randomized to receive 1mg of terbutaline versus 0.5mg of epinephrine. There was no statistical difference in improvement of respiratory parameters between the groups, though there was more tachycardia in the terbutaline group which called into question how selective this compound was for the beta2 receptor at increased doses. In Spiteri, et al. (1987), 20 patients with severe asthma exacerbations were randomized to either 0.5mg of terbutaline or 0.5mg epinephrine subcutaneously. When looking at the outcomes of peak expiratory flow (PEF) and FEV1, there was no statistical difference in the degree of improvement between the study groups.

In addition to its nonselective adrenergic properties, the need to inject epinephrine subcutaneously was felt to be invasive and contributing to increased pain and anxiety in patients, especially pediatric patients. This led to increased interest in both aerosolized/nebulized selective beta2-agonists as well as inhaled epinephrine. Becker, et al. (1983) examined nebulized albuterol with injected epinephrine in 40 pediatrics patients with acute asthma. Though they failed to show any benefit to one therapy over the other they did conclude that the noninvasive administration of albuterol was preferred over the more invasive subcutaneous epinephrine given the similar efficacy.

At this point in asthma treatment research, it had been demonstrated that nebulized administration of beta2-agonists was superior to IV administration in terms of side-effect profile. There was increased interest in determining whether nebulized administration of epinephrine might demonstrate a similar effect Kjellman, et al. (1980) compared nebulized racemic epinephrine to albuterol in a randomized crossover trial of ten children. Specifically, they compared the percent change in FEV1 as a response to the drug. Both racemic epinephrine and albuterol showed an improvement in FEV1 from baseline, and there was no statistical difference seen. Abroug, et al. (1995) compared nebulized albuterol and nebulized epinephrine in 22 adult patients presenting to an ED with an acute asthma exacerbation. Again, this study failed to show a statistically significant difference in the degree of bronchodilation, in this case by measuring PEFR. In probably the largest randomized study comparing nebulized albuterol to epinephrine, Plint, et al. (2000) randomized 120 pediatrics patients with pulmonary index score (PIS) as their primary outcome. The groups were well-balanced from a prognostic standpoint in regards to age, prior ED visits, inhaled beta agonist or steroid use, and each group had an average PIS of 8 on arrival. Neither group showed a statistically different improvement in PIS. There was also no statistical difference in SpO2 between the groups, though there was a greater decrease in heart rate by an average of 8bpm as well as increase in respiratory rate by 2 breaths/min in the albuterol group.

In a 2006 meta-analysis by Rodrigo, et al. (2006), the authors combined data from 6 trials, which reported FEV1 or PEFR when comparing nebulized albuterol to nebulized epinephrine. This pooled analysis showed no difference between the treatment modalities, however this analysis suffered from a high degree of heterogeneity as the different studies used different doses of epinephrine. When they dichotomized the data into a low dose epinephrine (1-2mg) and a high dose epinephrine (>2mg) group, they noted that albuterol was superior to low dose epinephrine with no difference compared to high dose epinephrine.

Though there is a paucity of evidence on the efficacy of intravenous epinephrine, there are two retrospective chart reviews describing the safety/adverse effects seen when it is administered to patients considered to have severe asthma. In Smith, et al. (2003), the authors searched for any patient admitted to the ICU from two separate ED’s who was given IV epinephrine over the course of 8 years. They identified 27 patients who met their study criteria. They looked for adverse events such as arrhythmia, cardiac ischemia, cerebral ischemia, hypotension or hypertension. They observed that 9 patients developed new tachycardia and 4 had new/worsening hypertension. They noted no incidents of arrhythmia or cardiac/cerebral ischemia in any patients. This led the authors to conclude that IV epinephrine was potentially safe for use in the severe asthmatic as an adjunct after failure of beta2-agonist therapy. On a similar safety note, Cydulka, et al., found subcutaneous epinephrine in anaphylaxis-style dosing caused no adverse events in ninety-five asthmatics aged 15 to 96 (Cydulka, 1988).

The second study, Putland, et al. (2006), was much larger and included 220 patients who were initiated on an epinephrine infusion for the treatment of severe asthma. The primary endpoints of this retrospective chart review were serious adverse events which they defined as death, non-sinus tachyarrhythmia, hyper- or hypo- tension with adverse outcome requiring treatment, EKG changes or biomarker elevation consistent with ischemia, non-transient neurologic sequelae, or an extensive area of local tissue necrosis. They also reported other adverse events such as sinus tachycardia, hypertension/hypotension not requiring intervention, chest pain without objective evidence of cardiac ischemia, and local tissue ischemia. Sixty-seven patients were noted to have at least one adverse event with an adverse event rate per episode of 3.6% with 2 non-sinus tachyarrhythmias (both SVT), 4 episodes of hypotension requiring intervention and 2 episodes of objective myocardial ischemia. There was a much higher rate of other adverse events (30.5%) with the majority of these being sinus tachycardia (23 patients) or hypertension (30 patients).

The problem with determining the usefulness of these studies is their small size, the lack of a standard therapy or control group, limited reporting of demographic data (only reported in Smith 2003 which was by far the smaller of the trials), a relatively young patient population in the ages reported (median age 25 with a range of 19-58 in Smith 2003) and no reporting of association of adverse events with age or other comorbidities. Additionally, there is minimal literature looking at the sickest subset of patients with asthma.

Bottom Line:

There is no good evidence that the use of epinephrine is superior to inhaled albuterol or other selective beta-agonists. There is the theoretical advantage that epinephrine appears to be largely safe to administer through an IV or IM route which may result in better drug delivery in patients with severely restricted air movement.


Author: Curry; Editors: Bryant, Berkowitz, Swaminathan


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Status Asthmaticus, Questions

1. When do you use non-invasive positive pressure ventilation (NPPV) in status asthmaticus?

EML Asthma Questions2. Do you start inhaled corticosteroids on asthma patients who are going to be discharged from the ED?

3. When, if ever, do you use ketamine for induction, or for treatment without intubation, in status asthmaticus?

4. When do you use epinephrine in status asthmaticus and when do you avoid it?

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Syncope, Answers

  1. In which patients with syncope do you get a NCHCT?

Syncope is defined as a transient loss of consciousness and postural tone. It has a rapid onset, short duration, spontaneous recovery and is due to transient global cerebral hypoperfusion. It may have a prodromal phase. In the Emergency Room, about 3% of patients present with a chief complaint of syncope. As part of the work-up, a non-contrast Head CT-scan (NCHCT) is often ordered. The question is whether such a test is necessary and who should get it?

A 2007 prospective observational study looked at 293 adult ED patients with syncope, of which 113 (39%) underwent head CT and of those, 5 patients (5%) had an abnormal head CT (Grossman 2007). These abnormal findings included 2 subarachnoid hemorrhages, 2 intracranial hemorrhages, and 1 stroke. Each of these patients either had a focal neurologic finding, headache, or signs of trauma. Of the patients who did not have a head CT, none were found to have a new neurologic disease during hospitalization or 30-day follow-up. The results from this study suggested that limiting head CT to patients with neurologic signs or symptoms, trauma above the clavicle, or use of warfarin would potentially reduce scans by over 50%.

