EMplify by EB Medicine – Détails, épisodes et analyse

In this episode, Sam Ashoo, MD interviews Nicholas Stark, MD, MBA & Zaid Altawil, MD about the Emergency Medicine Innovation Collaborative

1. Discussion on EMIC

  - Overview of the collaborative

  - Background and formation during the pandemic in late 2021

2. Growth of EMIC

  - Expansion from three members to over 500

  - Focus areas: Education, mentorship, opportunity

3. Achievements of EMIC

  - Examples of innovations and initiatives born from EMIC

  - Pitch event at ACEP annual conference and other engagements

4. Importance of Physicians in Innovation

  - Internal and external factors

  - Benefits of physicians leading innovation efforts in healthcare

5. Opportunities for Collaboration

  - Engaging with healthcare startups and companies

  - Expanding collaborations and growing the network

6. EMIC Fellowship

  - Ideal candidates

  - Application process and benefits

  - Success stories and projects undertaken

7. Long-Term Vision for EMIC

  - Goals for future growth and expansion

  - Bridging gaps between industry and physicians for better patient care

8. Membership Details

  - How to join EMIC

  - Benefits of membership

For more about the EM Innovation Collaborative... https://www.eminnovationcollaborative.org/

In this episode, Sam Ashoo, MD and T.R. Eckler, MD discuss the December 2024 Emergency Medicine Practice article, Diagnosis and Management of Acute Mesenteric Ischemia in the Emergency Department

• Introduction to Acute Mesenteric Ischemia
• Statistics on prevalence and mortality
• Pathophysiology and EtiologyMesenteric artery embolism
• Mesenteric artery thrombosis
• Mesenteric venous thrombosis
• Non-occlusive mesenteric ischemia
• Diagnosis
• Management and Treatment
• Special Populations
• Pediatric patients
• Pregnant patients
• Elderly patients

Emergency Medicine Residents, get your free subscription by writing resident@ebmedicine.net 

In this episode, Sam Ashoo, MD and T.R. Eckler, MD discuss the July 2024 Emergency Medicine Practice article, Emergency Department Management of Patients With Complications of Dialysis

Overview of Dialysis Complications

• Key Dialysis ComplicationsCardiovascular Disease
• Congestive Heart Failure
• Pericarditis and Cardiac Tamponade
• Neurological Sequelae
• Gastrointestinal Complications
• Hypotension
• Dialysis Disequilibrium Syndrome
• Air Embolism and Chloramine Toxicity

Disaster Preparedness

• Vascular Access ComplicationsHemorrhage risks and treatment
• Thrombosis, stenosis, and aneurysms
• Infection risks and management

Pre-Hospital Care

• ED History Differential diagnosis
•  Key questions to ask dialysis patients
• Examination Physical Exam Tips

Treatments

• Risk Management PitfallsCommon Pitfalls to Avoid

Conclusion

Jeff: Welcome back to Emplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. I’m Jeff Nusbaum, and I’m back with my co-host, Nachi Gupta. This month, we’re talking about a topic…

Nachi: … woah wait, slow down for a minute, before we begin this month’s episode – we should take a quick pause to wish all of our listeners a happy new year! Thanks for your regular listenership and feedback.

Jeff: And we’re actually hitting the two year mark since we started this podcast. At 25 episodes now, this is sort of our silver anniversary.

Nachi: We have covered a ton of topics in emergency medicine so far, and we are looking forward to reviewing a lot more evidence based medicine with you all going forward.

Jeff: With that, let’s get into the first episode of 2019 – the topic this month is first trimester pregnancy emergencies: recognition and management.

Nachi: This month’s issue was authored by Dr. Ryan Pedigo, you may remember him from the June 2017 episode on dental emergencies, though he is perhaps better known as the director of undergraduate medical education at Harbor-UCLA Medical center. In addition, this issue was peer reviewed by Dr. Jennifer Beck-Esmay, assistant residency director at Mount Sinai St. Luke’s, and Dr. Taku Taira, the associate director of undergraduate medical education and associate clerkship director at LA County and USC department of Emergency Medicine.

Jeff: For this review, Dr. Pedigo had to review a large body of literature, including thousands of articles, guidelines from the American college of obstetricians and gynecologists or ACOG, evidence based Practice bulletins, ACOG committee opinions, guidelines from the American college of radiology, the infectious diseases society of America, clinical policies from the American college of emergency physicians, and finally a series of reviews in the Cochrane database.

Nachi: There is a wealth of literature on this topic and Dr. Pedigo comments that the relevant literature is overall “very good.” This may be the first article in many months for which there is an overall very good quality of literature.

Jeff: It’s great to know that there is good literature on this topic. It’s incredibly important as we are not dealing with a single life here, as we usually do... we are quite literally dealing with potentially two lives as the fetus moves towards viability. With opportunities to improve outcomes for both the fetus and the mother, I’m confident that this episode will be worth your time.

Nachi: Oh, and speaking of being worth your time…. Don’t forget that if you’re listening to this episode, you can claim your CME credit. Remember, the indicates an answer to one of the CME questions so make sure to keep the issue handy.

Jeff: Let’s get started with some background. First trimester emergencies are not terribly uncommon in pregnancy. One study reported 85% experience nausea and vomiting. Luckily only 3% of these progressed to hyperemesis gravidarum. In addition, somewhere between 7-27% experience vaginal bleeding or miscarriage. Only 2% of these will be afflicted with an ectopic pregnancy. Overall, the maternal death rate is about 17 per 100,000 with huge racial-ethnic disparities.

Nachi: And vaginal bleeding in pregnancy occurs in nearly 25% of patients. Weeks 4-8 represent the peak time for this. The heavier the bleeding, the higher the risk of miscarriage.

Jeff: Miscarriage rates vary widely based on age, with an overall rate of 7-27%. This rises to nearly 40% risk in those over 40. And nearly half of miscarriages are due to fetal chromosomal abnormalities.

Nachi: For patient who have a threatened miscarriage in the first trimester, there is a 2-fold increased risk of subsequent maternal and fetal adverse outcomes.

Jeff: So key points here, since I think the wording and information you choose to share with often scared and worried women is important – nearly 25% of women experience bleeding in their first trimester. Not all of these will go on to miscarriages, though the risk does increase with maternal age. And of those that miscarry, nearly 50% were due to fetal chromosomal abnormalities.

Nachi: So can we prevent a miscarriage, once the patient is bleeding…?

Jeff: Short answer, no, longer answer, we’ll get to treatment in a few minutes. For now, let’s continue outlining the various first trimester emergencies. Next up, ectopic pregnancy…

Nachi: An ectopic pregnancy is implantation of a fertilized ovum outside of the endometrial cavity. This occurs in up to 2% of pregnancies. About 98% occur in the fallopian tube. Risk factors for an ectopic pregnancy include salpingitis, history of STDs, history of PID, a prior ectopic, and smoking.

Jeff: Interestingly, with respect to smoking, there is a dose-relationship between smoking and ectopic pregnancies. Simple advice here: don’t smoke if you are pregnant or trying to get pregnant.

Nachi: Pretty sound advice. In addition, though an IUD is not a risk factor for an ectopic pregnancy, if you do become pregnant while you have in IUD in place, over half of these may end up being ectopic.

Jeff: It’s also worth mentioning a more obscure related disease pathology here – the heterotopic pregnancy -- one in which there is an IUP and an ectopic pregnancy simultaneously.

Nachi: Nausea and vomiting, though not as scary as miscarriages or an ectopic pregnancy, represent a fairly common pathophysiologic response in the first trimester -- with the vast majority of women experiencing nausea and vomiting. And as we mentioned earlier, only 3% of these progress to hyperemesis gravidarum.

Jeff: And while nausea and vomiting clearly sucks, they seem to actually be protective of pregnancy loss, with a hazard ratio of 0.2.

Nachi: Although this may be protective of pregnancy loss, nausea and vomiting can really decrease the quality of life in pregnancy -- with one study showing that about 25% of women with severe nausea and vomiting had actually considered pregnancy termination. 75% of those women also stated they would not want to get pregnant again because of these symptoms.

Jeff: So certainly a big issue.. Two other common first trimester emergency are asymptomatic bacteriuria and UTIs. In pregnant patients, due to anatomical and physiologic changes in the GU tract – such as hydroureteronephrosis that occurs by the 7th week and urinary stasis due to bladder displacement – asymptomatic bacteriuria is a risk factor for developing pyelonephritis.

Nachi: And pregnant women are, of course, still susceptible to the normal ailments of young adult women like acute appendicitis, which is the most common surgical problem in pregnancy.

Jeff: Interestingly, based on epidemiologic data, pregnant women are less likely to have appendicitis than age-matched non-pregnant woman. I’d like to think that there is a good pathophysiologic explanation there, but I don’t have a clue as to why that might be.

Nachi: Additionally, the RLQ is the the most common location of pain from appendicitis in pregnancies of all gestational ages. Peritonitis is actually slightly more common in pregnant patients, with an odds ratio of 1.3.

Jeff: Alright, so I think we can put that intro behind us and move on to the differential.

Nachi: When considering the differential for abdominal pain or vaginal bleeding in the first trimester, you have to think broadly. Among gynecologic causes, you should consider miscarriage, septic abortion, ectopic pregnancy, corpus luteum cyst, ovarian torsion, vaginal or cervical lacerations, and PID. For non-gynecologic causes, you should also consider appendicitis, cholecystitis, hepatitis, and pyelonephritis.

Jeff: In the middle of that laundry list you mentioned there is one pathology which I think merits special attention - ovarian torsion. Don’t forget that patients undergoing ovarian stimulation as part of assisted reproductive technology are at a particularly increased risk due to the larger size of the ovaries.

Nachi: Great point. Up next we have prehospital care...

Jeff: Always a great section. First, prehospital providers should attempt to elicit an ob history. Including the number of weeks’ gestation, LMP, whether an IUP has already been confirmed, prior hx of ectopic, and amount of vaginal bleeding. In addition, providers should consider an early destination consult both to select the correct destination and to begin the process of mobilizing resources early in those patients who really need them, such as those with hemodynamic instability.

Nachi: As with most pathologies, the more time you give the receiving facility to prepare, the better the care will be, especially the early care, which is critical.

Jeff: Now that the patient has arrived in the ED we can begin our H&P.

Nachi: When eliciting the patient’s obstetrical history, it’s common to use the G’s and Ps. This can be further annotated using the 4-digit TPAL method, that’s term-preterm-abortus-living.

Jeff: With respect to vaginal bleeding, make sure to ask about the number of pads and how this relates to the woman’s normal number of pads. In addition, make sure to ask about vaginal discharge or even about the passage of tissue.

Nachi: You will also need to elicit whether or not the patient has a history of a prior ectopic pregnancies as this is a major risk for future ectopics. And ask about previous sexually transmitted infections also.

Jeff: And, of course, make sure to elicit a history of assisted reproductive technology, as this increases the risk of a heterotopic pregnancy.

Nachi: Let’s move on to the physical. While you are certainly going to perform your standard focused physical exam, just as you would for any non-pregnant woman - what does the evidence say about the pelvic exam? I know this is a HOTLY debated topic among EM Docs.

Jeff: Oh it certainly is. Dr. Pedigo takes a safe, but fair approach, noting, “A pelvic exam should always be performed if the emergency clinician suspects that it would change management, such as identifying the source of bleeding, or identifying an STD or PID.” However, it is noteworthy that the only real study he cites on this topic, an RCT of pelvic vs no pelvic in those with a confirmed IUP and first trimester bleeding, found no difference between the two groups. Obviously, the pelvic group reported more discomfort.

Nachi: You did leave out one important fact about the study enrollment - they only enrolled about 200 of 700 intended patients.

Jeff: Oh true, so a possibly underpowered study, but it’s all we’ve got on the topic. I think I’m still going to do pelvic exams, but it’s something to think about.

Nachi: Moving on, all unstable patients with vaginal bleeding and no IUP should be assumed to have an ectopic until proven otherwise. Ruptured ectopics can manifest with a number of physical exam findings including abdominal tenderness, with peritoneal signs, or even with bradycardia due to vagal stimulation in the peritoneum.

Jeff: Perhaps most importantly, no history or physical alone can rule in or out an ectopic pregnancy, for that you’ll need testing and imaging or operative findings.

Nachi: And that’s a perfect segue into our next section - diagnostic studies.

Jeff: Up first is the urine pregnancy test. A UPT should be obtained in all women of reproductive age with abdominal pain or vaginal bleeding, and likely other complaints too, though we’re not focusing on them now.

Nachi: The UPT is a great test, with nearly 100% sensitivity, even in the setting of very dilute urine. False positives are certainly plausible, with likely culprits being recent pregnancy loss, exogenous HCG, or malignancy.

Jeff: And not only is the sensitivity great, but it’s usually positive just 6-8 days after fertilization.

Nachi: While the UPT is fairly straight forward, let’s talk about the next few tests in the context of specific disease entities, as I think that may make things a bit simpler -- starting with bHCG in the context of miscarriage and ectopic pregnancy.

Jeff: Great starting point since there is certainly a lot of debate about the discriminatory zone. So to get us all on the same page, the discriminatory zone is the b-HCG at which an IUP is expected to be seen on ultrasound. Generally 1500 is used as the cutoff. This corresponds nicely to a 2013 retrospective study demonstrating a bHCG threshold for the fetal pole to be just below 1400.

Nachi: However, to actually catch 99% of gestational sacs, yolk sacs, and fetal poles, one would need cutoffs of around 3500, 18000, and 48,000 respectively -- much higher.

Jeff: For this reason, if you want to use a discriminatory zone, ACOG recommends a conservatively high 3,500, as a cutoff.

Nachi: I think that’s an understated point in this article, the classic teaching of a 1500 discriminatory zone cutoff is likely too low.

Jeff: Right, which is why I think many ED physicians practice under the mantra that it’s an ectopic until proven otherwise.

Nachi: Certainly a safe approach.

Jeff: Along those lines, lack of an IUP with a bHCG above whatever discriminatory zone you are using does not diagnose an ectopic, it merely suggests a non-viable pregnancy of undetermined location.

Nachi: And if you don’t identify an IUP, serial bHCGs can be really helpful. As a rule of thumb -- in cases of a viable IUP -- b-HCG typically doubles within 48 hours and at a minimum should rise 53%.

