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


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?

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