Cartoon Faint

Several other small retrospective studies have shown a low yield for obtaining a head CT in syncope patients. In a 2005 study in Emergency Radiology, 128 patients presented to a community hospital with syncope of which 44 received a head CT scan (Giglio 2005). Only 1 CT (2%) showed acute evidence of a posterior circulation infarction. In another retrospective review of patients who got a head CT for syncope alone, none of the 117 patients had CT findings that were clinically related to the syncopal event (Goyal 2006). The authors concluded that a head CT in the absence of focal neurologic findings may not be necessary. It is important to note that the reason for obtaining head CTs in these retrospective studies is unclear. Additionally, syncope patients who did not get a head CT were not analyzed.

A more recent prospective study looked at 254 head CT patients (out of 292 with syncope) and classified them into four groups: 1) normal CT / normal neuro exam; 2) abnormal CT / abnormal neuro exam; 3) abnormal CT not related to their syncope presentation; 4) abnormal CT / normal neuro exam. The last group (abnormal head CT with normal neuro exam) which we are interested in capturing in the ED only included 2 patients (0.7%) (Al-Nsoor 2010).

Bottom Line: For patients presenting to the Emergency Department with a chief complaint of syncope, a NCHCT is of low yield and should only be considered in patients with focal neurologic deficits, complaints of headache, or signs of head trauma. This is consistent with the ACEP clinical policy for syncope, which states that no test should be routinely used in the absence of specific findings on physical exam or history (ACEP 2007).

  1. In which patients with syncope do you get a troponin?

Cardiovascular etiologies are at the top of the differential for dangerous causes of syncope. Identifying those at risk for adverse cardiac outcome after syncope is challenging.  Cardiac markers such as troponins are often sent on patients with syncope as part of a standard work up, presumably as a general screen for cardiac etiology such as acute myocardial infarction (AMI).  As with any test, its results are only relevant if interpreted correctly. To that end, the diagnostic and prognostic utility of troponin in syncope patients is examined here.

AMI is a relatively rare cause of syncope, accounting for approximately 1.4-3.5% of cases (Link 2001, Grossman 2003, Hing 2005).  The diagnosis of AMI in patients without EKG changes on presentation is even less common, likely due to the significant infarct required to induce either a non-perfusing dysrrhythmia or severely impaired cardiac output, which manifests in syncope. The utility of ED troponins for diagnosis of AMI is quite limited, especially in the patient without EKG changes.  One prospective cohort study evaluating troponin-I at 12 hours post-syncope for diagnosis of AMI diagnosed four AMIs, 1.5% of their 289 patients (Reed 2010).   Of these four patients, all had ischemic changes on their presenting EKG.

A larger prospective cohort study of 1474 patients found a 3.1% incidence of AMI within 30 days of a syncopal event (McDermott 2009).  Of these patients, 80% had abnormal EKGs on presentation (any change from baseline or any abnormality-overtly ischemic or not- if no comparison). A normal EKG showed a negative predictive value of 99%.  Of these AMI patients, only 50% had positive troponins obtained in the ED.  Along with an abnormal EKG, being male gender, having history of coronary artery disease (CAD) were both significantly more sensitive than a positive troponin in detecting AMI.

Although the utility of troponins in patients with syncope and normal EKGs looking for AMI is limited, a troponin may be useful in risk stratification of patients with alternate causes of syncope. Pulmonary embolism, type A dissection, and intracranial hemorrhage can all cause syncope and can cause type II ischemia (e.g. supply/demand ischemia).  Additionally, an elevated troponin in the setting of syncope has been associated with worse outcomes. In one study, 50% of patients with a positive troponin (at 12 hours post-syncope) had a serious outcome (not including AMI) or all-cause death at 1 month, as opposed to only 6% of patients without the positive biomarker (Reed 2010).

A similar study design performed by the same research group used a lower cutoff for a diagnostically positive troponin-I and examined the outcomes in patients with any detectable troponin level (Reed 2012).  They found the majority of syncope patients (77%) to have detectable values and 20% to have troponin levels above the new diagnostic threshold (although only 2.9% diagnosed with AMI).  At both one month and one year, patients with any detectable troponin level were at higher risk of adverse outcomes and mortality.  This risk increased with higher troponin values.

Another prospective study similarly showed a positive troponin-T (taken at least 4 hours post-syncope) to strongly predict adverse cardiac outcome (Hing 2005). However, a positive troponin proved to have no added value in predicting adverse cardiac outcomes over the OESIL* score (Colivicci 2003).  The study also reports troponin to have a sensitivity of only 13% and a low negative predictive value.

*The OESIL score is a risk stratification score to predict recurrent syncope or adverse outcome and includes the following risk factors:

  1. Age >65years old
  2. History of cardiovascular disease (CAD, CHF, cerebrovascular or peripheral vascular disease)
  3. Syncope without prodrome
  4. Abnormal EKG

The benefit of a troponin’s prognostic ability in syncope patients has not been clearly determined.  A recent study reports on the significantly improved clinical outcomes associated with using troponin-I at a lower threshold to detect positive values in patients with suspected acute coronary syndrome (Mills 2011).  While this is a different subset of patients with a clearly defined disease, the results raise the question of whether the test’s prognostic value may translate into improved outcomes in syncope patients.

Bottom Line

As a diagnostic screening test for AMI in syncope patients without chest pain or EKG changes, a single troponin is inadequate and does not appear to be helpful in risk stratification.  Admitting syncope patients for serial troponins, or ‘rule-out AMI,’ is also low-yield and should be considered only in conjunction with patients’ symptoms and significant risk factors such as known CAD or CHF, older age, syncope preceded by palpitations or without prodrome.  However, the value of a positive troponin is not limited to diagnosis of AMI.  The value of a troponin as a predictor of adverse outcome may have utility for an inpatient team and potentially in the ED as high sensitivity troponins become more ubiquitous.  Whether obtaining this prognostic data significantly improves outcomes is not clear.

  1. Do you get orthostatic measurements in patients with syncope and how do you use them?

Volume depletion (i.e. dehydration) and blood loss are two of the myriad reasons for patients to present with syncope in the Emergency Department. While it isn’t difficult for us to determine whether the patient with an active upper gastrointestinal bleed has significant volume loss, this determination can be more challenging in other patients (i.e. the elderly patient with a urinary tract infection). Thus, clinicians would benefit from having an easy bedside test that assesses volume status, particularly, one that improves our ability to pick up patients with moderate volume depletion or blood loss.

Orthostatic blood pressure measurements have historically been taught to be useful in determination of volume status. It is defined as either:

  1. A drop in systolic blood pressure (SBP) > 20 mm Hg OR
  2. Increase in heart rate (HR) by > 30 beats per minute (bpm)

when a patient stands from a supine position (McGee 1999). It is unclear from the available literature how these numbers were originally derived, but they are likely based on consensus rather than empirical data. Even available consensus statements differentiate the entities of symptomatic and asymptomatic orthostatic hypotension, bringing the overall utility of the test in to question. (Kaufmann 1996).