Jeff: In perhaps one of the most concerning things I’ve read in awhile, one study showed that ⅓ of patients with an ectopic had a bCHG rise of 53% in 48h and 20% of patients with ectopics had a rate of decline typical to that of a miscarriage.

Nachi: Definitely concerning, but this is all the more reason you need to employ our favorite imaging modality… the ultrasound.

Jeff: All patients with a positive pregnancy test and vaginal bleeding should receive an ultrasound performed by either an emergency physician or by radiology. Combined with a pelvic exam, this can give you almost all the data necessary to make the diagnosis, even if you don’t find an IUP.

Nachi: And yes, there is good data to support ED ultrasound for this indication, both transabdominal and transvaginal, assuming the emergency physician is credentialed to do so. A 2010 Meta-Analysis found a NPV of 99.96% when an er doc identified an IUP on bedside ultrasound. So keep doing your bedside scans with confidence.

Jeff: Before we move on to other diagnostic tests, let’s discuss table 2 on page 7 to refresh on key findings of each of the different types of miscarriage. For a threatened abortion, the os would be closed with an IUP seen on ultrasound. For a completed abortion, you would expect a closed OS with no IUP on ultrasound with a previously documented IUP. Patients may or may not note the passage of products of conception.

Nachi: A missed abortion presents with a closed os and a nonviable fetus on ultrasound. Findings such as a crown-rump length of 7 mm or greater without cardiac motion is one of several criteria to support this diagnosis.

Jeff: An inevitable abortion presents with an open OS and an IUP on ultrasound. Along similar lines, an incomplete abortion presents with an open OS and partially expelled products on ultrasound.

Nachi: And lastly, we have the septic abortion, which is sort of in a category of its own. A septic abortion presents with either an open or closed OS with essentially any finding on ultrasound in the setting of an intrauterine infection and a fever.

Jeff: I’ve only seen this two times, and both women were incredibly sick upon presentation. Such a sad situation.

Nachi: For sure. Before we move on to other tests, one quick note on the topic of heterotopic pregnancies: because the risk in the general population is so incredibly low, the finding of an IUP essentially rules out an ectopic pregnancy assuming the patient hasn’t been using assisted reproductive technology. In those that are using assisted reproductive technology, the risk rises to 1 in 100, so finding an IUP, in this case, doesn’t necessarily rule out a heterotopic pregnancy.

Jeff: Let’s move on to diagnostic studies for patients with nausea and vomiting. Typically, no studies are indicated beyond whatever you would order to rule out other serious pathology. Checking electrolytes and repleting them should be considered in those with severe symptoms.

Nachi: For those with symptoms suggestive of a UTI, a urinalysis and culture should be sent. Even if the urinalysis is negative, the culture may still have growth. Treat asymptomatic bacteriuria and allow the culture growth to guide changes in antibiotic selection.

Jeff: It’s worth noting, however, that a 2016 systematic review found no reliable evidence supporting routine screening for asymptomatic bacteriuria, so send a urinalysis and culture only if there is suspicion for a UTI.

Nachi: For those with concern for appendicitis, while ultrasound is a viable imaging modality, MRI is gaining favor. Both are specific tests, however one study found US to visualize the appendix only 7% of the time in pregnant patients.

Jeff: Even more convincingly, one 2016 meta analysis found MRI to have a sensitivity and specificity of 94 and 97% respectively suggesting that a noncontrast MRI should be the first line imaging modality for potential appendicitis.

Nachi: You kind of snuck it in there, but this is specifically a non-contrast MRI. Whereas a review of over a million pregnancies found no associated fetal risk with routine non-contrast MRI, gadolinium-enhanced MRI has been associated with increased rates of stillbirth, neonatal death, and rheumatologic and inflammatory skin conditions.

Jeff: CT is also worth mentioning since MRI and even ultrasound may not be available to all of our listeners. If you do find yourself in such a predicament, or you have an inconclusive US without MRI available, a CT scan may be warranted as the delay in diagnosis and subsequent peritonitis has been found to increase the risk of preterm birth 4-fold.

Nachi: Right, and a single dose of ionizing radiation actually does not exceed the threshold dose for fetal harm.

Jeff: Let’s talk about the Rh status and prevention of alloimmunization. While there are no well-designed studies demonstrating benefit to administering anti-D immune globulin to Rh negative patients, ACOG guidelines state “ whether to administer anti-D immune globulin to a patient with threatened pregnancy loss and a live embryo or fetus at or before 12 weeks of gestation is controversial, and no evidence-based recommendation can be made.”

Nachi: Unfortunately, that’s not particularly helpful for us. But if you are going to treat an unsensitized Rh negative female with vaginal bleeding while pregnant with Rh-immune globulin, they should receive 50 mcg IM of Rh-immune globulin within 72 hours, or the 300 mcg dose if that is all that is available. It’s also reasonable to administer Rh(d)-immune globulin to any pregnant female with significant abdominal trauma.

Jeff: Moving on to the treatment for miscarriages - sadly there isn’t much to offer here. For those with threatened abortions, the vast majority will go on to a normal pregnancy. Bedrest had been recommended in the past, but there is little data to support this practice.

Nachi: For incomplete miscarriages, if visible, products should be removed and you should consider sending those products to pathology for analysis, especially if the patient has had recurrent miscarriages.

Jeff: For those with a missed abortion or incomplete miscarriages, options include expectant management, medical management or surgical management, all in consultation with an obstetrician. It’s noteworthy that a 2012 Cochrane review failed to find clear superiority for one strategy over another. This result was for the most part re-confirmed in a 2017 cochrane review. The latter study did find, however, that surgical management in the stable patient resulted in lower rates of incomplete miscarriage, bleeding, and need for transfusion.

Nachi: For expectant management, 50-80% will complete their miscarriage within 7-10 days.

Jeff: For those choosing medical management, typically with 800 mcg of intravaginal misoprostol, one study found this to be 91% effective in 7 days. This approach is preferred in low-resource settings.

Nachi: And lastly, remember that all of these options are only options for stable patients. Surgical management is mandatory for patients with significant hemorrhage or hemodynamic instability.

Jeff: Since the best evidence we have doesn’t suggest a crystal clear answer, you should rely on the patient’s own preferences and a discussion with their obstetrician. For this reason and due to the inherent difficulty of losing a pregnancy, having good communication is paramount.

Nachi: Expert consensus recommends 6 key aspects of appropriate communication in such a setting: 1

assess the meaning of the pregnancy loss,

give the news in a culturally competent and supportive manner,

inform the family that grief is to be expected and give them permission to grieve in their own way,

learn to be comfortable sharing the products of conception should the woman wish to see them,

5. provide support for whatever path she chooses,

6. and provide resources for grief counselors and support groups.

Jeff: All great advice. The next treatment to discuss is that for pregnancy of an unknown location and ectopic pregnancies.

Nachi: All unstable patients or those with suspected or proven ectopic or heterotopic pregnancies should be immediately resuscitated and taken for surgical intervention.

Jeff: For those that are stable, with normal vitals, and no ultrasound evidence of a ruptured ectopic, with no IUP on ultrasound, -- that is, those with a pregnancy of unknown location, they should be discharged with follow up in 48 hours for repeat betaHCG and ultrasound.

Nachi: And while many patients only need a single additional beta check, some may need repeat 48 hour exams until a diagnosis is established.

Jeff: For those that are stable with a confirmed tubal ectopic, you again have a variety of treatment options, none being clearly superior.

Nachi: Treatment options here include IM methotrexate, or a salpingostomy or salpingectomy.

Jeff: Do note, however, that a bHCG over 5000, cardiac activity on US, and inability to follow up are all relative contraindications to methotrexate treatment. Absolute contraindications to methotrexate include cytopenia, active pulmonary disease, active peptic ulcer disease, hepatic or renal dysfunction, and breastfeeding.

Nachi: Such decisions, should, of course, be made in conjunction with the obstetrician.

Jeff: Always good to make a plan with the ob. Moving on to the treatment of nausea and vomiting in pregnancy, ACOG recommends pyridoxine, 10-25 mg orally q8-q6 with or without doxylamine 12.5 mg PO BID or TID. This is a level A recommendation as first-line treatment!

Nachi: In addition, ACOG also recommends nonpharmacologic options such as acupressure at the P6 point on the wrist with a wrist band. Ginger is another nonpharmacologic intervention that has been shown to be efficacious - 250 mg by mouth 4 times a day.

Jeff: So building an algorithm, step one would be to consider ginger and pressure at the P6 point. Step two would be pyridoxine and doxylamine. If all of these measures fail, step three would be IV medication - with 10 mg IV of metoclopramide being the agent of choice.

Nachi: By the way, ondansetron carries a very small risk of fetal cardiac abnormalities, so the other options are of course preferred.

Jeff: In terms of fluid choice for the actively vomiting first trimester woman, both D5NS and NS are appropriate choices, with slightly decreased nausea in the group receiving D5NS in one randomized trial of pregnant patients admitted for vomiting to an overnight observation unit.

Nachi: Up next for treatment we have asymptomatic bacteriuria. As we stated previously, asymptomatic bacteriuria should be treated. This is due to anatomical and physiologic changes which put these women at higher risk than non-pregnant women.

Jeff: And this recommendation comes from the 2005 IDSA guidelines. In one trial, treatment of those with asymptomatic bacteriuria with nitrofurantoin reduced the incidence of developing pyelonephritis from 2.4% to 0.6%.

Nachi: And this trial specifically examined the utility of nitrofurantoin. Per a 2010 and 2011 Cochrane review, there is not evidence to recommend one antibiotic over another, so let your local antibiograms guide your treatment.

Jeff: In general, amoxicillin or cephalexin for a full 7 day course could also be perfectly appropriate.

Nachi: A 2017 ACOG Committee Opinion analyzed nitrofurantoin and sulfonamide antibiotics for association with birth defects. Although safe in the second and third trimester, they recommend use in the first trimester -- only when no other suitable alternatives are available.

Jeff: For those, who unfortunately do go on to develop pyelo, 1g IV ceftriaxone should be your drug of choice. Interestingly, groups have examined outpatient care with 2 days of daily IM ceftriaxone vs inpatient IV antibiotic therapy and they found that there may be a higher than acceptable risk in the outpatient setting as several required eventual admission and one developed septic shock in their relatively small trial.

Nachi: And the last treatment to discuss is for pregnant patient with acute appendicitis. Despite a potential shift in the standard of care for non pregnant patients towards antibiotics-only as the initial treatment, due to the increased risk of serious complications for pregnant women with an acute appy, the best current evidence supports a surgical pathway.

Jeff: Perfect, so that wraps up treatment. We have a few special considerations this month, the first of which revolves around ionizing radiation. Ideally, one should limit the amount of ionizing radiation exposure during pregnancy, however avoiding it all together may lead to missed or delayed diagnoses and subsequently worse outcomes.

Nachi: It’s worth noting that the American College of Radiology actually lists several radiographs that are such low exposure that checking a urine pregnancy test isn’t even necessary. These include any imaging of the head and neck, extremity CT, and chest x-ray.

Jeff: Of course, an abdomen and pelvis CT carries the greatest potential risk. However, if necessary, it’s certainly appropriate as long as there is a documented discussion of the risk and benefits with the patient.

Nachi: And regarding iodinated contrast for CT -- it appears to present no known harm to the fetus, but this is based on limited data. ACOG recommends using contrast only if “absolutely required”.

Jeff: Right and that’s for iodinated contrasts. Gadolinium should always be avoided. Let me repeat that Gadolinium should always be avoided

Nachi: Let’s also briefly touch on a controversial topic -- that of using qualitative urine point of care tests with blood instead of urine. In short, some devices are fda-approved for serum, but not whole blood. Clinicians really just need to know the equipment and characteristics at their own site. It is worth noting that there have been studies on determining whether time can be saved by using point of care blood testing instead of urine for the patient who is unable to provide a prompt sample. Initial study conclusions are promising. But again, you need to know the characteristics of the test at your ER.

Jeff: One more controversy in this issue is that of expectant management for ectopic pregnancy. A 2015 randomized trial found similar outcomes for IM methotrexate compared to placebo for tubal ectopics. Inclusion criteria included hemodynamic stability, initial b hcg < 2000, declining b hcg titers 48 hours prior to treatment, and visible tubal pregnancy on trans vaginal ultrasound. Another 2017 multicenter randomized trial found similar results.

Nachi: But of course all of these decisions should be made in conjunction with your obstetrician colleagues.

Jeff: Let’s move on to disposition. HDS patients who are well-appearing with a pregnancy of undetermined location should be discharged with a 48h beta hcg recheck and ultrasound. All hemodynamically unstable patients, should of course be admitted and likely taken directly to the OR.

Nachi: Also, all pregnant patients with acute pyelonephritis require admission. Outpatient tx could be considered in consultation with ob.

Jeff: Patient with hyperemesis gravidarum who do not improve despite treatment in the ED should also be admitted.

Nachi: Before we close out the episode, let’s go over some key points and clinical pearls...

J Overall, roughly 25% of pregnant women will experience vaginal bleeding and 7-27% of pregnant women will experience a miscarriage

2. Becoming pregnant with an IUD significantly raises the risk of ectopic pregnancy.

3. Ovarian stimulation as part of assisted reproductive technology places pregnant women at increased risk of ovarian torsion.

4. Due to anatomical and physiologic changes in the genitourinary tract, asymptomatic bacteriuria places pregnant women at higher risk for pyelonephritis. As such, treat asymptomatic bacteriuria according to local antibiograms.

5. A pelvic exam in the setting of first trimester bleeding is only warranted if you suspect it might change management.

6. Unstable patients with vaginal bleeding and no IUP should be assumed to have an ectopic pregnancy until proven otherwise.

7. If you are to use a discriminatory zone, ACOG recommends a beta-hCG cutoff of 3500.

8. The beta-hCG typically doubles within 48 hours during the first trimester. It should definitely rise by a minimum of 53%.

9. For patients using assisted reproductive technology, the risk of heterotopic pregnancy becomes much higher. Finding an IUP does not necessarily rule out a heterotopic pregnancy.

N. Send a urine culture for patients complaining of UTI symptoms even if the urinalysis is negative.

J. The most common surgical problem in pregnancy is appendicitis.

N, If MRI is not available and ultrasound was inconclusive, CT may be warranted for assessing appendicitis. The risk of missing or delaying the diagnosis may outweigh the risk of radiation.

J. ACOG recommends using iodinated contrast only if absolutely required.

N. For stable patients with a pregnancy of unknown location, plan for discharge with follow up in 48 hours for a repeat beta-hCG and ultrasound.

J For nausea and vomiting in pregnancy, try nonpharmacologic treatments like acupressure at the P6 point on the wrist or ginger supplementation. First line pharmacologic treatment is pyridoxine. Doxylamine can be added. Ondansetron may increase risk of fetal cardiac abnormalities

N So that wraps up episode 24 - First Trimester Pregnancy Emergencies: Recognition and Management.

J: Additional materials are available on our website for Emergency Medicine Practice subscribers. If you’re not a subscriber, consider joining today. You can find out more at www.ebmedicine.net/subscribe. Subscribers get in-depth articles on hundreds of emergency medicine topics, concise summaries of the articles, calculators and risk scores, and CME credit. You’ll also get enhanced access to the podcast, including the images and tables mentioned. You can find everything you need to know at ebmedicine.net/subscribe.

N: And the address for this month’s credit is ebmedicine.net/E0119, so head over there to get your CME credit. As always, the you heard throughout the episode corresponds to the answers to the CME questions. Lastly, be sure to find us on iTunes and rate us or leave comments there. You can also email us directly at emplify@ebmedicine.net with any comments or suggestions. Talk to you next month!

Jeff: Welcome back to Emplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. I’m Jeff Nusbaum, and I’m back with my co-host, Nachi Gupta. This month, we’re talking about a topic that is ripe for review this time of year. We’re talking Influenza… Diagnosis and Management.

Nachi: Very appropriate as the cold is settling in here in NYC and we’re already starting to see more cases of influenza. Remember that as you listen through the episode, the means we’re about to cover one of the CME questions for those of you listening at home with the print issue handy.

Jeff: This month’s issue was authored by Dr. Al Giwa of the Icahn School of Medicine at Mount Sinai, Dr. Chinwe Ogedegbe of the Seton Hall School of Medicine, and Dr. Charles Murphy of Metrowest Medical Center.

Nachi: And this issue was peer reviewed by Dr. Michael Abraham of the University of Maryland School of Medicine and by Dr. Dan Egan, Vice Chair of Education of the Department of Emergency Medicine at Columbia University.

Jeff: The information contained in this article comes from articles found on pubmed, the cochrane database, center for disease control, and the world health organization. I’d say that’s a pretty reputable group of sources. Additionally, guidelines were reviewed from the american college of emergency physicians, infectious disease society of america, and the american academy of pediatrics.

Nachi: Some brief history here to get us started -- did you know that in 1918/1919, during the influenza pandemic, about one third of the world’s population was infected with influenza?

Jeff: That’s wild. How do they even know that?

Nachi: Not sure, but also worth noting -- an estimated 50 million people died during that pandemic.

Jeff: Clearly a deadly disease. Sadly, that wasn’t the last major outbreak… fifty years later the 1968 hong kong influenza pandemic, H3N2, took between 1 and 4 million lives.

Nachi: And just last year we saw the 2017-2018 influenza epidemic with record-breaking ED visits. This was the deadliest season since 1976 with at least 80,000 deaths.

Jeff: The reason for this is multifactorial. The combination of particularly mutagenic strains causing low vaccine effectiveness, along with decreased production of IV fluids and antiviral medication because of the hurricane, all played a role in last winter’s disastrous epidemic.

Nachi: Overall we’re looking at a rise in influenza related deaths with over 30,000 deaths annually in the US attributed to influenza in recent years. The ED plays a key role in outbreaks, since containment relies on early and rapid identification and treatment.

Jeff: In addition to the mortality you just cited, influenza also causes a tremendous strain on society. The CDC estimates that epidemics cost 10 billion dollars per year. They also estimate that an epidemic is responsible for 3 million hospitalized days and 31 million outpatient visits each year.

Nachi: It is thought that up to 20% of the US population has been infected with influenza in the winter months, disproportionately hitting the young and elderly. Deaths from influenza have been increasing over the last 20 years, likely in part due to a growing elderly population.

Jeff: And naturally, the deaths that we see from influenza also disproportionately affect the elderly, with up to 90% occurring in those 65 or older.

Nachi: Though most of our listeners probably know the difference between an influenza epidemic and pandemic, let’s review it anyway. When the number of cases of influenza is higher than what would be expected in a region, an epidemic is declared. When the occurrence of disease is on a worldwide spectrum, the term pandemic is used.

Jeff: I think that’s enough epidemiology for now. Let’s get started with the basics of the influenza virus. Influenza is spread primarily through direct person-to-person contact via expelled respiratory secretions. It is most active in the winter months, but can be seen year-round.

Nachi: The influenza virus is a spherical RNA-based virus of the orthomyxoviridae family. The RNA core is associated with a nucleoprotein antigen. Variations of this antigen have led to the the 3 primary subgroups -- influenza A, B, and C, with influenza A being the most common.

Jeff: Influenza B is less frequent, but is more frequently associated with epidemics. And Influenza C is the form least likely to infect humans -- it is also milder than both influenza A or B.

Nachi: But back to Influenza A - it can be further classified based on its transmembrane or surface proteins, hemagglutinin and neuraminidase - or H and N for short. There are actually 16 different H subtypes and 9 different N subtypes, but only H1, H2, H3, and N1 and N2 have caused epidemic disease.

Jeff: Two terms worth learning here are antigen drift and anitgen shift. Antigen drift refers to small point mutations to the viral genes that code for H and N. Antigen shift is a much more radical change, with reassortment of viral genes. When cells are infected by 2 or more strains, a new strain can emerge after genetic reassortment.

Nachi: With antigen shift, some immunity may be maintained within a population infected by a similar subtype previously. With antigen drift, there is loss of immunity from prior infection.

Jeff: The appearance of new strains of influenza typically involves an animal host, like pigs, horses, or birds. This is why you might be hear a strain called “swine flu”, “equine flu”, or “avian flu”. Close proximity with these animals facilitates co-infection and genetic reassortment.

Nachi: I think that’s enough basic biology for now, let’s move on to pathophysiology. When inhaled, the influenza virus initially infects the epithelium of the upper respiratory tract and alveolar cells of the lower respiratory tract. Viral replication occurs within 4 to 6 hours. Incubation is 18 to 72 hours. Viral shedding is usually complete roughly 7 days after infection, but can be longer in children and immunocompromised patients.

Jeff: As part of the infectious process and response, there can be significant changes to the respiratory tract with inflammation and epithelial cell necrosis. This can lead to viral pneumonia, and occasionally secondary bacterial pneumonia.

Nachi: The secondary bacterial pathogens that are most common include Staph aureus, Strep pneumoniae, and H influenzae.

Jeff: Despite anything you may read on the internet, vaccines work and luckily influenza happens to be a pathogen which we can vaccinate against. As such, there are 3 methods approved by the FDA for producing influenza vaccines -- egg-based, cell-based, or recombinant influenza vaccine. Once the season’s most likely strains have been determined, the virus is introduced into the medium and allowed to replicate. The antigen is then purified and used to make an injection or nasal spray.

Nachi: It isn’t easy to create vaccines for all strains. H3N2, for example, is particularly virulent, volatile, and mutagenic, which leads to poor prophylaxis against this particular subgroup.

Jeff: In fact, a meta-analysis on vaccine effectiveness from 2004-2015 found that the pooled effectiveness against influenza B was 54%, against the H1N1 pandemic in 2009 was 61%, and against the H3N2 virus was 33%. Not surprisingly, H3N2 dominant seasons are currently associated with the highest rates of influenza cases, hospitalizations, and death.

Nachi: Those are overall some low percentages. So should we still be getting vaccinated? The answer is certainly a resounding YES.. Despite poor protection from certain strains, vaccine effectiveness is still around 50% and prevents severe morbidity and mortality in those patients.

Jeff: That’s right. The 2017-2018 vaccine was only 40% effective, but this still translates to 40% less severe cases and a subsequent decrease in hospitalizations and death.

Nachi: But before we get into actual hospitalization, treatment, and preventing death, let’s talk about the differential. We’re not just focusing on influenza here, but any influenza like illness, since they can be hard to distinguish. The CDC defines “influenza-like illness” as a temperature > 100 F, plus cough or sore throat, in the absence of a known cause other than influenza.

Jeff: Therefore, influenza should really be considered on the differential of any patient who presents to the ED with a fever and URI symptoms. The differential when considering influenza might also include mycoplasma pneumoniae, strep pneumoniae, adenovirus, RSV, rhinovirus, parainfluenza virus, legionella, and community acquired MRSA.

Nachi: With the differential in mind, let’s move on to prehospital care. For the prehospital setting, there isn’t much surprising here. Stabilize and manage the respiratory status with all of your standard tools - oxygen for those with mild hypoxia and advanced airway maneuvers for those with respiratory distess.

Jeff: Of note, EMS providers should use face masks themselves and place them on patients as well. As community paramedicine and mobile integrated health becomes more common, this is one potential area where EMS can potentially keep patients at home or help them seek treatment in alternate destinations to avoid subjecting crowded ED’s to the highly contagious influenza virus.

Nachi: It’s also worth noting, that most communities have strategic plans in the event of a major influenza outbreak. Local, state, and federal protocols have been designed for effective care delivery.

Jeff: Alright, so now that the EMS crew, wearing proper PPE of course, has delivered the patient, who is also wearing a mask, to the ED, we can begin our ED H&P. Don’t forget that patients present with a range of symptoms that vary by age. A typical history is 2-5 days of fever, nasal congestion, sore throat, and myalgias. You might see tachycardia, cough, dyspnea, and chills too.

Nachi: Van Wormer et al conducted a prospective analysis of subjective symptoms to determine correlation with lab confirmed influenza. They found the most common symptoms were cough in 92%, fatigue in 91%, and nasal congestion in 84%, whereas sneezing was actually a negative predictor for influenza.

Jeff: Sneezing, really? Can’t wait to get the Press-Gany results from the sneezing patient I discharge without testing for influenza based on their aggressive sneezes!

Nachi: Aggressive sneezes…? I can’t wait to see your scale for that.

Jeff: Hopefully I’ll have it in next month’s annals. In all seriousness, I’m not doing away with flu swabs just yet. In another retrospective study, Monto et al found that the best multivariate predictors were cough and fever with a positive predictive value of 79%.

Nachi: Yet another study in children found that the predominant symptoms were fever in 95%, cough in 77%, and rhinitis in 78%. This study also suggested that the range of fever was higher in children and that GI symptoms like vomiting and diarrhea were more common in children than adults.

Jeff: Aside from symptomatology, there are quite a few diagnostic tests to consider including viral culture, immunofluoresence, rt-pcr, and rapid antigen testing. The reliability of testing varies greatly depending on the type of test, quality of the sample, and the lab. During a true epidemic, formal testing might not be indicated as the decision to treat is based on treatment criteria like age, comorbidities, and severity of illness.

Nachi: We’ll get to treatment in a few minutes, but diving a bit deeper into testing - there are 3 major categories of tests. The first detects influenza A only. The second detects either A or B, but cannot distinguish between them; and the third detects both influenza A and B and is subtype specific. The majority of rapid testing kits will distinguish between influenza A and B, but not all can distinguish between them. Fluorescent antibody testing by DFA is relatively rapid and yields results within 2 to 4 hours.

Jeff: Viral culture and RT-PCR remain the gold standard, but both require more time and money, as well as a specialized lab. As a result, rapid testing modalities are recommended. Multiple studies have shown significant benefit to the usefulness of positive results on rapid testing. It’s safe to say that at a minimum, rapid testing helps decrease delays in treatment and management.

Nachi: Looking a bit further into the testing characteristics, don’t forget that the positive predictive value of testing is affected by the prevalence of influenza. In periods of low influenza activity (as in the summer), a rapid test will have low PPV and high NPV. The test is more likely to yield false positive results -- up to 50% according to one study when prevalence is below 5%.

Jeff: And conversely, in periods of high influenza activity, a rapid test will have higher PPV and lower NPV, and it is more likely to produce a false negative result.

Nachi: In one prospective study of patients who presented with influenza-like illness during peak season, rapid testing was found to be no better than clinical judgement. During these times, it’s probably better to reserve testing for extremely ill patients in whom diagnostic closure is particularly important. And since the quality of the specimen remains important, empiric treatment of critically ill patients should still be considered.

Jeff: Which is a perfect segway into our next topic - treatment, which is certainly the most interesting section of this article. To start off -- for mild to moderate disease and no underlying high risk conditions, supportive therapy is usually sufficient.

Nachi: Antiviral therapy is reserved for those with a predicted severe disease course or with high risk conditions like long-standing pulmonary disease, pregnancy, immunocompromise, or even just being elderly.

Jeff: Note to self, avoid being elderly.

Nachi: Good luck with that. Anyway, early treatment with antivirals has been shown to reduce influenza-related complications in both children and adults.

Jeff: Once you’ve decided to treat the patient, there are two primary classes of antivirals -- adamantane derivatives and neuraminidase inhibitors. Oh and then there is a new single dose oral antiviral that was just approved by the FDA… baloxavir marboxil (or xofluza), which is in a class of its own -- a polymerase endonuclease inhibitor.

Nachi: The oldest class, the adamantane derivatives, includes amantadine and rimantadine. Then the newer class of neuraminidase inhibitors includes oseltamavir (which is taken by mouth), zanamavir (which is inhaled), and peramivir (which is administered by IV).

Jeff: Oseltamavir is currently approved for patients of all ages. A 2015 meta analysis showed that the intention-to-treat infected population had a shorter time to alleviation of all symptoms from 123 hours to 98 hours. That’s over a day less of symptoms, not bad! There were also fewer lower respiratory tract complications requiring antibiotics and fewer admissions for any cause. Really, not bad!

Nachi: Zanamavir is approved for patients 7 and older -- or for children 5 or older for disease prevention. Zanamavir has been associated with possible bronchospasm and is contraindicated in patients with reactive airway disease.