Despite the traditional teaching, orthostatic measurements have little if any proven utility. There are two major criticisms:

  1. Many patients without signs or symptoms of intravascular volume depletion will demonstrate orthostatic vital signs when measured


  1. Many patients with clear evidence of intravascular volume depletion will not exhibit orthostatic vital signs.

How prevalent are orthostatic vital sign measurements among asymptomatic patients? A number of studies investigated elderly patients living in nursing facilities. Results of these studies are inconsistent. Mader et al and Aronow et al found relatively low prevalence (6.4% and 8% respectively) of orthostatic vital signs in absence of symptoms (Mader 1987, Aronow 1988). These studies, however, were small and excluded elderly patients on medications that may cause hypotension reducing generalizability to the general population of elderly patients. More recent larger studies on unselected elderly patients showed higher rates ranging from 28 – 50% (Raiha 1995, Ooi 1997). Studies in adolescents show similarly poor numbers with approximately 44% of patients exhibiting orthostatic changes (Stewart 2002).

Witting et al attempted to define vital sign thresholds that would decrease false positives. They performed tilt-table testing in healthy volunteers after blood donation (moderate blood loss). In patients < 65 years of age, a change in pulse > 20 bpm or a change in SBP > 20 mm Hg had a sensitivity/specificity of 47%/84% (Witting 1994). This yields a (+) LR = 2.94 and a (-) LR = 0.63. Sensitivity and specificity were similar in patients > 65 (41%/86%) with similarly poor (+) LR = 2.93 and (-) LR = 0.69. McGee et al performed a systematic review in 1999 showing similarly dismal sensitivity for moderate blood or fluid loss (McGee 1999)

Sensitivity Specificity
Blood Loss – Pulse Change (> 30 bpm) 22% NA
Blood Loss – SBP Change (> 20 mm Hg) 7-27% NA
Fluid Loss – Pulse Change (> 30 bpm) 43% 75%
Fluid Loss – SBP Change (> 20 mm Hg) 29% 81%

Mendu et al performed a retrospective study that stands as one of the few studies supporting the use of orthostatic blood pressure management in patients with syncope (Mendu 2009). The researchers found that in 18% of patients, orthostatics affected the final diagnosis and affected management in 25% of patients. However, the study is deeply flawed. The utility of the measurements was determined by the clinician with no gold standard for diagnosis with which to compare. Additionally, 55% of patients in whom orthostatics were measured were found to have abnormal results but far less of these findings were thought to be relevant. Finally, the average age in this study was near 80 years of age, the exact population in which prior studies (previously discussed) have shown poor sensitivity and specificity of these measurements (Raiha 1995, Ooi 1997).

Based on the available literature, orthostatic vital signs do not appear to be either sensitive for screening patients for moderate blood or fluid loss or specific.

Bottom Line: Many asymptomatic patients will have positive orthostatic vital signs and many patients with moderate volume loss won’t have orthostatic vital signs. This makes checking orthostatic vital signs of questionable utility. More important is to see what the patient’s symptoms are. If the patient feels lightheaded or dizzy when they go from lying supine to sitting or from sitting to standing, they are orthostatic and this should be addressed.

  1. Do you manage patients with near-syncope differently than those with syncope?

Pre-syncope is a chief complaint commonly evaluated in the Emergency Department (ED). Defined as the sense of impending loss of consciousness, its symptoms can include lightheadedness, weakness, visual disturbances, “feeling faint”, and other nonspecific complaints. While there have been several attempts to develop and derive clinical prediction tools for syncope, most have been unsuccessful due to poor sensitivity and specificity and large performance variability (Constantino 2014, Birnbaum 2008, Serrano 2010). As one can imagine, if validation of prediction rules for the objective finding of syncope is fraught with difficulty, prediction rules for the more subjective and vague symptoms of pre-syncope would be an arduous task. As such, there is a lack of guidance when it comes to management and disposition decisions for patients who present to the ED with pre-syncope.

Though classically pre-syncope was thought to be benign with many of these patients being discharged from the ED, this may not be the case. In a study of approximately 200 patients presenting to the ED with nonspecific complaints (including weakness, dizziness, and feeling unwell) and Emergency Severity Index (ESI) scores of 2 or 3 with normal vital signs, 59% had a serious condition diagnosed within 30 days, and 30-day mortality was 6% (Nemec 2010). The median age of the study’s cohort was 82 years, and most had co-morbidities. While this study did not specifically assess patients with pre-syncope, given the overlap of the included symptoms with the symptoms seen in pre-syncope, it suggests that pre-syncope may similarly be a harbinger of serious disease.

Early syncope studies often excluded pre-syncope since its definition is poorly defined. However, recent literature corroborates the potential severity of pre-syncope. Some experts purport that the pathophysiologic mechanism for pre-syncope is the same as that for syncope except that the global cerebral hypoperfusion is not significant enough to cause complete loss of consciousness (Quinn 2014). A prospective observational pilot study of 244 patients with pre-syncope and 293 patients with syncope found similar ED hospitalization and 30-day adverse outcome rates in the two groups- 23% and 20% respectively (Grossman 2012). One of the reasons that the rates were so high may have been the broad and inclusive definition of adverse outcome (which included, amongst other conditions, cortical stroke, carotid stenosis and endarterectomy, and alterations in antidysrhythmics medications).

A larger prospective cohort study in 2014 found a significant number of adverse outcomes in pre-syncope patients. Of 881 adult patients with pre-syncope (which constituted 0.5% of total ED visits), 5.1% had serious outcomes at 30-day follow-up (Thiruganasambandamoorthy 2014). Furthermore, physicians were not accurate in predicting which patients were high risk for serious outcomes after their ED visit, with an area under the receiver operating characteristic (ROC) curve of 0.58-slightly better than a coin flip.

Should we be managing patients with pre-syncope similarly to those with syncope? Despite the paucity of literature on outcomes for ED patients presenting with pre-syncope, it appears as though the potential severity of pre-syncope has been under-appreciated. Once thought to be low-risk, recent literature challenges this dogma and suggests that a significant proportion of patients with pre-syncope suffer adverse outcomes similar to those who present with syncope. Intuitively it makes sense that true pre-syncope, syncope, and cardiac arrest exist on the same spectrum, differentiated by severity and duration of hypoperfusion, and thus should be risk stratified and managed similarly. However, to date no evidence exists on whether managing pre-syncope patients the same as syncope patients improves outcomes. As such, future studies are needed to further explore which patients with pre-syncope are at higher risk for adverse outcomes, with the ultimate goal to derive and validate a clinical decision rule for this patient population.

Bottom Line:

Previously thought to be a benign diagnosis, recent literature suggests that, like syncope, a non-insignificant proportion of patients with pre-syncope suffer serious adverse outcomes. Further studies are needed to determine which patients with pre-syncope are at higher risk for adverse outcomes, as we currently do not have clinical decision rules to guide our management for this patient population.


Grossman SA, Fisher C, Bar JL, Lipsitz LA, Mottley L, Sands K, Thompson S, Zimetbaum P, Shapiro NI. The yield of head CT in syncope: a pilot study. Intern Emerg Med. Mar 31 2007. PMID: 17551685

Giglio P, Bednarczyk EM, Weiss K, Bakshi R. Syncope and head CT scans in the emergency department. Emergency Radiology. Dec 12 2005. PMID: 16292675

Goyal N, Donnino MW, Vachhani R, Bajwa R, Ahmed T, Otero R. The utility of head computed tomography in the emergency department evaluation of syncope. Intern Emerg Med. 2006. PMID: 17111790

Al-Nsoor NM, Marat AS. Brain computed tomography in patients with syncope. Neurosciences (Riyadh). 2010 April 15. PMID: 20672498

ACEP Clinical Policy Subcommittee on Syncope. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department with Syncope. Annals of Emerg Med. April 2007. PMID: 18035161

Link MS, Lauer EP, Homoud MK et al. Low yield of rule-out myocardial infarction protocol in patients presenting with syncope. Am J Cardiol 2001;88:7067. PMID: 11566406

Grossman SA, Van Epp S, Arnold R et al. The value of cardiac enzymes in elderly patients presenting to the emergency department with syncope. J Gerontol A Biol Sci Med Sci 2003;58:1055–8. PMID: 14630890

Hing R, Harris R. Relative utility of serum troponin and the OESIL score in sycnope. Emerg Med Australas 2005;17:31-8. PMID: 15675902

Reed MJ, Newby ED, Coull AJ, et al. Diagnostic and prognostic utility of troponin estimation in patients presenting with syncope: a prospective cohort study. Emerg Med J. 2010;27:272-276. PMID: 20385677

Colivicchi F, Ammirati F, Melina D, et al. Development and prospective validation of a risk stratification system for patients with syncope in the emergency department: the OESIL risk score.  Eur Heart J. 2003 May;24(9):811-9. PMID: 12727148

McDermott D, Quinn JV, Murphy CE. Acute myocardial infarction in patients with syncope. CJEM. 2009 Mar;11(2):156-60. PMID: 19272217

Reed MJ, Mills NL, Weir CJ. Sensitive troponin assay predicts outcome in syncope. Emerg Med J. 2012;29:1001-1003. PMID: 22962048

Mills NL, Churchouse AM, Lee KK, et al. Implementation of a sensitive troponin I assay and risk of recurrent myocardial infarction and death in patients with suspected acute coronary syndrome. JAMA. 2011 Mar 23;305(12):1210-6. PMID: 21427373

McGee S, Abernethy WB, Simel DL. The rational clinical examination. Is this patient hypovolemic. JAMA 1999; 281(11): 1022-9. PMID: 10086438

Kaufmann H. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auto res 1996; 6: 125-6. PMID: 8726100

Witting MD, Wears RL, Li S. Defining the positive tilt test: a study of healthy adults with moderate acute blood loss. Ann Emerg Med 1994; 23(6): 1320-3. PMID: 8198307

Mader SL, Josephson KR, Rubenstein LZ. Low prevalence of postural hypotension among community-dwelling elderly. JAMA 1987; 258: 1511-14. PMID: 3625952

Aronow WS, Lee NH, Sales FF, Etienne F. Prevalence of postural hypotension in elderly patients in a long-term health care facility. Am J Cardiology 1988; 62(4): 336. PMID: 3135742

Raiha I, Luutonen S, Piha J, Seppanen A et al. Prevalence, predisposing factors and prognostic importance of postural hypotension. Arch Intern Med 1995; 155: 930-935. PMID: 7726701

Ooi WL, Barrett S, Hossain M, Kelley-Gagnon M, Lipsitz LA. Patterns of orthostatic blood pressure change and the clinical correlates in a frail, elderly population. JAMA 1997; 277: 1299-1304. PMID: 9109468

Stewart JM. Transient orthostatic hypotension is common in adolescents. J Pediatr 2002; 140: 418-24. PMID: 12006955

Mendu ML et al. Yield of diagnostic tests in evaluating syncopal episodes in Older patients. Arch Intern Med 2009; 169: 15: 1299-1305. PMID: 1963031

Birnbaum A, et al. Failure to Validate the San Francisco Syncope Rule in an Independent Emergency Department Population. Ann Emerg Med. 2008 Aug;52(2):151-9. PMID: 18282636

Constantino G, et al. Syncope Risk Stratification Tools vs Clinical Judgement: An Individual Patient Data Meta-analysis. Am J Med. 2014 Nov;127(11):1126.e13-25. PMID: 24862309

Grossman SA, et al. Do Outcomes of Near Syncope Parallel Syncope? Am J Emerg Med. 2012 Jan;30(1):203-6. PMID: 21185670

Nemec M et al. Patients Presenting to the Emergency Department with Non-specific Complaints: The Basel Non-specific Complaints (BANC) Study. Acad Emerg Med. 2010 Mar;17(3):284-92. PMID: 20370761

Quinn, JV. Syncope and Presyncope: Same Mechanism, Causes, and Concern. Ann Emerg Med. 2014 Oct 31. pii: S0196-0644(14)01257-8. PMID: 25441246

Serrano LA, et al. Accuracy and Quality of Clinical Decision Rules for Syncope in the Emergency Department: A Systematic Review and Meta-analysis. Ann Emerg Med. 2010 Oct;56(4):362-373. PMID: PMC2946941/

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Syncope, Questions

Syncope1. In which patients presenting with syncope do you get a Non-Contrast Head CT (NCHCT)?

2. In which patients presenting with syncope do you get a troponin?

3. Do you get orthostatic vital sign measurements in patients presenting with syncope? How do you use them?

4. Do you manage patients presenting with near-syncope differently than those presenting with syncope?

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Spinal Cord Injury, “Answers”

1. What imaging do you use for patients with possible acute, traumatic spinal cord injury?

Patients who can be cleared using the Nexus or Canadian C-spine criteria should be cleared clinically. However, those with moderate to high risk of a cervical spine (C-spine) injury should have cross sectional imaging, based on substantial amounts of data. The Eastern Association for the Surgery of Trauma (EAST) referenced 52 articles to construct guidelines recommending against plain radiographs in the assessment of potential C-spine injuries (Como, 2009). Although the C-spine is actually only injured in approximately 3% of all major trauma patients, (Crim, 2001) these tend to be some of the most disabling injuries. There is less data regarding the type of imaging preferred for patients with possible thoracic and lumbar spine injuries.

EML Spinal Cord AnswersIn patients in whom you cannot clear their C-spine clinically and you suspect an acute, traumatic spinal cord injury, computerized tomography (CT) scanning is the most appropriate initial imaging. There is a growing body of literature stating that plain films miss many clinically significant injuries, and have little to no role in evaluating spinal fractures, particularly those of the C-spine.

The argument against this is that some patients may actually be appropriate for plain film imaging of the C-spine. These are patients who are deemed low risk mechanism, younger, and in whom good views can be obtained. There will still be some fractures that are missed, but these have a low chance of being clinically significant, and in a patient with low pre-test probability, this may be appropriate utilization of plain film imaging. The most compelling argument for this comes from the original NEXUS study. Of 34,069 patients with blunt trauma, 1,496 had C-spine injuries. Plain films missed 564 injuries in 320 patients. However, for 436 of these injuries, 0.80% of all patients, the plain films were interpreted as abnormal (although non diagnostic) or abnormal. Only 23 (0.07%) of all patients in the studies had injuries that were not seen on plain films that were also read as negative. Three of these patients had unstable c-spine injuries (Mower, 2001). In a retrospective review of a trauma database of 3,018 patients, 116 (9.5%) had a C-spine fracture. The injury was only seen in 75 of these patients on plain film. In the remaining 41 patients (3.2%), the injury was detected on CT scan, and in all cases these injuries required treatment. It is important to recognize that the mean Glasgow coma score (GCS) of this patient population was 13, thus, they were likely a high acuity patient population overall. These authors concluded that there was no role for plain imaging in patients in whom a C-spine injury is suspected in the Emergency Department population (Griffen, 2003).  Most recently, Mathen, et al. performed a prospective cohort study of 667 patients who required C-spine imaging. They found that plain radiography missed 15 of 27 (55.5%) clinically significant c-spine injuries (Mathen, 2007).