Jeff: Peramivir, the newest drug in this class, is given as a single IV dose for patients with uncomplicated influenza who have been sick for 2 days or less. Peramavir is approved for patients 2 or older. This is a particularly great choice for a vomiting patient.

Nachi: And as you mentioned before, just last month, the FDA approved baloxavir, a single dose antiviral. It’s effective for influenza type A or B. Note that safety and efficacy have not been established for patients less than 12 years old, weighing less than 40 kg, or pregnant or lactating patients.

Jeff: Unfortunately, there has been some pretty notable antiviral resistance in the recent past, moreso with the adamantane class, but recently also with the neuraminidase inhibitors. In 2007-2008, an oseltamivir-resistant H1N1 strain emerged globally. Luckily, cross-resistance between baloxavir and the adamantanes or neuraminidase inhibitors isn’t expected, as they target different viral proteins, so this may be an answer this year, and in the future.

Nachi: Let’s talk chemoprophylaxis for influenza.. Chemoprophylaxis with oseltamavir or zanamavir can be considered for patients who are at high risk for complications and were exposed to influenza in the first 2 weeks following vaccination, patients who are at high risk for complications and cannot receive the vaccination, and those who are immunocompromised.

Jeff: Chemoprophylaxis is also recommended for pregnant women. For postexposure prophylaxis for pregnant women, the current recommendation is to administer oseltamivir.

Nachi: We should also discuss the efficacy of treatment with antivirals. This has been a hotly debated topic, especially with regards to cost versus benefit… In a meta-analysis, using time to alleviation of symptoms as the primary endpoint, oseltamavir resulted in an efficacy of 73% (with a wide 95% CI from 33% to 89%). And this was with dose of 150mg/day in a symptomatic influenza patient.

Jeff: Similarly zanamavir given at 10mg/day was 62% effective, but again with a wide 95% CI from 15% to 83%. And, of note, other studies have looked into peramivir, but have found no significant benefits other than the route of delivery.

Nachi: In another 2014 study by Muthuri et al., neuraminidase inhibitors were associated with a reduction in mortality -- adjusted OR = 0.81 (with a 95% CI 0.70 to 0.93). Also when comparing late treatment with early treatment (that is, within 2 days of symptom onset), there was a reduction in mortality risk with adjusted OR 0.48 (95%CI 0.41-0.56). These associations with reduction in mortality risk were less pronounced and less significant in children.

Jeff: Mortality benefit, not bad! They further found an increase in mortality hazard ratio with each day’s delay in initiation of treatment up to 5 days, when compared to treatment initiated within 2 days.

Nachi: But back to the children for a second -- another review of neuraminidase inhibitors in children < 12 years old found duration of clinical symptoms was reduced by 36 hours among previously healthy children taking oseltamivir and 30 hours by children taking zanamivir.

Jeff: I think that’s worth summarizing - According to this month’s author’s review of the best current evidence, use of neuraminidase inhibitors is recommended, especially if started within 2 days, for elderly patients and those with comorbidities.

Nachi: Seems like there is decent data to support that conclusion. But let’s not forget that these medications all have side effects.

Jeff: These drugs actually tend to be well tolerated.The most frequently noted side effect of oseltamavir is nausea and vomiting, while zanamavir is associated with diarrhea.

Nachi: Amazing. Let’s talk disposition for your influenza patient.

Jeff: Disposition will depend on many clinical factors, like age, respiratory status, oxygen saturation, comorbid conditions, and reliability of follow up care. Admission might be needed not only to manage the viral infection, but also expected complications.

Nachi: If you’re discharging a patient, be sure to engage in shared decision making regarding risks and benefits of available treatments. Ensure outpatient follow up and discuss return to er precautions.

Jeff: Also, the CDC recommends that these patients stay home for at least 24 hours after their fever has broken.

Nachi: With that -- Let’s summarize the key points and clinical pearls from this month’s issue

J: Even though influenza vaccine effectiveness is typically only 50%, this still translates to a decrease in influenza-related morbidity and mortality.

2. The CDC defines influenza-like illness as a temperature > 100 F with either cough or sore throat, in the absence of a known cause other than influenza.

3. When influenza is suspected in the prehospital setting, patients and providers should wear face masks to avoid spreading the virus.

4. In the emergency department, standard isolation and droplet precautions should be maintained for suspected or confirmed infections.

5. The most common symptoms of influenza in adults are cough, fatigue, nasal congestion, and fever. Sneezing is a negative predictor in adults.

6. In children, the most common presenting symptoms are fever, cough, and rhinitis. Vomiting and diarrhea is also more common in children than adults.

7. Rapid testing and identification results in decreased delays in treatment and management decisions.

8. During peak flu season, clinical judgement may be as good as rapid testing, making rapid testing less necessary.

J: Rapid testing may be more beneficial in times of lower disease prevalence.

10. Empiric treatment of critically ill patients should be considered even if rapid testing is negative.

J: For mild to moderate disease and no underlying high-risk conditions, supportive therapy is usually sufficient.

12.For more ill patients or those at substantial risk for complications, consider antiviral treatment.

13.Oseltamivir is approved for patients of all ages, and reduces the length of symptoms by one day.

14.When treating influenza, peramivir is an ideal agent for the vomiting patient.

15.Baloxavir is a new single-dose antiviral agent approved by the FDA in October 2018. It works in a novel way and is effective for treatment of influenza A and B.

16.Chemoprophylaxis with oseltamivir or zanamivir should be considered in patients who are immunocompromised or patients who are at elevated risk for complications and cannot receive the vaccination.

17.Consider oseltamivir as post exposure prophylaxis in pregnant women.

18.Neuraminidase inhibitors are associated with decreased duration of symptoms and complications, especially if started within 2 days of symptom onset.

J: So that wraps up episode 23 - Influenza: Diagnosis and Management in the Emergency Department.

N: Additional materials are available on our website for Emergency Medicine Practice subscribers. For our subscribers: be sure to go online to get your CME credit for this issue, which includes 3 pharmacology CME credits.

J: Also, for our NP and PA listeners, we have a special offer this month: You can get a full year of access to Emergency Medicine Practice for just $199--including lots of pharmacology, stroke, and trauma CME--and so much more! To get this special deal, go to www.ebmedicine.net/APP. Again, that’s www.ebmedicine.net/APP.

N: If you’re not a subscriber, consider joining today. You can find out more at www.ebmedicine.net/subscribe. Subscribers get in-depth articles on hundreds of emergency medicine topics, concise summaries of the articles, calculators and risk scores, and CME credits. You’ll also get enhanced access to the podcast, including the images and tables mentioned. You can find everything you need to know at ebmedicine.net/subscribe.

J: And the address for this month’s credit is ebmedicine.net/E1218. As always, the you heard throughout the episode corresponds to the answers to the CME questions. Lastly, be sure to find us on iTunes and rate us or leave comments there. You can also email us directly at emplify@ebmedicine.net with any comments or suggestions. Talk to you next month!

Jeff: Welcome back to Emplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. I’m Jeff Nusbaum, and I’m back with my co-host, Nachi Gupta. This month, we’re back with our old routine – no special guests.

Nachi: Don’t sound so sad about it! Jeremy was great last month, and he’s definitely paved the way for more special guests in upcoming episodes.

Jeff: You’re right. But this month’s episode is special in its own way - we’ll be tackling Electrical Injuries in the emergency department - from low and high voltage injuries to the more extreme and rare lightning related injuries.

Nachi: And this is obviously not something we see that often, so listen up for some easy to remember high yield points to help you when you get an electrical injury in the ED. And pay particular attention to the , which, as always, signals the answer to one of our CME questions.

Jeff: I hate to digress so early and drop a cliché, “let’s start with a case…” but we, just a month ago, had a lightning strike induced cardiac arrest in Pittsburgh, so this hits really close to home. Thankfully, that gentleman was successfully resuscitated despite no bystander CPR, and if you listen carefully, we hope to arm you with the tools to do so similarly.

Nachi: This month’s print issue was authored by Dr. Gentges and Dr. Schieche from the Oklahoma University School of Community Medicine. It was peer reviewed by Dr. O’Keefe and Dr. Silverberg from Florida State University College of Medicine and Kings County Hospital, respectively.

Jeff: And unlike past issues covering more common pathologies, like, say, sepsis, this month’s team reviewed much more literature than just the past 10 years. In total, they pulled references from 1966 until 2018. Their search yielded 477 articles, which was narrowed to 88 after initial review.

Nachi: Each year, in the US, approximately 10,000 patients present with electrical burns or shocks. Thankfully, fatalities are declining, with just 565 in 2015. On average, between 25 and 50 of the yearly fatalities can be attributed to lightning strikes.

Jeff: Interestingly, most of the decrease in fatalities is due to improvements in occupational protections and not due so much to changes in healthcare.

Nachi: That is interesting and great to hear for workers. Also, worth noting is the trimodal distribution of patients with electrical injuries: with young children being affected by household currents, adolescent males engaging in high risk behaviors, and adult males with occupational exposures and hazards.

Jeff: Electrical injuries and snake bites – leave it to us men to excel at all the wrong things… Anyway, before we get into the medicine, we unfortunately need to cover some basic physics. I know, it might seem painful, but it’s necessary. There are a couple of terms we need to define to help us understand the pathologies we’ll be discussing. Those terms are: current, amperes, voltage, and resistance.

Nachi: So, the current is the total amount of electrons moving down a gradient over time, and it’s measured in amperes.

Jeff: Voltage, on the other hand, is the potential difference between the top and bottom of a gradient. The current is directly proportional to the voltage. It can be alternating, AC, or direct, DC.

Nachi: Resistance is the obstruction of electrical flow and it is inversely proportional to the current. Think of Ohm’s Law here. Voltage = current x resistance.

Jeff: Damage to the tissues from electricity is largely due to thermal injury, which depends on the tissue resistance, voltage, amperage, type of circuit, and the duration of contact.

Nachi: That brings us to an interesting concept – the let-go threshold. Since electrical injuries are often due to grasping an electric source, this can induce tetanic muscle contractions and therefore the inability to let go, thus increasing the duration of contact and extent of injury.

Jeff: Definitely adding insult to injury right there. With respect to the tissue resistance, that amount varies widely depending on the type of tissue. Dry skin has high resistance, far greater than wet or lacerated skin. And the skin’s resistance breaks down as it absorbs more energy. Nerve tissue has the least resistance and can be damaged by even low voltage without cutaneous manifestations. Bone and fat have the highest resistance. In between nerve and bone or fat, we have blood and vascular tissue, which have low resistance, and muscle and the viscera which have a slightly higher resistance.

Nachi: Understanding the resistances will help you anticipate the types of injuries you are treating, since current will tend to follow the path of least resistance. In high resistance tissues, most of the energy is lost as heat, causing coagulation necrosis. These concepts also explain why you may have deeper injuries beyond what can be visualized on the surface.

Jeff: And not only does the resistance play a role, but so too does the amount and type of current. AC, which is often found in standard home and office settings, but can also be found in high voltage transmission lines, usually affects the electrically sensitive tissues like nerve and muscle. DC has a higher let-go threshold and does not cause as much sensation. It also requires more amperage to cause v-fib. DC is often found in batteries, car and computer electrical systems, some high voltage transmission lines, and capacitors.

Nachi: Voltage has a twofold effect on tissues. The first mechanism is through electroporation, which is direct damage to cell membranes by high voltage. The second is by overcoming the resistance of body tissues and intervening objects such as clothes or water. You’re probably familiar with this concept when you see high voltages arcing through the air without direct contact with the actual electrical source, leading to diffuse burns.

Jeff: As voltage increases, the resistance of dry skin is -- not surprisingly -- reduced, leading to worse injuries.

Nachi: And for this reason, the US Department of Energy has set 600 Volts as the cutoff for low vs high voltage electrical exposure.

Jeff: It is absolutely critical that we also mention and then re-mention throughout this episode, that those with electrical injuries often have multisystem injuries due to not only the thermal injury, electrical damage to electrically sensitive tissue, but also mechanical trauma. Injuries are not uncommon both from forceful pulling away from the source or a subsequent fall if one occurs.

Nachi: That’s a great point which we’ll return to soon, as it plays an important role in destination selection. But before we get there, let’s review the common clinical manifestations of electrical injuries.

Jeff: First up is – the cutaneous injuries. Most electrical injuries present with burns to the skin. Low voltage exposures typically cause superficial burns at the entry and exit sites, whereas high voltage exposures cause larger, deeper burns that may require skin grafting, debridement, and even amputation.

Nachi: High voltage injuries can also travel through the sub-q tissue leading to extensive burns to deep structures despite what appears to be relatively uninjured skin. In addition, high voltage injuries can also result in superficial burns to large areas secondary to flash injury.

Jeff: Electrical injuries can also lead to musculoskeletal injuries via either thermal or mechanical means. Thermal injury can lead to muscle breakdown, rhabdo, myonecrosis, edema, and in worse cases, compartment syndrome. In the bones, it can lead to osteonecrosis and periosteal burns.

Nachi: In terms of mechanical injury – electrical injury often leads to forceful muscular contraction and falls. In 2 retrospective studies, 11% of patients with high voltage exposures also had traumatic injuries.

Jeff: While not nearly as common, the rarer cardiovascular injuries are certainly up there as the most feared. Pay attention to the entry and exit sites, as the pathway of the shock is predictive of the potential for myocardial injury and arrhythmia. Common arrhythmias include AV block, bundle branch blocks, a fib, QT prolongation and even ventricular arrhythmias, including both v-fib and v-tach, both of which typically occur immediately after the injury.

Nachi: There is a school of thought out there that victims of electrical injury can have delayed onset arrhythmias and require prolonged cardiac monitoring – however several well-designed observational studies, including 1000s of patients, have demonstrated no such evidence.

Jeff: It’s also worth noting that ST elevation MIs have also been reported, however this is usually due to coronary artery vasospasm rather than acute arterial occlusion.

Nachi: Respiratory injuries are somewhat less common. Acute respiratory failure usually occurs secondary to electrical injury-induced cardiac arrest. Thoracic tetany can cause paralysis of respiratory muscles. Late findings of respiratory injury including pulmonary effusions, pneumonitis, pneumonia, and even PE. The electrical resistance of lung tissue is relatively high, which may account for why pulmonary injury is less common.

Jeff: Vascular injuries include coagulation necrosis as well as thrombosis. In addition, those with severe burns are at increased risk of DVT, especially in those who are immobilized. In at least one study, the incidence of DVT in hospitalized burn patients was as high as 23%. That’s -- high.

Nachi: Neurologic complaints are far more common as nerve tissue is highly conductive. While the most common injury from an electric shock is loss of consciousness, other common neurologic insults include weakness, paresthesias, and difficulty concentrating.

Jeff: And if the entry and exit sites traverse the spinal cord – this also puts the patient at risk for spinal cord lesions. Specifically with respect to high voltage injuries – these victims are at risk for posterior cord syndrome. In addition, depression, pain, anxiety, mood swings, and cognitive difficulties have all been commonly described.

Nachi: Rounding out our discussion of electrical injuries, visceral injuries are rather rare, with bowel perforation being the most common. High voltage injuries have also been associated with cataracts, macular injury, retinal detachment, hearing loss, tinnitus, and vertigo.

Jeff: Perfect. I think that more or less rounds out an overview of organ specific electrical injuries. Let’s talk about prehospital care for these patients -- a broad topic in this case. As always, the first, and most important step in prehospital care is protecting oneself from the electrical exposure if the electrical source is still live.

Nachi: In cases of high voltage injuries from power lines or transformers or whatever oddity the patient has come across, it may even be necessary to wait for word from the local electrical authority prior to initiating care. Remember, the last thing you want to do is become a victim yourself.

Jeff: For those whose electrical injury resulted in cardiac arrest, follow your standard ACLS guidelines. These aren’t your standard arrest patients though, they typically have many fewer comorbidities – so CPR tends to be more successful.

Nachi: Intubation should also be considered especially early in those with facial or neck burns, as risk of airway loss is high.

Jeff: And as we mentioned previously, concurrent trauma and therefore traumatic injuries is very common, especially with high voltage injuries, so patients with electrical injuries require a complete survey and not just a brief examination of their obvious injuries.

Nachi: When determining destination, trauma takes priority over burn, so patients with significant trauma or those who are obtunded or unconscious should be transported to an appropriate trauma center rather than a burn center if those sites are different.

Jeff: Let’s move on to evaluation in the emergency department. As always, it’s ABC and IV, O2, monitor first with early airway management in those with head and neck burns being a top priority. After that, complete your primary and secondary surveys per ATLS guidelines.

Nachi: During your survey, make sure the patient is entirely undressed and all constricting items, like jewelry is removed.

Jeff: Next, make sure that all patients with high voltage injuries have an EKG and continuous cardiac monitoring. Those with low voltage injuries and a normal EKG do not require monitoring.

Nachi: Additionally, for those with severe electrical injuries, an IV should be placed and fluid resuscitation should begin. Fluid requirements will likely be higher than those predicted by the parkland formula, and you should aim for a goal of maintaining urine output of 1-1.5 ml/kg/h.

Jeff: With your initial stabilization underway, you can begin to gather a more thorough history either from bystanders or EMS if they are still present. Try to ascertain whether the current was AC or DC, and whether it was high or low voltage. Don’t forget to ask about the setting of the injury as this may point to other concurrent traumatic injuries, that may in fact take precedence during your work up.

Nachi: Moving on to the physical exam. As mentioned previously, disrobe the patient and complete a primary and secondary survey.

Jeff: If the patient has clear entry and exit wounds, the path through the body may become apparent and offer clues about what injuries to expect.

Nachi: A single exam will not suffice for electrical injury patients. All patients with serious electrical injuries will require serial exams to evaluate for vascular compromise and compartment syndrome.

Jeff: So that wraps up the physical, let’s move onto diagnostic studies.

Nachi: First off -- I know we’ve said it, but it’s definitely worth reiterating. All patients presenting with a history of an electric shock require an EKG

Jeff: In those with a low voltage injury without syncope and a normal EKG, you don’t routinely need cardiac monitoring. However, in the setting of high voltage injuries, the data is less clear. Based on current literature, the authors recommend overnight monitoring for at least 8 hours for all high voltage injuries.

Nachi: While no routine labs work is required for minor injuries, those with more serious injuries require a cbc, cmp, CK, CK-MB, and urinalysis.

Jeff: The CK is clearly for rhabdo, but interestingly, a CK-MB greater than 80 ng/mL is actually predictive of limb amputation. Oh and don’t forget that urine pregnancy test when appropriate.

Nachi: In terms of imaging, you’ll have to let your history guide your diagnostic studies. Perform a FAST exam to screen for intra-abdominal pathology for anyone with concern for concurrent trauma. Keep a low threshold to XR or CT any potentially injured body region.

Jeff: Real quick – in case you missed it – ultrasound sneaks in again. Maybe I should reconsider and do an US fellowship – seems like that’s where the money is at - well maybe not money but still. Let’s move on to treatment.

Nachi: In those with minor injuries like small burns and a low voltage exposure – if they have a normal EKG and no other symptoms, these patients require analgesia only. Give return precautions and have them follow up with their PCP or a burn center.

Jeff: In those with more severe injuries, as we mentioned before, but we’ll stress again, protect the patient’s airway early especially if you are considering transfer and have any concerns. In one study, delays in intubation was associated with a high risk of a difficult airway. Always make sure you have not only your tool of choice but also all of your backup airway devices ready as all deeper airway injuries may not be apparent externally.

Nachi: Fluid resuscitation with isotonic fluids is the standard -- again -- with a goal urine output of 1-1.5 ml/kg/h.

Jeff: Address pain with analgesia – likely in the form of opiates – and don’t be surprised if large doses are needed.

Nachi: Dress burned areas with an antibiotic dressing and update the patient’s tetanus if needed. While there is ongoing debate about the role of prophylactic antibiotics, best evidence at this point recommends against them. We talked about thermal burns in Epsiode 13 also, so go back and listen there for more...

Jeff: There is also a range of practice variation with respect to early surgical exploration of the burned limb with severe injuries. At this time, however, the best current evidence supports a conservative approach.

Nachi: Serial exams and watch and wait it is. . We have some interesting special populations to discuss this month. First up, as is often the case, the kids.

Jeff: Young children are sadly more likely to present with orofacial burns due to, well, everything ending up in their mouth. And since many of our listeners are likely in boards study mode – why don’t you fill us in on the latest evidence with respect to labial artery bleeding.

Nachi: Sure – . There is up to a 24% risk of labial artery bleeding and primary tooth damage with oral electrical injuries. Although there isn’t a clear consensus, current evidence supports early ENT consultation and a strong consideration for admission and observation for delayed bleeding.

Jeff: Keep in mind though, that labial artery bleeding is often delayed and has been reported as far as 2 weeks out from the initial insult.

Nachi: Moral of the story: don’t put electrical cords in or anywhere near your mouth. Next, we have pregnant patients. Case reports of pregnant patients suffering electrical injuries have described fetal arrhythmias, ischemic brain injury, and fetal demise. For this reason, those that are past the age of fetal viability should have fetal monitoring after experiencing an electric shock.

Jeff: If not already done, an ultrasound should be obtained as well and a two week follow up ultrasound will be needed.

Nachi: We’re switching gears a bit with this next special population – those injured by an electrical control device or taser.

Jeff: Tasers typically deliver an initial 50,000 volt shock, with a variable number of additional shocks following that.

Nachi: Most taser injuries are thankfully direct traumatic effects of the darts or indirect trauma from subsequent falls.

Jeff: While there are case reports of taser induced v fib, the validity of taser induced arrhythmias remains questionable due to confounders such as underlying disease and previously agitated states like excited delirium

Nachi: Basically, [DING SOUND} those with taser injuries should be approached as any standard trauma patient would be, with the addition of an EKG for all of these patients.

Jeff: The next special population --- the one I’m sure you’ve all been waiting patiently for -- is lightning strike victims. Lightening carries a voltage in the millions with amperage in the thousands, but with an incredibly short exposure time. Because of this, lightening causes injuries in a number of different ways.

Nachi: First, because it’s often raining when lightning strikes, wet skin may cause the energy to stay on the skin in what is known as a flashover effect.

Jeff: Similarly and not surprisingly, burns are common after a lightning strike. Lichtenberg figures are superficial skin changes that resemble bare tree branches and are pathognomonic for lightning injury. Thankfully, these usually disappear within a few weeks without intervention.

Nachi: Next, the rapid expansion of the air around the strike can lead to a concussive blast and a variety of traumatic injuries including ocular and otologic injury like TM rupture which occurs in up to two thirds of cases.

Jeff: An ophthalmologic consult should be obtained in most, if not all of these cases.

Nachi: Making matters worse, lightning can also travel through electric wiring and plumbing to cause a shock to a person indoors nearby the strike!

Jeff: And like we mentioned earlier, just as was the case with my fellow Pittsburgher or ‘Yinzer.

Nachi: Yinzer?

Jeff: Forget about it, it’s just what Pittsburghers call themselves for some reason or another - but we’re still talking lightning. Cardiac complications including death, contusion and vasospasm have all been reported secondary to lightning injury. But don’t lose hope – in fact – you should gain hope as these patients have a much higher than typical survival rates.

Nachi: From the neurologic standpoint – it’s a bit more complicated. CNS dysfunction may be immediate or delayed and can range from strokes to spinal cord injuries. Cerebral salt wasting syndrome, peripheral nerve lesions, spinal cord fracture, and cerebral hemorrhages have all been described. An MRI may be required to elucidate the true diagnosis.

Jeff: Clearly victims of lighting strikes are complex and, for that reason, among many others, the American College of Surgeons recommends that victims of lightning strikes be transferred to a burn center for a comprehensive eval.

Nachi: Let’s touch upon any other details regarding disposition.

Jeff: Those with low voltage exposures, a normal EKG and minimal injury may be discharged home with PCP follow up and strict return precautions.

Nachi: High voltage injuries on the other hand require admission to a burn center and the involvement of a burn surgeon, even if it involves transferring the patient.

Jeff: And remember, trauma takes precedence over burn and those with traumatic injuries or the possibility of traumatic injuries should be evaluated at a trauma center. Don’t forget to take the airway early if there is any concern, and consider transporting via air as the services of a critical care transport team may be required.

Nachi: That wraps up Episode 22, but let’s go over some key points and clinical pearls.

During evaluation, consider multisystem injuries due to not only the thermal injury and electrical damage to electrically sensitive tissue, but also mechanical trauma.

Thermal injury can lead to muscle breakdown, rhabdomyolysis, myonecrosis, edema, compartment syndrome, osteonecrosis, and even periosteal burns.

Mechanical injury can be a result of forceful muscular contractions, and trauma can manifest as fractures, dislocations, and significant muscular injuries.

Electrical injuries due to grasping an electric source can induce tetanic muscle contractions and therefore the inability to let go, increasing the duration of contact and extent of injury.

Current tends to follow the path of least resistance, which explains why you might have deeper injuries beyond what can be visualized in the surface.

Nerve tissue has the least resistance and can be damaged by even low voltage without cutaneous manifestations. Bone and fat, on the other hand, have the highest resistance to electrical injury.

High voltage injuries place patients at risk for spinal injuries, most notably posterior cord syndrome. High voltage injuries have also been associated with cataracts, macular injury, retinal detachment, hearing loss, tinnitus, and vertigo.

All patients with electrical injury require an EKG. Low voltage injuries with a normal presenting EKG do not always require cardiac monitoring. High voltage injuries require cardiac monitoring for at least 8 hours.

Intubation should be considered early in patients with facial or neck burns, as risk of airway loss is high. Make sure to have airway adjuncts and back up equipment at bedside, as deeper airway injuries may not be obvious upon external exam.

For severe injuries, target a urine output rate of 1-1.5 mL/kg/hr.

All patients with serious electrical injuries require serial exams to evaluate for vascular compromise and compartment syndrome.

Address pain with analgesia. Larger than expected doses may be needed.

Dress burned areas with an antibiotic dressing and update the patient’s tetanus if required.

For pediatric patients with oral electric injuries from biting on a cord, consult ENT early and consider admission for observation of delayed arterial bleeding.

Pregnant patients who are past the age of fetal viability should have fetal monitoring and ultrasound after experiencing an electric shock.

Tympanic membrane rupture is a commonly noted blast injury after a lightning strike.

Cardiac resuscitation should follow ACLS guidelines and is more likely to be successful than your tyipcal cardiac arrest patient as the patient population is typically younger and without significant comorbidities.

When determining destination, trauma centers take priority over burn centers if those sites are different.

So that wraps up episode 22 - managing electrical injury in the emergency department.

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Disclaimer: This is the unedited transcript of the podcast. Please excuse any typos.

Jeff:  Welcome back to Emplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. I’m Jeff Nusbaum, and I’m back with my co-host, Nachi Gupta. This month, we’ll be talking Updates and Controversies in the Early Management of Sepsis and Septic Shock. We have a special  episode for you this month… We’ve brought Dr. Jeremy Rose, one of the peer reviewers, and a sepsis expert, on with us to talk through the content this month.

Jeremy: Dr. Jeremy Rose here. Thanks for having me in on this conversation.  I’m always happy to talk about this topic because it’s clearly important.  There’s a great deal of confusion around sepsis and I hope that in the next couple minutes we can clarify things in a way that really help your average front line doc trying to get it right.

Nachi: So Dr. Rose, before we get started, tell us a bit about your background and your interest in sepsis…

Jeremy: I’m the Assistant Medical Director and Sepsis Chair at Mount Sinai Beth Israel in Manhattan.  For those listening, my hospital probably looks a little bit like yours.  We’re busy, interesting, and just a little rough around the edges.  We like it that way.  More importantly, though, we mirror the national averages regarding sepsis.  Roughly half of in-hospital mortality is associated with septic  in some fashion.  Pretty incredible when you think about it.  Half.

Jeff:  Sepsis chair... clearly this is an important topic if it warrants it’s own chair at a major hospital in NYC. But getting back to the article this month. This month’s issue was authored by Faheem Guirgis, Laurent Page Black, and Elizabeth DeVos of the University of Florida, Department of Emergency Medicine.

Nachi: And it was peer reviewed by Michael Allison, Assistant Director of the Adult ICU at Saint Agnes Hospital, and Jeremy Rose and Eric Steinberg of Mount Sinai Beth Israel.