In a cost effectiveness analysis, CT was found to be the preferred modality for imaging in moderate to high risk patients, given that missed C spine fractures and resultant paralysis may be devastating to both the patient and society (Blackmore, 1999).

Unlike C-spine fractures, we have no clinical decision rules to help guide our care of patients with potential thoracolumbar fractures. There is considerably less data on thoracolumbar injuries. According to a literature review published in the Journal of the American College of Radiology, which looked at studies on TL spine imaging comprising several thousand patients, those who should be evaluated for thoracic or lumbar spine injuries are those with high force mechanism and any of the following findings: back pain or midline tenderness, local signs of thoracolumbar injury, abnormal neurologic signs, C-spine fracture, GCS < 15, major distracting injury, or drug or alcohol intoxication (Daffner, 2007).

There is evidence to suggest that many injuries may be missed by plain films of the thoracolumbar regions. One study of seventy intubated trauma patients found that thin slice CT discovered 100% of unstable fractures in comparison with 56-80% (depending on spinal level) seen by conventional radiographs (Herzog, 2004). A prospective evaluation of 1.915 trauma patients presenting to a Level I trauma center compared the sensitivity of CT versus plain film in the detection of the 78 thoracic or lumbar spine fractures sustained by the group. CT sensitivity was 97% and 95% for thoracic and lumbar injuries, respectively. For plain films those numbers were 62% and 82% (Sheridan, 2003). Yet another study in high acuity trauma patients found the sensitivity of CT to be 97% and that for plain films to be an abysmal 33.3% (Wintermark, 2003). In a retrospective review of 3,537 patients, the only fractures missed by CT scan were a cervical compression fracture identified on MRI, and a thoracic compression fracture identified by plain films. This study recommended that plain films of the spine are unnecessary in the evaluation of blunt trauma patients. Furthermore, after a panel reviewed all literature on the topic, the American College of Radiology Appropriateness Criteria recommended that patients with potential thoracic or lumbar spine injury undergo CT scan, as opposed to plain films (Daffner, 2007). The ACR grades on a scale of 1-9, with 1-3 being usually not appropriate, 4-6 may be appropriate, and 7-9 usually appropriate. Their level of recommendation in this indication is a 9.

Due to the data regarding imaging, most patients should undergo CT imaging for possible spinal trauma. Only the lowest risk patients who have adequate plain films should be cleared without CT imaging.

2. How do you treat neurogenic shock?

Neurogenic shock is a form of distributive shock unique to patients with spinal cord injuries. Fewer than 20% of patients with a cervical cord injury have the classic diagnosis of neurogenic shock upon arrival to the emergency department, and it is a relatively uncommon form of shock overall (Guly, 2008). Patients with injuries at T4 or higher are most likely to be affected by neurogenic shock (Wing, 2008). It is caused by the loss of sympathetic tone to the nervous system, ultimately leading to an unopposed vagal tone (Stein, 2012). Many times the terms “spinal shock” and “neurogenic shock” are used interchangeably, although they are two separate entities. Spinal shock consists of the loss of sensation and motor function immediately following a spinal cord injury (Nacimiento, 1999). During this period of spinal shock, reflexes are depressed or absent distal to the site of the injury. Spinal shock may last for several hours to several weeks post injury (Nacimiento, 1999).

Symptoms of neurogenic shock consist of bradycardia and hypotension (Grigorean, 2009). Bradycardia is typically not present in other forms of shock, and may provide a clue to clinicians that a patient has sustained a spinal cord injury. However, emergency physicians should recognize that hemorrhagic shock needs to be first ruled out, even in patients with bradycardia, many patients with hemorrhagic shock are not tachycardic (Stein, 2012). Cardiac dysfunction is another feature of neurogenic shock, and patients may present with dysrhythmias following injury to the spinal cord (Grigorean, 2009).

The American Spinal Injury Association (ASIA) has classified injuries based on motor and sensory findings at the time of injury. ASIA A and B injuries are the worst; with A being a complete motor and sensory loss with no preserved function in the sacral segments S4-S5. ASIA B includes patients who have sacral sparing, meaning that they have function of S4 and S5 (Marino, 2003). Neurogenic shock is rarely encountered in the emergency department, however, it is important to recognize that almost 100% of patients who sustain complete motor cervical ASIA A or ASIA B injuries develop bradycardia. Thirty five percent of these patients ultimately require vasopressors, so management of neurogenic shock is imperative for emergency physicians (McKinley, 2006). There is no conclusive data regarding the optimal time to start vasopressors, however, it is important to maintain appropriate hemodynamic goals in patients with spinal cord injuries.

Hemodynamic goals in patients with spinal cord injuries are unique. A systolic blood pressure <90 mmHg must be corrected immediately (Muzevich, 2009). The American Association of Neurological Surgeons and the Congress of Neurological Surgeons Guidelines for the Acute Management of Spinal Cord Injuries both recommend a MAP at 85 to 90 mm Hg for the first seven days following a spinal cord injury based on observational descriptions of the hemodynamics in spinal cord injured patients (Levi, 1993; Licina, 2005).

Patients who are suspected of being in neurogenic shock should receive adequate fluid resuscitation prior to initiating vasopressors (Wing, 2008). However, there are no current recommendations regarding the first line vasopressor for neurogenic shock (Stein, 2012). Depending on a patient’s hemodynamics, this vasopressor will likely be norepinephrine, phenylephrine, or dopamine.

Norepinephrine is an excellent first line vasopressor in neurogenic shock due to its alpha and some beta activity, thus leading to its ability to improve blood pressure and heart rate (Stein, 2012). Phenylephrine is another common choice because it is easy to titrate and can be given through a peripheral line. A disadvantage of phenylephrine is the fact that it can lead to reflex bradycardia due to its lack of beta agonism. This drug may be most appropriate in patients who are not bradycardic (Wing, 2008). Dopamine is another option, however, it may lead to diuresis and ultimately worsened hypovolemia (Stein, 2012). It does have beta agonism, and in bradycardic patients may be favored over phenylephrine (Muzevich, 2009). Dopamine is unlikely to be tolerated in patients who are experiencing dysrhythmias.

3. What is your management and disposition for elderly patients with vertebral compression fractures?

Vertebral compression fractures of the thoracic and lumbar vertebrae are extremely common in the elderly population, with an annual incidence of 1.5 million vertebral compression fractures per year (Barr, 2000). They are most commonly seen in patients with osteoporosis, although may be seen in younger patients, particularly those with malignancy. The majority of patients are treated non-surgically, usually with bed rest and hyperextension bracing (Gardner, 2006). Pain is typically the presenting symptom, and neurologic deficits are rare unless there is retropulsion of bone into the vertebral canal. This presentation is rare in compression fractures, but it does constitute a surgical emergency (Kavanagh, 2013).