Jeff: So as well all know Sepsis is bread and butter emergency medicine, but, what is sepsis?  It seems that every month or so we have a new guideline, bundle, definition, or whatever… I think it’s best to start with the basics -  At its core, sepsis is a dysregulated response to infection that can be life-threatening.

Nachi: Right and it’s the combined inflammatory with immunosuppressive features of sepsis that lead to the devastating organ dysfunction and even death. Optimal management of septic patients has been a source of intense research, stemming from the landmark study by Rivers in 2001. Jeremy, can you give us a little historical context there?

Jeremy: Rivers was a real pioneer.  He found a 16% mortality reduction with randomization to an early aggressive care bundle.  Amazing work.  That being said, many components of that bundle have since been disregarded.  For example, Manny Rivers would measure CVP in all of his patients, something we rarely do.

Nachi: Not to cut you off and steal your thunder there, but we’ll get to the most recent updates in management shortly. Let’s first talk definitions and terminology, and specifically, diagnosis, which is definitely a big elephant in the room. As Jeff mentioned a few minutes ago, diagnostic criteria have undergone so so so many changes.

Jeff: Yes it has! 1991 marked the first standardized definition.  Then in 2001, sepsis-2 was introduced.  In 2014, the Society of Critical Care Medicine and the European Society of Intensive Care Medicine started a task force, and by 2016, updated definitions were out again! Sepsis-3!! A lot of this came after the realization that SIRS was just too broad and was overly sensitive and non-specific. Jeremy, why don’t you take us through Sepsis 3.

Jeremy: So just to back up a little and frame this:

Here’s the fundamental problem:  As we likes to say, “there’s no troponin for sepsis.”  And if you look at our patients, we tend not to miss the hypotensive, tachycardic, febrile patient.  We know they’re septic.  But how do we find the ones who don’t look as sick.  Frequently elderly, possibly with normal-ish vitals and no fever.  Those can be a lot harder to spot, but they may indeed be septic.  Also, for research purposes we have to have a common definition, so Sepsis 3 came up with something called the SOFA score.

The problem with the SOFA score is that its difficult to perform in the ED.  It has parameters like bilirubin that often aren’t available when we want to screen out very sick patients.  Fortunately there is the abridged version qSOFA, which identifies non-icu patients who are at high risk of inpatient mortality.

So here it is, and if you get one thing from this episode, this is it:

There are ONLY 3 criteria to the qSOFA.  3 Criteria. RR > 22; AMS; SBP <= 100. That’s it. If you have two of these criteria, you are up to 14 times more likely to die of sepsis during a hospital admission. That’s pretty profound; these patients are very sick.  This is meant to replace SIRS.  It also captures  a much sicker population than the patients included in the Medicare definition.

Jeff: So why do you think these parameters turn out to be so useful?

Jeremy:  Drilling down into these criteria you can see the pathophysiology at work. Obviously, SBP < 100 means sick.  Interestingly, an elevated RR also turns out to be prognostic, because you’re seeing the compensation for an underlying acidosis.  WHen you see a patient breathing quickly, it’s either from a primary respiratory problem or them trying to relieve an underlying acidosis. The caveat here is that you have to check it. At our hospital in southern Manhattan, patients tend to breathe around 16.  At our hospital in northern Manhattan they like to breath around 18. It’s probably because the air is thinner.  Seriously though, you have to actually measure RR for this to work. Temp is not in QSOFA but we should be checking that too. And I mean checking it by putting something that measures temperature inside the patient. We’ve looked at the forehead and tympanic thermometers and in real world conditions, they tend to underestimate by a degree or more. Think about that. A patient with a headache and a temperature of 99.5 is a very different patient than one with a temp of 100.5.  Make sure you measure temperature.

Nachi: Very true and these two patients can definitely go down very different management pathways! Rounding out our discussion on sepsis-3. We should note that severe sepsis is now a term of the past under Sepsis-3. And sepsis-3 redefined septic shock as “hypotension not responsive to fluid resuscitation” with the added requirement of vasopressors to maintain a MAP greater than or equal to 65 and with a lactate > 2. So quite a few changes!

Jeff: And Jeremy, sticky topic coming up here. Center for Medicare and Medicaid Services (or CMS) quality measures - They haven’t really caught on to and adapted to Sepsis-3 yet, have they?

Jeremy:  The CMS mandate is based on the presence of SIRS criteria. Sepsis 3 is based on SOFA.  This is definitely confusing.  Part of the challenge in discussing this topic is separating out the QI guidelines from what is actually relevant to patient care based on the latest evidence-based medicine.

Nachi: That seems fair.  We’re really going to put you in an uncomfortable spot for a second and push you here Jeremy. Do you have any insight into why CMS isn’t interested in following the mountains of research that have led to sepsis-3? Is there a reason they are sticking to their current criteria?

Jeremy:  I think some of it is the slow pace of bureaucracy and the time that it takes to develop a consensus on management.  Even if we can agree on who is septic, it’s really hard, if not impossible to link the care to a pay-for-performance metric which is what CMS ultimately would like to see.  That’s not how Sepsis-3, or for that matter, SIRS, was designed to be used.  You’re trying to take a tool which was originally designed for research and mold them into a tool used for pay for performance.

Nachi: What a struggle. The CMS metrics are slightly different from the 2001 sepsis guidelines also. Take a look at Table 2 of the article for a quick comparison of sepsis-3, 2001 sepsis, and cms side-by-side. And for those on twitter, we’ll be sure to tweet this table out too for your review.

Jeff: With so many different scores and definitions, I think that adequately sets the stage for the challenge this month’s authors faced coming up with real evidenced based guidelines.

Nachi: Oh absolutely.  And to make matters worse - this is a HUGE problem. We’re talking up to 850,000 ED visits annually in the US, and 19 million cases worldwide. Compounding this, sepsis results in death in approximately 1 out of 4 cases. Not only is it lethal, it is also very costly -- 17 billion dollars per year in the US alone!

Jeff: And don’t forget importantly the 30-day hospital readmission rate. Sepsis is coming in at a higher readmission rate and cost per admission than acute MI, CHF, COPD, and PNA.

Nachi: Let’s speak briefly on the etiology and pathophysiology of sepsis: we all know that sepsis is due to local infections that then become systemic. Previously, it was believed that the bacterial infection itself was the cause of the clinical syndrome of sepsis. However, we now know now that the syndrome of sepsis is due to the inflammatory and immunosuppressive mediators that were triggered by the infection. Normal immune regulatory safeguards fail and this leads to the syndrome. And interestingly, several studies have shown that critically ill septic patients experience reactivations of specific viruses that were previously limited to patients with severe immunosuppression.

Jeff: Definitely something to look out for in your critically ill septic patients.  We should talk  briefly about the most common inciting infections that lead to sepsis. In order, these are: pneumonia, intra-abdominal infections, and urinary tract infections. No surprises there!

Nachi: Yeah, that basically parallels my own experience, so that’s reassuring!  That takes us to our next potentially controversial topic - blood cultures.  Jeremy - we’re going to punt this one back to you

Jeremy: This is another interesting topic that has received plenty of attention.   CMS loves blood cultures.  It’s an easy metric to track.  That doesn’t mean they’re always helpful.  We looked at our patients with lactates between 2.1 and 4.0 which had “severe sepsis.”  These patients were normotensive though, In other words, the ones that aren’t that sick.  We found that blood cultures are useful about 20% of the time.  That’s not bad.  So what do we do? We draw cultures before pushing antibiotics.  Is that helpful? Sometimes yes, does it waste money?  Debatable.  Does it help us meet our metrics, yes.

Jeff: And I think that gets at the crux of the problem here: we don’t want to delay antibiotics on anybody, but we must balance this with the potential harm of further increasing the drug resistant bacterial population via sound antibiotic stewardship.  Remember also that there is a broad differential for sepsis, with several “sepsis mimics”. To name a few, we have PE, MI, CHF, acute pulmonary edema, DKA, thyroid storm, GI bleeds, drug intoxications, and withdrawal syndromes, just to name a few.  In case that wasn’t enough check out Table 3 of the article.

Nachi:  And we already mentioned the leading causes of sepsis, that’s pneumonia, intra abdominal infections, and uti’s. But remember the source can be anywhere. Be sure to also think of pyelonephritis, central line associated bloodstream infections, prosthetics, endocarditis, necrotizing fasciitis, and meningitis.

Jeff:  I don’t think we need to dwell on this much longer - basically the differential is huge.  Let’s move on to my favorite section - prehospital care.

Jeremy: 20 pages of evidenced based recommendations and your favorite is the prehospital section, what’s up with that?

Jeff: I’m an EMS fellow, what can I say… Anyway, on to my favorite section -- prehospital care.  This is always a hot topic because the prehospital period is a special opportunity to get early interventions in for septic patients  as 40 - 70% of all severe sepsis hospitalizations arrive via EMS.

Nachi: And in one study taking place in a large metropolitan area, prehospital care time was over 45 minutes, and less than  37% arrived with IV access. Of course, these numbers would vary significantly based on where you practice.

Jeff: So get this -- one study showed that out-of-hospital shock index and respiratory rate were highly predictive of ICU admission. So clearly early recognition and therapy may play a role here. Another study, however, showed knowledge gaps by advanced EMS providers in diagnosis and management of sepsis. And yet another study showed that only 18 to 21% of confirmed septic patients were suspected of having sepsis by EMS. Out of hospital fluids were started in only half of patients with severe sepsis. In essence, there is likely a strong role here for pre hospital protocols for identifying and treating sepsis.

Nachi: In terms of pre hospital treatments though, prehospital IV fluids haven’t been shown to improve mortality, but have been associated with shorter hospital stays. Prehospital sepsis protocols have been described, but in general more research is needed in this area.

Jeff: While prehospital care hasn’t yet been shown to improve the prognosis of septic patients, those presenting via EMS do have shorter delays to initiation of antibiotics, IV fluids, and early care bundles. EMS should focus primarily on stabilizing vital signs and providing efficient transport. If it’s possible to establish an IV and initiate fluids without delaying transport, EMS should do that as well.

Nachi: And of course, oxygen for the hypoxic patients! Moving on to history and physical for your presumed septic patient. Jeremy, what are the big hitting things here that you always ask and check for, and that you make sure your residents are doing?

Jeremy:  After ABC’s and glucose, AMS is really important, it’s in the QSOFA SCORE.  Unfortunately, this can be hard in many septic patients where they’re baseline mental status is less than perfect.  The other thing is to try and find the source.  Finding the source lets you make wise choices about therapy.

Jeff:  Great point about the mental status - so many of our older population have an altered baseline, but recognizing changes from that baseline is key.

Nachi:  Absolutely, with that in mind, let’s talk diagnostic studies, especially lactate.  Where I trained, basically everybody was getting a lactate, even tired looking residents seemed to be having their lactates checked, and trust me, they weren’t looking that good...

Jeremy:  Brace yourself: lactate is really important in septic patients.  That being said, not every cause of elevated lactate is sepsis.  There is this animal called Type B lactic acidosis can come from numerous drugs like albuterol. Just because you see elevated lactate doesn’t mean you can forget about the other causes.  That being said, we know that patients with sepsis do better when they clear lactate.

Jeff: Seems like the evidence is definitely in favor of serial lactate testing…

Jeremy: For sure.  At least until you have a reasonable trend towards improvement.  We know lactate clearers do better.  We’ve looked at our own lactate numbers.  Interestingly, the takeoff point for sepsis seems to be around 2.5.  Meaning that patients with altered vitals and lactates above 2.5 tend to do worse.  But, there is a broad ddx to elevated lactate.   What is true, though, is that lactate is a marker for badness.  If your patient’s lactate is rising, yours should be too.

Nachi: I bet I’m a “lactate clearer”. I may add “lactate clearer to my CV,” sounds impressive.  But I digress…  Next up we have Procalcitonin.   Since procalcitonin becomes elevated in those with bacterial infections, intuitively, this should be a valuable marker to assess in potentially septic patients.  Unfortunately procalcitonin lacks negative predictive value so most literature supports its use in diagnosing pulmonary infections and for antibiotic de-escalation.

Jeff: Good to know, I’ve seen it being used a lot more recently and wondered how evidence based this test was.

Jeremy:  Honestly, I don’t see Procalcitonin changing ED management at the moment.  If you’re   waiting for Procalcitonin to start antibiotics or fluids, you’re waiting too long.

Nachi: Moving on, let’s talk imaging.  Based on current studies, the authors recommend focused imaging only.  In addition, they also note that our good friend, the point of care ultrasound, likely plays a role, as in one study, POCUS demonstrated a 25% improvement in sensitivity from clinical impression alone.

Jeremy:  I think there are two ways POCUS comes in.  One, lung ultrasound can be really useful to find that occult pneumonia or differentiating pneumonia from CHF.   Two, your ultrasound is your best tool for assessing volume status.  I try to look at the IVC of all my septic patients and echo them when possible.

Nachi: Right.  So now we’ve examined, drawn labs and cultures, checked a lactate, may be obtained imaging… next up we should probably start treating the patient. Whether you like it or not, we have to discuss CMS.

Jeremy: Just to clarify before we start.  CMS defines “severe sepsis” as SIRS + infection with a lactate of 2.1-4.0. Septic shock is SIRS + infection with hypotension or a lactate > 4.0. That’s where we’re at.

Jeff:  Good point.  Back to treatment: within the first 3 hours, for any patient with sepsis and septic shock, you must measure a lactate, obtain 2 sets of blood cultures, administer antibiotics, and give an isotonic fluid challenge with 30 cc/kg to patients with hypotension or a lactate greater than 4.   Then, within the first 6 hours, you must apply vasopressors to achieve a MAP of at least 65, re-assess volume status and perfusion, and remeasure a lactate.

Nachi: This begs the question - are these recommendations evidenced based? Jeremy….

Jeremy: I’m so glad you asked that . Let’s start with fluids. Patient’s need adequate fluid resuscitation.  Interestingly there are 3 large RCT’s, PROMISE, PROCESS and ARISE,  that compared a Rivers type bundle to usual care.  Surprisingly, they showed no difference.  But when your drill down into these 3 trials, you see that “the usual care,” now generally includes at least 2 liters of fluid.