Although some patients may experience mild or minor symptoms related to a vertebral compression fractures, many patients will have a significant degree of pain and decreased quality of life associated with their fracture (Adachi, 2002). At a minimum, patients with very mild symptoms and a normal neurologic exam may be discharged home with adequate pain control and spine surgery follow up established.

Therapy should be tailored toward avoiding a prolonged period of bed rest as well as adequate pain control (Wong, 2013). Prolonged immobilization may lead to poor pulmonary toilet, venous thromboembolism, and deconditioning, especially in elderly patients. Non-steroidal anti-inflammatory drugs (NSAIDS) are first line therapy since they are non-sedating, but may be poorly tolerated in certain groups of patients such as the elderly or those with underlying peptic ulcer disease (Wong, 2013). Opiates and muscle relaxers may be necessary for pain control, but should be used with caution in the geriatric population, especially those at risk of falls.

Although admission of elderly patients with vertebral compression fractures may not result in surgical management, it may provide other avenues of therapy that are unavailable or difficult to arrange in the ED setting. One of these therapies includes physical therapy, which may help patients regain early mobility if introduced appropriately. Physical therapy is also helpful in training patients to strengthen other extra-axial muscles, particularly the spine extensors (Wong, 2013). Several trials have demonstrated effectiveness of physical therapy in patients with vertebral compression fractures. Malmros et al evaluated a 10-week physical therapy program in a placebo-controlled, randomized, single-blinded study that demonstrated improved quality of life and reduction in pain and analgesic use (Malmros, 1998). Papioannou, et al. conducted a randomized controlled trial consisting of a 6 month home exercise program and found that patients in the physical therapy arm had significant improvement of quality of life scores and improved balance at one year (Papaioannou, 2003).

The decision of when to use thoracolumbosacral orthosis (TLSO) brace in a patient with a vertebral compression fracture is somewhat controversial. Pfeifer, et al. demonstrated in a randomized trial that the use of a brace increased trunk muscle strength and was associated with an improved quality of life, decreased pain, and improved daily functioning in patients with compression fractures (Pfeifer, 2004). However, an electromyelography study demonstrated increased muscle spasming in patients with brace placement (Lantz, 1986). Furthermore, braces may contribute to skin breakdown, especially in geriatric patients. If a TLSO brace is given to patients, it should be done in consultation with a spine surgeon.

Surgical management options for vertebral compression fractures include kyphoplasty and vertebroplasty. Both procedures are minimally invasive, but are traditionally only performed if patients are in pain several weeks following diagnosis of a compression fracture (Wong, 2013).

Patients who are discharged from the ED with compression fractures need to be able to ambulate and perform activities of daily living prior to discharge. If pain control limits these activities, they will likely require admission for pain control, physical therapy, and potentially rehabilitation.

4. How do you clear a C-spine after a negative CT in a trauma patient who is awake, neuro intact, wearing a collar?

According to EAST guidelines, there are multiple appropriate options in patients who are awake, neurologically intact, and still have midline tenderness after a negative CT (Como, 2009). Although CT scans will pick up the majority of injuries, it is well documented that they specifically may miss ligamentous injuries, subluxations, and dislocations (Woodring, 1992).

The first option is to obtain an MRI within 72 hours post injury. Very little data exists in the literature regarding this option. Schuster, et al. evaluated prospectively collected registry data for 2854 blunt trauma patients, 93 of whom had a normal neurologic exam at admission, a negative CT result, and persistent C-spine pain. These patients all had an MRI. In all 93 of these patients, the MRI was negative for clinically significant injury. However, the argument could also be made that since no clinically significant injury was detected by MRI in this case, that there was no need for any further imaging (Schuster, 2005).

The second option is to continue the C-spine immobilization until there is no midline tenderness and the patient has been followed up as an outpatient. This is not ideal in centers where there is no trauma team to assist in outpatient management of these patients. Furthermore, the collar itself poses a risk of skin breakdown and decubitus ulcers when worn for a prolonged period of time. This option may work best for patients who can rapidly be seen in a trauma clinic.

The third option is to obtain flexion-extension films in patients with a negative CT of the C-spine. Although studies have evaluated the utility of flexion-extension films in patients with negative plain films of the C spine, no study has completely evaluated flexion-extension films following a negative CT of the C-spine. Insko et al reviewed 106 patients with negative plain films or negative CT imaging in areas that were not visualized by plain films. This study demonstrated a false negative rate of zero in diagnosing C spine fractures when flexion extension films were performed in patients who were persistently tender (Insko, 2002).

Ultimately, more information is needed to determine the best course of action to take in a patient with persistent pain following negative CT imaging of the C-spine (Como, 2009). However, at this time, there are three potential options in ruling out a C-spine injury in these patients. The decision may largely depend on local practice patterns, clinical suspicion for injury, as well as a patient’s ability to follow up.

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Spinal Cord Injury, Questions

1. What imaging do you use for patients with possible acute, traumatic spinal cord injury?

2. How do you treat neurogenic shock?

3. What is your management and disposition for elderly patients with vertebral compression fractures?

4. How do you clear a C-spine after a negative CT in a trauma patient who is awake, neuro intact, wearing a collar?

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Infectious Diseases, “Answers”

1. Which patients with neutropenic fever do you consider for outpatient management?

Neutropenic fever is a common presentation to the Emergency Department, especially in tertiary hospitals where many oncology patients are undergoing chemotherapy. According to the Infectious Disease Society of America (IDSA), fever in neutropenic patients is defined as a single oral temperature of >38.3°C (101°F) or a temperature of >38.0°C (100.4°F) sustained for >1 hour. Rectal temperature measurements (and rectal exams) are not recommended by the IDSA to prevent colonizing gut organisms from entering the surrounding mucosa and soft tissues (Freifeld, 2011). The definition of neutropenia varies from institution to institution; the IDSA defines it as an (ANC) <500 cells/microL or an ANC that is expected to decrease to <500 cells/microL over the next 48 hours. Profound or severe neutropenia occurs when the ANC is < 100 cells/micromol. The National Cancer Institute defines neutropenia as an ANC < 1000 cells/micromol (HHS 2010).

Patients with neutropenic fever are usually started on broad spectrum IV antibiotics and admitted to the hospital, however there are a subgroup of patients who can be safely managed as outpatients. The official wording from the IDSA guidelines is that “Carefully selected low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy (B-I)”. Grade B is defined as moderate evidence to support a recommendation for use, and Level I is evidence from ≥1 properly randomized, controlled trial. The data which they derived these recommendations include one large series of patients, where oral outpatient treatment for low-risk fever and neutropenia was deemed successful in 80% of patients, with 20% patient requiring readmission. Factors predicting readmission include age > 70, grade of mucositis >2, poor performance status, and ANC < 100 cells/microL at onset of fever (Escalante 2006). Klastersky et al studied 178 low-risk patients who were treated with oral antibiotics. Only 3 patients were readmitted resulting in a 96% success rate (Klastersky 2006) .