Jeff: Ok, so it seems that there is some pretty good data to support a rapid fluid challenge of at least 30 cc/kg.  But how do we determine who needs more fluids and how much more they need.  There must be an endpoint to all of this?

Jeremy: Another million dollar question. 30cc/kg is probably a good place to start.  How much is too much?  I think we need to be smart about our fluids.  Some patients will need less and some will need much more.  So, I remind my resident’s to be smart about fluids.  Sono an IVC, trend a lactate, follow a urine output, do a passive leg raise, even check JVP.  I mean just because you haven’t seen a unicorn doesns’t mean they’re not real.  Do something to monitor volume status.

Nachi: Very important. Put your ultrasound skills to work here. They’ll only improve as you practice more.  Jeff, let’s get started on the ever important topic of antibiotics.

Jeff: Sounds good.  Current guidelines recommend that broad spectrum antibiotics be administered within the first hour of presentation for those with sepsis or septic shock, ideally with blood cultures being drawn beforehand. In one study, every hour of delayed abx administration was associated with an 8% increase in mortality.  Since this 2006 study, other studies have had mixed results - with studies showing increased odds of death with delays in abx administration and others showing only a benefit in those with septic shock with or without hypotension with no benefit to those without shock.

Nachi:  In terms of antibiotic coverage - you need to consider the site of infection, local resistance patterns, the presence of immunosuppression, and the patient’s age and comorbidities.  Table 5 of the article is very thorough and should be kept as a quick reference. Jeremy do you have any specific recommendations for our listeners on how we should approach antibiotic usage in the septic patient?

Jeremy: I like to think about antibiotics a little more simply than referencing a table.  I ask a couple questions.  Does my patient need MRSA coverage ?  Does my patient need Pseudomonal coverage?  If the answer is no and no, then narrow your coverage.  You don’t necessarily have to use a bunch of Vanco, or a big gun antipseudomonal like Pip/tazo.  Also, have a look at your local antibiogram.  I can’t tell you how many times this changes prescribing habits for even things like simple UTIs.  I’m going to stray into some controversial territory here. The benefits of sepsis protocols are measured one patient at a time, but the harms are only measured in the aggregate.  What does that mean?  CMS metrics have caused us to  use to use more broad spectrum antibiotics.  As a result, we’re seeing more resistance.  My resident’s tell me to make it easy, give em VZ (that’s vanco/zosyn) and it kills me.   Every time you put a Z-pack into the world a pneumococcus gets it’s wings. So think more about your antibiotics, and know your local biograms.

Jeff: That’s a great way to think about it, I fear I’ve given a lot of pneumococci wings during my training…  Next we’re on to vasopressors.  The data is pretty clear on this one - norepinephrine is the recommended first line vasopressor for septic shock.  In numerous trials comparing Norepi to dopamine, NE was far superior, with dopamine increasing arrhythmias in one trial and associated with an increased risk of death as compared to NE in another trial.

Jeremy:  So here’s a question I get all the time: How can I give Norepi without a central line.  Let’s use Dopamine, its safe peripherally.  Ok, so follow that through.  We’re going to give a drug to increase blood pressure by constricting blood vessels, but don’t worry, it’s safe peripherally.  What does that mean?  It means it doesn’t work!!  It doesn’t give much blood pressaure.  Dopamine is a lousy pressor.  It causes a lot of tachycardia, which is not what you want in failing septic hearts.  So what do we do if we don’t have a central line?   We start norepi peripherally into a large bore IV for the time it takes us to get a central line.  That’s where the evidence is.  There’s a mortality benefit to NE over dopaine in septic shock.

Jeff:  Right, this month’s authors note peripheral pressors may be safe for brief periods in settings with close monitoring.  While this is commonplace in some hospitals, others haven’t yet jumped on that bandwagon. I think it’s important to mention that this is becoming more and more commonplace, even in the prehospital realm.  With the service I fly for, we routinely start peripheral vasopressors without hesitation.  But this isn’t limited to the air.  Many ground 911 services have also adopted peripheral vasopressors in a variety of settings.

Nachi: I’m sure there are many trials to come in the future documenting their safety profile, but moving on to the next pressor to discuss... vasopressin. This should be your second line vasopressor for septic shock.  In the VASST trial, low-dose vasopressin was found to be noninferior to NE.  In other trials, vasopressin also appeared to show a potential benefit in those with AKI and sepsis, although the subsequent VANISH trial (perhaps the best name for a clinical trial so far) failed to demonstrate a benefit to vasopressin titration with regard to renal outcomes in septic shock. Vasopressin has also been shown to reduce NE dosing when administered at a fixed dose of 0.03-0.04 units/min.

Jeff: Next we have epinephrine.  In one study epinephrine and NE were equivalent in achieving MAP goals in ICU patients with shock, however several of those receiving epi developed marked tachycardia, lactic acidosis, or an increased insulin requirement.  The increasing lactic acidosis could confound the trending of lactates, so in those requiring inotropy in addition to some peripheral squeeze - the authors recommend adding dobutamine to norepinephrine instead of starting epinephrine. Although, keep in mind, this can lead to some hypotension so remember to start at low doses.

Nachi: Phenylephrine, a pure alpha adrenergic agent, is next and should be considered neither first nor second line, but it may have a role as a push dose agent while preparing other vasoactive agents.

Jeff: And lastly, we have angiotensin 2.  One recent 2017 study examining the role of angiotensin 2 in those with septic shock already on 0.2 mcg/kg/min of NE found that those receiving AT2 had significant improvements in MAPs as well as cardiovascular SOFA score at 48h with no difference in mortality.  Unfortunately, these benefits do not come without risk as AT2 may increase risk of arterial and venous thrombosis and potentially thromboembolism.  Clearly, one study isn’t enough to change practice, but it’s certainly food for thought.

Nachi: So that wraps up vasopressors. Jeremy, we’re on to corticosteroids -- another hotly debated topic. When do you give steroids in sepsis?

Jeremy:  Hmmm steroids, this is an age old question.  No study has clearly supported the blanket use of steroids in septic shock. Several like CORTICUS and ADRENAL showed no difference.  I will use hydrocortisone for pressor refractory shock. Meaning, you’ve tried everything else, so you might as well try.  Also, I do tend to avoid Etomidate, given the possibility of adrenal suppression and that there are several other induction agents, notably Ketamine  that don’t have this problem.

Jeff: Those trials are certainly important, thanks for bringing them up - Especially with all the FOAM content out there, it’s incredibly important to look back at the data to understand where certain recommendations are coming from.   Anyway… one quick note on blood transfusions before we move on to special populations - Although part of the original early goal directed therapy, thanks to data from the TRISS trial which showed no difference in outcomes with a transfusion goal of 7 vs 9, transfusions are reserved for those with a hbg of less than 7.

Jeremy:  One population we should make sure to mention and be careful with is end stage liver disease.  In the ER, we tend to miss SBP alot.  Mostly because these patients have lots of reasons to be sick and they already have elevated lactate because of their deceased clearance.  My practice is to give a dose of Ceftriaxone and sent a diagnostic tap to patients who are sick and have ascites.

Nachi: Alright Jeremy, let’s talk controversies in sepsis. We’re giving you all the big questions this month!

Jeremy:  We’ve already talked about fluids and how much to give.  Just a reminder that a history of CHF doesn’t preclude proper fluid resuscitation.  I think broad spectrum antibiotics for relatively well patients is a big controversy.  Our national rates of antibiotic resistance are terrible, and yet we’re using more antibiotics all the time.  There are very few if any antibiotics coming down the pharma pipeline and we’re going to have to face the music eventually.  Finally, we need national metrics that mirror clinical evidnece.  Protocols should be a tool and not a crutch.  You know what’s best for the patient in front of you, so don’t let metrics or protocols make you do things you think are not in your patient’s best interest.

Nachi: So how do you escape the hospital protocols and CMS and do what’s best for your patient without “getting in trouble”?

Jeremy: Here’s how I deal with it as the one who reads and QI’s all of our sepsis charts. I tell my colleagues to do what’s right, and if you need to deviate from the protocol tell me why.  As long as you can explain your decision, I’ll support it.  Explaining your thinking is good clinical practice and is good medico-legal practice. CMS has been unable to link these metric  to payment, simply because no hospital can meet them with any regularity.  It’s important that we advocate for our patients or nothing will change. Make them respect you for the highly educated professional that you are, and your patients will ultimately benefit.

Jeff: Preach!! And before we close out with disposition, there are a few new therapies and trials on the horizon to keep a lookout for. The RACE trail examined the role of L-carinitine.  The VICTAS trial is looking at vitamin C, thiamine, and steroids in sepsis.  The CLOVERS trial is looking at early vasopressors vs a crystalloid liberal strategy.  And lastly, IL-7 is also being investigated.  All really cool stuff that could change how we manage sepsis in the future..

Nachi  A few quick notes on disposition before we close this episode out.  Certainly not all patients meeting SIRS require admission, but many do.  Those with qSOFA of 2 or higher represent a sick population and an ICU admission should be considered.   Even for those with a qSOFA of 1 but a lacate over 2 -- they have a mortality approaching that of patients with a qSOFA of 2.  Be careful just sending a patient who is on the fence to the floor because several studies have demonstrated that patients who are later upgraded have worse outcomes.

Jeff: That’s in line with the general themes we’ve laid out today - definitely better to start early with aggressive care rather than play catch up later.  Jeremy - in 30 seconds or less, what are the most salient points in the management of sepsis that you would like our listeners to take with them from this episode.

Jeremy:  Here are my take aways:

• qSOFA, RR, AMS SBP < 100
• Norepi, not Dopamine - it doesn’t work!
• Be smart about fluids!!
• Be smarter about antibiotic use!
• You are the best advocate for your patient, despite what anyone else says!

Jeff: Excellent, so that wraps up the October 2018 episode of Emplify. A big thanks to Jeremy Rose for joining us.

Jeremy: Thank you for having me!!! It was great talking with you.

Nachi: For our listeners -- additional materials are available on our website for Emergency Medicine Practice subscribers. If you’re not a subscriber, consider joining today. You can find out more at www.ebmedicine.net/subscribe. Subscribers get in-depth articles on hundreds of emergency medicine topics, concise summaries of the articles, calculators and risk scores, and CME credits. You’ll also get enhanced access to the podcast, including the images and tables mentioned. You can find everything you need to know at ebmedicine.net/subscribe.

Jeff: And the address for this month’s credit is ebmedicine.net/E1018, so head over there to get your CME credit.  As always, the ding sound  you heard throughout the episode corresponds to the answers to the CME questions.

Nachi: Lastly, be sure to find us on iTunes and rate us or leave comments there. You can also email us directly at emplify@ebmedicine.net with any comments or suggestions. Talk to you next month!

Jeff:  Welcome back to Emplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. I’m Jeff Nusbaum, and I’m back with my co-host, Nachi Gupta and we’ll be taking you through the September 2018 issue of Emergency Medicine Practice - Emergency Department Management of North American Snake envenomations.

Nachi: Although this isn’t something we encountered too frequently – it does seem like I’ve been hearing more about snake bites in the recent months.

Jeff: I actually flew someone just the other day because the local ED ran out of CroFab after an envenomation in Western PA.

Nachi: Yeah, this is definitely more than “just a boards topic,” and it’s really important to know about in those rare circumstances. In terms of incidence, there are actually about 10,000 ED visits in the US for snake bites each year, and 1/3 of these involve venomous species.

Jeff:  That’s a good teaser, so let’s start by recognizing this month’s team – the two authors, Dr. Sheikh, a medical toxicologist, and Patrick Leffers, a pharmD, and emergency medicine and clinical toxicology fellow. Both are at the University of Florida Jacksonville, and they reviewed a total of 120 articles from 2006-2017, in addition to reviews from both Cochrane and Dare.

Nachi: And don’t forget our peer reviewers this month, Dr. Daniel Sessions, a medical toxicologist working at the South Texas Poison Center, and our very own editor-in-chief, Dr. Andy Jagoda, who is also Chair of the Department of Emergency Medicine at Mount Sinai in New York City.

Jeff: What a team! But, let’s get back to the snakes. As some background, from 2006-2015 there were almost 66,000 reported snake exposures and 31 deaths from snake envenomation in the US.  Of course, this number likely underestimates the true total.

Nachi: And there are two key subfamilies of venomous snakes to be aware of – the Crotalinae – or pit vipers – which includes rattlesnakes, copperheads, and water moccasins; and the Elapidae – of which you really only need to know about the coral snake.

Jeff:  And while those are the only two NATIVE snake subfamilies to be acutely aware of, don’t forget that exotic snakes, which are shockingly popular pets -- they can also cause significant morbidity and mortality.

Nachi:  Oh, and one other quick note before we get into the epidemiology – most of the recommendations this month come from expert opinion, as high quality RCTs are obviously difficult.  In addition, many of the studies were based in other countries, where the snakes, the anti-venoms and their availability, and the general healthcare systems are different from those that most of us work in.

Jeff:  Unless we have listeners abroad? Do we have listeners in other countries?

Nachi: Oh we definitely do... but we are going to be a bit biased towards US envenomation today. In any case, venomous snake bites occur most frequently in men aged 18 to 49 during warmer months with provoked bites occurring more frequently in the upper extremities and unprovoked bites in the lower extremities.

Jeff:  In one study of poison center data from the last decade, nearly half of all victims of snake bites were victims of unknown type snakes.  However, of those that were known, copperheads were the most common, while rattlesnakes caused the most fatalities – 19 of 31 in this dataset.

Nachi:  In a separate study of snake bites in the early 2000s, 32% of exposures were from venomous snakes and 59% of those resulted in admission. That’s remarkably high.

Jeff:  Snake bite severity depends on several key factors: the amount of venom, the composition of the venom, the body size of the bite victim, the victim's clothing, the size of the bite, comorbid conditions, and the timing and quality of medical care the victim receives.

Nachi:  To be a bit more specific - First, the amount of venom will depend on the species of snake, with variations even occurring within the same species.  Secondly, while there is a correlation between rattlesnake size and bite severity, there is much more at play.  Some snakes can even vary the amount of venom based on threat risk – with defensive bites having different profiles than bites to strike prey.