The IDSA formally risks stratifies using the Multinational Association for Supportive Care in Cancer (MASCC) scoring system. The adult guidelines from Australia, European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO) also recommend the use of the MASCC index (Gea-Banacloche 2013). Low-risk patients have a MASCC score ≥ 21.


The index has been validated in multiple settings and performs well, although it may function better in solid tumors than in hematologic malignancies (Klastersky 2013). An issue with the major criteria of “burden of febrile neutropenia” is that there is no standardized definition for this criteria, making uniform application of the MASCC confusing (Kern 2006).

Based on the best available data prior to the 2010 guidelines release, the IDSA developed an algorithm to risk stratify neutropenic fever patient and their appropriate management:



Ciprofloxacin plus amoxicillin-clavulanate is recommended for oral empirical treatment (Friefeld 2010). Other oral regimens, including levofloxacin or ciprofloxacin monotherapy or ciprofloxacin plus clindamycin, are less well studied but are commonly used. In low-risk patients, the risk of invasive fungal infection is low, and therefore routine use of empirical antifungal therapy is not recommended. Respiratory virus testing and chest radiography are indicated for patients with upper respiratory symptoms and/or cough .

A systematic review and meta-analysis of 14 RCTs was published in 2011 and not, therefore, included in the 2010 guidelines (Teuffel 2011). The meta-analysis concluded that inpatient versus outpatient management was not significantly associated with treatment failure; death occurred with no difference between the two groups; and outpatient oral versus outpatient parenteral antibiotics were similarly efficacious with no association between route of administration and treatment failure.

It must be said without questions that the patients whom you are treating as outpatients need to have easily accessible and very close follow up with their oncologists. They should be vigilantly examined for a source of infection, including a thorough skin, mucosal, and neurologic exam, as any obvious focal infection may necessitate inpatient treatment.

Bottom Line: Based on the IDSA guidelines and other meta-analyses, it is reasonable to treat a certain subset of low risk febrile neutropenic patients with oral antibiotics as an outpatient with good follow up.

2. Which patients with community-acquired pneumonia do you admit?

Community-acquired pneumonia (CAP) is defined as an acute infection of the pulmonary parenchyma in a patient who has acquired the infection in the community, as distinguished from hospital-acquired (nosocomial) pneumonia, which occurs 48 hours or more after hospital admission and is not present at time of admission. A third category of pneumonia, designated “healthcare-associated pneumonia,” is acquired in other healthcare facilities such as nursing homes, dialysis centers, and outpatient clinics or within 90 days of discharge from an acute or chronic care facility. The most common validated prediction rules for prognosis in community-acquired pneumonia include the Pneumonia Severity Index, CURB, and CURB-65 severity scores.

Question 2


According to the Pneumonia Severity Index (PSI), patients in risk classes I-III are defineQuestion 2 2d as low risk for short-term mortality and are considered for outpatient treatment. In the original derivation study of the PSI, Mortality ranged from 0.1 to 0.4 percent for class I patients, from 0.6 to 0.7 percent for class II, and from 0.9 to 2.8 percent for class III (Fine 1997). This older but well validated rule can be difficult to remember and apply; as a result, a relatively simpler CURB score with a total point score ranging from 0-4 was described and externally validated (Ewig 2004). A modified version, the CURB-65, which added age ≥ 65 as another positive risk factor was internally validated to stratify short term mortality for patients with CAP (Lim 2003). Patients scoring CURB < 1 and CURB-65 < 2 are considered low-risk and candidates for outpatient treatment. The CURB and CURB-65 scores are easier to remember and apply, however it does require laboratory data (BUN), whereas the lowest PSI risk class I can be attained without getting blood draws, a benefit appreciated in outpatient settings.

The three prediction rules were pitted against each other in a prospective study of over 3000 patients with community-acquired pneumonia from 32 hospital EDs to see which one was better at predicting 30-day mortality (Aujesky, 2005). Inclusion criteria included age ≥ 18 with a clinical diagnosis of pneumonia and new radiographic pulmonary infiltrate. Exclusion criteria included hospital acquired pneumonia, immunosuppression, psychosocial problems incompatible with outpatient treatment, or pregnancy.

The PSI classified a significantly greater proportion of patients as low risk (68%) than the CURB (51%) and the CURB-65 (61%). Of the low-risk by PSI (class I-III), the aggregate 30-day mortality was 1.4%, which is less than the CURB (score < 1) low-risk mortality rate of 1.7% and also 1.7% mortality for CURB-65 low-risk group (score <2). High-risk patients based on the PSI (class IV-V) had a higher mortality of 11.1% compared with high-risk CURB (≥1) and high risk CURB-65 (≥2), with respective mortality rates of 7.6% and 9.1%.

The PSI had a slightly higher sensitivity and negative predictive value across each risk cut-off point compared to the CURB and CURB-65. In addition, by comparing the areas under the receiver operating characteristic (ROC) curves, the PSI had a statistically significantly greater discriminatory power to predict 30-day mortality. CURB-65 showed a higher overall discriminatory power than the original CURB score.

Based on the estimation of 4 million annual cases of community acquired pneumonia in the USA (DeFrances, 2007), and the average cost of inpatient versus outpatient care of $7500 vs $264; using the PSI would identify an additional 650,000 low-risk patients vs. CURB and 250,000 vs. CURB-65, saving a significant amount of healthcare dollars, while still maintaining a low 30-day mortality rate (Aujesky, 2005) .

The 2007 (most current) Infectious Diseases Society of America (IDSA) recommendations on managing CAP revolve around the initial assessment of severity. “Severity-of-illness scores such as the CURB-65 criteria, or prognostic models, such as the Pneumonia Severity Index (PSI), can be used to identify patients with CAP who may be candidates for outpatient treatment. (Strong recommendation; level I evidence).” In addition to objective data, the IDSA also recommends supplementing with subjective factors, including the ability to safely and reliably take oral medications and the availability of outpatient support resources (Strong recommendation; level II evidence). (Mandell, 2007).

Bottom Line: Based on the validated prognostic scoring systems and recommendations from the IDSA, a subgroup of low-risk patients with community acquired pneumonia can safely be managed as outpatients. Their prognosis can be reliably predicted by 3 scoring systems, where the PSI performs slightly better but is more complex to apply than the CURB and CURB-65.

  1. Which patients with influenza do you treat with oseltamivir?

Neuraminidase inhibitors, specifically oseltamivir, have been increasingly used in the last 5 years for the treatment of patients with symptoms of influenza. In fact, between May and December of 2009, around 18.3 million prescriptions were written for the drug in seven countries (Australia, Canada, France, Germany, Japan, UK and USA) (Muthuri 2014). Additionally, hundreds of millions of doses have been stockpiled in various countries as a safe guard against pandemic influenza and the World Health Organization (WHO) lists oseltamivir as an essential drug. Physicians have been encouraged to prescribe osletamivir to patients by drug companies, professional society recommendations, hospitals and by patient pressure. Despite widespread use, the evidence of benefit for oseltamivir has never sat on firm evidence-based grounds. Much of this stems from the reluctance of the pharmaceutical giant Roche to release all relevant study data on the drug. This changed in 2013 when all of the data was made available for analysis.

Before we delve into the recently released data surrounding oseltamivir, let’s look at the prior recommendations and the basis for these recommendations. In 2009, the BMJ published a review of a number of observational studies looking at the effect of oseltamivir in the treatment of influenza (Freemantle 2009). This publication looked at randomized controlled studies provided by Roche pharmaceutical at that time. The limited available evidence supported the role of oseltamivir in reducing the rate of post-influenza pneumonia in otherwise healthy adults. There was no evidence of a mortality benefit and limited safety data (Freemantle 2014). Additionally, the available data supported the idea of using oseltamivir for chemoprophylaxis in patients who were at risk of exposure. A Cochrane group review in 2010 echoed these results but also stated that there was extensive bias present in the available studies and without a full disclosure of all the research, no strong recommendation could be made (Jefferson 2014). In spite of the limited evidence, broad recommendations were made including treatment of patients with multiple comorbidities, pregnant patients, those with immunocompromise and chemoprophylaxis for close contacts (Harper 2009).

In 2013, Roche pharmaceuticals released all of the study data. The Cochrane Respiratory group subsequently published an updated systematic review of all of the randomized controlled trials (Jefferson 2014) as well as a summary statement in the BMJ (Jefferson 2014). A number of statements from the prior review stand: there are minimal studies on efficacy and safety in pregnant patients, and no mortality benefit was seen. They did not find a reduction in post-influenza pneumonia and posited that this prior finding was likely due to publication bias. The below table summarizes the major outcomes of the 2014 Cochrane systematic review:

Outcome Measure Finding
Alleviation of Symptoms Shortened by 16.8 hrs with oseltamivir
Admission to Hospital No Difference
Reduction in Confirmed Pneumonia No Difference
Other Complications No Difference
Transmission in Prophylaxis Group No Reduction

Additionally, the group reported on a number of common side effects:

Side Effect Results
Nausea Increased (NNH 28)
Vomiting Increased (NNH 22)
Psychiatric Events Increased (NNH 94)
Headache Increased (NNH 32)

Overall, we see a mild shortening in the duration of symptoms with no reduction in admission, confirmed, post-influenza pneumonia or other complications. The same findings were seen in pediatric patients as well. There is minimal evidence in regards to efficacy or safety in pregnancy as pregnancy was an exclusion criteria in most of the studies. Side effects were common. Also, chemoprophylaxis did not reduce transmission of the disease. These results call into question the utility of oseltamivir for the treatment of influenza in any patient.

In June 2014, the PRIDE Consortium Investigators published a study challenging the Cochrane group findings (Muthuri 2014). In this large observational cohort (n=29,234 patients) Murthi et al found an association with decreased mortality (adjusted OR = 0.81) and an additional benefit to early (< 2 days) treatment versus later treatment (adjusted OR = 0.48). This study, however, has major flaws and biases that question the validity of their conclusions. Only 19% of centers that were contacted agreed to contribute data to the Consortium. Thus there is a high potential for bias. Additionally, the researchers do not assess the quality of the studies included in their meta-analysis (Antes 2014). Regardless, observational data should not be used to trump the RCT data included in the Cochrane review.

Bottom Line: The best available evidence demonstrates that oseltamivir leads to a mild reduction in the duration of symptoms of influenza. There is no proven benefit for mortality, hospital admissions or confirmed influenza related complications including pneumonia. The frequency of side effects may outweigh the mild symptom reduction benefit of the drug. The results of the 2014 Cochrane meta-analysis should be used to update the current CDC recommendations.

4. Which adult patients getting worked up for a urinary tract infection do you send a urine culture on?

A Urinary tract infection (UTI) is a condition in which bacteriuria is present with evidence of host invasion (presence of dysuria, frequency, flank pain, or fever). The “gold standard” in defining significant bacteriuria is the detection of any microorganisms by suprapubic aspiration. Since this method is not typically employed, many sources utilize a definition of more than 105 cfu/ml on a midstream urine culture to indicate true infection.

The American College of Emergency Physicians has recently kicked off the “Choosing Wisely” campaign (ACEP 2013) in an attempt to limit unnecessary testing in the Emergency Department. Although urine culture was not one of the five tests that was addressed, it is one of the most commonly sent laboratory tests in the ED making it a potential place to curb costs. In 1997, UTIs accounted for one million ED visits in the United States (Foxman 2002). Numerous publications and practice guidelines have recommended against the use of routine urine cultures in uncomplicated UTIs. Despite this, a 1999 survey of 269 EM physicians showed that 24% of them would order a urine culture on a 30-year-old non-pregnant woman with an uncomplicated UTI with dysuria of recent onset (Wigton 1999).

Werman et al in 1986 tackled the question of the “Utility of Urine Cultures in the Emergency Department” (Werman 1986). They concluded that urine cultures should only be obtained in patients at high risk for pyelonephritis or bacteremia/urosepsis, as well as in those expected to have uncommon or resistant organisms. This paper cited studies showing that routine urine cultures in nonpregnant women with acute cystitis do not affect management. Morrow et al showed that treatment of women seen in the ED with suspected cystitis proceeded with little attention to urine culture results, despite the fact that cultures were obtained routinely (Morrow 1976). Winickoff et al demonstrated that patients who did not have follow-up urine cultures after a UTI had no greater risk for reinfection or complications than did patients in whom follow-up cultures were obtained (Winickoff 1981). Additionally, a positive culture does not necessarily indicate the absolute need for antibiotics. In a study of 53 women with culture-proven UTIs, no patient progressed to pyelonephritis or bacteremia in spite of the fact that all were treated with placebo (Mabeck 1972).

In 2011, Johnson et al. addressed the question “Do Urine Cultures for Urinary Tract Infections Decrease Follow-up Visits?” (Johnson 2011). This retrospective cohort study looked at 779 female patients age 18-65 diagnosed with a UTI or acute cystitis treated in a family medicine clinic (exclusion criteria: pregnancy, diabetes, UTI or antibiotic use in preceding 6 weeks, other medical condition making UTI complicated). The follow-up rate for patients without urine cultures was 8.4%, which showed no statistical difference between the follow-up rate of 8.7% for patients with urine cultures. Ordering a urine culture was not associated with a decreased rate of follow-up visits (adjusted OR 1.11 [CI 0.65-1.90]). Of all 447 urine cultures ordered, only 1 grew bacteria resistant to nitrofurantoin, a common antibiotic used in the ED for uncomplicated cystitis. A 2006 UK study found that 23 women required a urine culture to prevent one follow-up visit from resistance-based failure; thus, empiric treatment with no urine culture was recommended (McNulty 2006).

Bottom Line: Although there are no prospective randomized controlled trials looking specifically at ED patients with UTI symptoms, it is safe to say that a urine culture in healthy adult non-pregnant females with new onset urinary symptoms without concern for pyelonephritis or bacteremia is unlikely to change management or outcome.

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Infectious Diseases, Questions


Screen Shot 2014-12-18 at 7.31.12 PM1. Which patients with neutropenic fever do you consider for outpatient management?

2. Which patients with community-acquired pneumonia do you admit?

3. Which patients with influenza do you treat with oseltamivir?

4. Which adult patients getting worked up for a urinary tract infection do you send a urine culture on?

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