Jeff: I found it pretty interesting that  an estimated 10-25% of pit viper bites are considered dry bites, that is, ones in which no venom is released.

Nachi:  Right, this is just one reason why all victims shouldn’t immediately get anti-venom, but we’ll get there.

Jeff:  We definitely will.  As we already stated – venom composition varies greatly.  Pit vipers produce a predominantly hemotoxic venom.  Systemic effects include tachycardia, tachypnea, hypotension, nausea, vomiting, weakness, and diaphoresis.  Neurotoxicity is rare and is usually due to inter-breeding between species.

Nachi:  While rattlesnake bites are associated with higher morbidity and mortality, the more common copperhead bites typically only cause local tissue effects.  More serious systemic findings such as coagulopathy and respiratory failure have been reported though.

Jeff:  So that’s a solid background to get us started.  Let’s talk about the individual snakes.  Why don’t you start with the crotalinae family – aka the pit vipers.

Nachi:  Sure – the crotalinae includes rattlesnakes, cottonmouths (also known as water moccasins), and copperheads.  These make up the vast majority of reports to the poison centers.  They can be identified by their heat sensing pits located behind their nostrils (hence pit vipers).  As a general rule, you can also identify the venomous snakes by their triangular or spade-like head, elliptical pupils, and hollow retractable fangs.

Jeff:  wait, so you want me to walk up to the snake and ask to see if their fangs retract… yea, no thanks.

Nachi: Haha, of course not, I’m just giving you some of the general principles here. In contrast, non-venomous pit vipers have rounded heads, round pupils, a double row of vertical scales, and they lack fangs.

Jeff: In terms of location, rattlesnakes are found in all states but Hawaii, and cottonmouths and copperheads are distributed mostly throughout the southern and southeastern states, with copperheads also extending further north, even into Massachusetts.

Nachi: Moving on to the Elapidae –  there are 3 species of coral snakes, only two of which you need to know about, Micrurus fulvius fulvius or the eastern coral snake and Micrurus tener or the Texas coral snake.  Of the two, the eastern or Micrurus fulvius fulvius produces more potent venom.

Jeff:  As you may have guessed by their names, the eastern coral snake is found in the southeastern united states, specifically, east of the Mississippi -- whereas the Texas coral snake lives west of the Mississippi.

Nachi:  Venomous North American coral snakes can be recognized by the red and yellow bands around their bodies whereas their nonvenomous counterparts can be recognized by their characteristic black band between the red and yellow bands. I’m sure you’ve heard the popular mnemonic for this… Red touch yellow kill a fellow, red touch black, venom lack.

Jeff:  I have heard that one, and it’s not a bad mnemonic. Just remember that this is more of a guideline than a rule, as it doesn’t always hold true.

Nachi: Coral snakes also tend to chew rather than bite thanks to their short, fixed, hollow fangs.  Locally, bites can lead to muscle destruction thanks to a certain myotoxin.  Systemic signs of infection include nausea, vomiting, abdominal pain, and dizziness. 

Jeff: The venom also contains a neurotoxin which can lead to diplopia, difficulty swallowing and speaking and generalized weakness.

Nachi: Complicating matters even further, the onset of these symptoms may be delayed for many hours.

Jeff:  Alright, so I think that about wraps up the background.  Let’s move on to the meat and potatoes of this article, starting with the differential.

Nachi:  For differential this month, we are really focusing on differentiating a venomous snake from a non-venomous one.

Jeff: Oh yeah, this is where you want us to ask the snake if it can retract its fangs, right?

Nachi: Ha very funny – Although the type of snake may be obvious if the patient owns the snake, for most cases you see in the ED, the type of snake won’t be clear. Try to get a description of the snake and consider your local geography. Some patients may even bring the snake in with them.

Jeff: yea, no thanks. As for prehospital care, it’s actually pretty interesting stuff as recommendations have changed many times.  You may have heard of the recommendations for incision / excision, use of venom extraction devices, tourniquets, chill methods and even electroshock therapy – well these methods are all OUT.

Nachi:  Not only are they out, they actually worsen outcomes, so definitely don’t pursue any of them.  Instead,  since no treatment has been shown to improve outcome, you should prioritize prompt transport.

Jeff: And while we definitely don’t want to encourage ill-advised attempts at capturing the snake, taking pictures at a distance may be helpful in identifying it.  Oh and the authors do note- pretty terrifying stuff coming up here so brace yourself - even if the snake is dead the bite reflex is still intact…

Nachi: And that’s why I work in city hospitals…

Jeff:  There’s also a bit of controversy here with regards to pressure immobilization, which is definitely something I thought we were supposed to do in the prehospital setting. Apparently in other countries, like Australia, prehospital providers frequently employ pressure immobilization – that is, wrapping bandages proximally up a splinted limb to impede lymphatic toxin spread.

Nachi:  Right, but in Australia, not only are the snakes more venomous but the hospital transport distances are much longer, so, basically they sacrifice the limb to potentially save a life.  In the US, with our current indigenous snake population and the relatively short transport distances, this isn’t justified at all!

Jeff:  Take home: based on the current literature, the American College of Medical Toxicology, other experts, and Drs. Sheikh and Leffers recommend against pressure immobilization in lieu of prompt patient transport to definitive treatment.

Nachi:  Good to know – alright so now we have the patient in the emergency department, let’s begin ED care.  As always – IV, O2, Monitor including end tidal CO2 if you suspect a neurotoxic or exotic snake bite.  Of course, avoid using the affected limbs for vitals…

Jeff: If not done already, remove any constrictive clothing or jewelry and mark the leading edge of pain, edema, and erythema both above and below the bite.  If EMS has placed bandages, leave them in place until antivenom and resuscitative equipment is ready.

Nachi:  And definitely involve the poison control center or a medical toxicology service early as they are an amazing resource. It’s an easy number to remember.. 1-800-222-1222. If you just type “poison control center” into google, that number will come up immediately.

Jeff: Hypotension should be treated with isotonic fluids and, as usual, anaphylaxis should be treated with the usual cocktail of antihistamines and epinephrine at first IM and then via infusion if refractory. Note that antivenom will NOT reverse anaphylaxis on its own.

Nachi:  When eliciting a history, there are a number of important factors to look out for, including – time and location of the bite, description of the snake, tetanus status, comorbid conditions, medications and allergies, any systemic or neurologic symptoms, muscle cramps, perioral tingling or numbness, metallic taste, history of previous snakebites and any reactions to previous envenomation or antivenom treatment.

Jeff: Moving on to the physical exam, when examining the wound, look specifically for local tissue effects which occur in over 90% of patients after pit viper envenomations.  In such cases, you would expect pain, erythema, swelling, tenderness, and myonecrosis beginning at the wound site and then spreading via the lymphatic system.

Nachi:  In addition, specifically with pit viper envenomations, monitor the patient for possible compartment syndrome as the venom can lead to local tissue destruction, increased cell permeability, third spacing of fluids, and bleeding.  And remember that while the local compartment may be hypertensive, the patient may also have systemic hypotension.

Jeff: Just to reiterate what I said before – hypotension may indicate severe anaphylaxis and its not necessarily just due to third spacing.  Regardless, the treatment is the same – epinephrine.

Nachi:  Good point, but let’s focus on compartment syndrome for a minute.  True compartment syndrome is actually quite rare --- its really subcutaneous hypertension with preservation of otherwise normal compartment pressures that you’re most likely to see.  Compartment syndrome should therefore only be diagnosed by actual compartment measurements and not just the exam.  However, if you are dealing with compartments that can’t be measured, like in the fingers, you’re only choice is to be guided by the exam…

Jeff:  Risk factors for compartment syndrome in the setting of a snake bite include envenomations in small children, involvement of digits, application of ice or cold packs, and delayed or inadequate antivenom administration.

Nachi: In terms of respiratory effects of envenomations – they aren’t common.  Both bites to the head or neck and neurotoxin containing venom are potential causes. In the setting of respiratory failure, be prepared with advanced airway maneuvers like nasotracheal intubation or cricothyroidotomy. Antivenom will not reverse respiratory failure.

Jeff: Neurologic effects may be present upon arrival but may also be delayed up to 12 hours in the case of eastern coral snake bites.

Nachi: It’s noteworthy that in one study of almost 400 eastern coral snake exposures, the onset of systemic symptoms occurred on average 5.6 hours after the bite.  So definitely remember that repeat exams and observation will be tremendously important.

Jeff:  The actual neurologic symptoms to look for depend on the snake.  Coral snake venom can produce a descending flaccid paralysis characterized by motor weakness, especially of the cranial nerves.  Similarly pit vipers, especially the Mojave rattlesnake, have also been associated with muscular weakness of the cranial nerves and even respiratory insufficiency.

Nachi:  Pit viper envenomation can also lead to myokymia which is repetitive small muscle fasciculations.  Unfortunately, this myokymia may not respond to antivenom administration and myokymia of the chest well and torso can necessitate intubation in extreme cases.  Both myokymia and myonecrosis may lead to rhabdo in the case of significant envenomations.

Jeff:  Pit viper envenomation can also cause hematologic effects.  Fibrinolysis and platelet consumption at the bit site can lead to decreased fibrinogen and thrombocytopenia.  In severe cases this can lead to systemic bleeding and even hemorrhagic shock.  Those on anticoagulants and anti-platelet agents are at increased risk.

Nachi:  Dermal effects such as edema, ecchymosis, bullae, and bleeding are not uncommon, but up to 50% of coral snake bite victims may have none of these.

Jeff:  And to round out this section – just be aware that rare effects such as osteonecrosis, ischemic stroke, massive PE, and septic shock have all been reported.

Nachi: Let’s move on to diagnostic studies.  Most patients require a CBC, coags, and a fibrinogen concentration.  Those with systemic toxicity should also have their electroyltes, CPK, creatinine, glucose, and urine tested.

Jeff:  And while the data is somewhat mixed, one study suggests that all patients with pit viper envenomations need their coags checked, not just those with severe symptoms as in one series nearly 90% of patients had missed coagulation abnormalities.  The clinical consequences of this aren’t clearly explained, so the authors don’t make a specific recommendation.

Nachi:  In terms of imaging, a chest x-ray should be obtained in those with respiratory symptoms and ultrasound may even have an expanding role here for tracking edema, looking for fluid collections, and assessing deep muscle compartments and vascular flow.

Jeff: I feel like we should get some entry music for every ultrasound reference because it seems to make its way into just about every episode.

Nachi: What would it sound like? You bring this up every month. I’ll look into something for a future episode. If any of our listeners have a suggestion, shoot us an e-mail at emplify@ebmedicine.net. In terms of monitoring and observation, this is important, ALL patients with suspected pit viper envenomations should be observed for 8-12 hours with the leading edge marked every 15-30 minutes.

Jeff:  In addition, serial diagnostic testing may also be needed as such changes will be used to guide treatment.  In those with systemic symptoms, lab testing will be required every 4-6 hours prior to discharge.

Nachi:  Before we move onto treatment – let me quickly mention grading.  There is no universal grading system.  The snakebite severity score, the minimum-moderate-severe score, and grade 1-4 score which consider symptoms, exam findings, and lab abnormalities have all been studied.  None have been validated and none track changes, so the authors recommend relying on severity of symptoms and progression of symptoms to guide treatment.

Jeff:  The crux of treatment for pit viper envenomations is with supportive care and anti-venom.

Nachi:  FabAV or CroFab is the antivenom of choice for pit viper envenomations.  This antivenom is made from extracting the Fab portion of anti-venom antibodies from envenomated sheep and processing them with papain.

Jeff:  Since the sheep are injected with venom from the western diamondback, eastern diamondback and Mojave rattlesnake as well as the cottonmouth, the FabAV is most effective against venom from these snakes, however it does have cross reactivity to other immunologically similar venoms.

Nachi:  Indications for FabAV include a more than minimal local swelling, rapid progression of swelling, swelling crossing a major joint, evidence of hemotoxicity, signs of systemic toxicity including hemodynamic compromise, neuromuscular toxicity, and late or recurrent new-onset coagulopathy.

Jeff:  Initially, dose FabAV as a bolus of 4-6 vials, IV.  With life threatening envenomations or those with cardiovascular collapse, double the starting dose to 8-12 vials.  The goal is arresting progression, improvement in coagulation abnormalities, and resolution of systemic symptoms.

Nachi: Although FabAV will reduce the duration and severity of symptoms and lab abnormalities, it will not reverse tissue necrosis and may not reverse neurologic effects.

Jeff:  Once the symptoms have been controlled after the bolus dose or a second bolus dose, maintenance dosing of 2 vials every 6 hours for 3 doses is recommended to prevent recurrence.

Nachi:  So to reiterate.  4-6 vial bolus to start, doubled in severe cases and then 2 vials every 6 hours for 18 hours after that.

Jeff:  You got it.

Nachi:  And like most, maybe all medicines, there are side effects and contraindications to be aware of.  Hypersensitivity reactions and serum sickness to FabAV have been reported as 8% and 13% respectively.   Most are mild and can be treated with your standard bundle of steroids, antihistamines, fluids and epi.

Jeff:  Risk factors for developing allergic reactions to FabAV include  a known allergy to papaya, papain, chymopapin, pineapple enzyme bromelain, and previous allergic reaction to FabAV.

Nachi:  Although FabAV isn’t produced using copperhead venom, it may be effective in severe envenomations and in one study, FabAV reduced limb disability compared to placebo.

Jeff:  Therefore, the authors very reasonably advise that you should use the patient’s clinical picture and individual factors rather than the snake species to guide your treatment.

Nachi:  Interestingly, compartment syndrome should be treated with the initial 4-6 vial dose of antivenom and not necessarily a fasciotomy.  Fasciotomies have not been shown to improve outcomes and are reserved only for those failing anti-venom treatment.

Jeff:  The reason for this is that antivenom may reduce tissue pressures obviating the need for fasciotomy.  In addition, fasciotomy wouldn’t affect muscle necrosis that is occurring so fascia removal really doesn’t solve anything.

Nachi:  And just as anti-venom can be used to treat elevated compartment pressures, it can also be used to treat coagulopathy.

Jeff:  Blood products should be used for those who are actively bleeding or severely anemic as venom does not discriminate and will destroy whatever blood it comes across.

Nachi:  Recurrent and late onset coagulopathy after FabAV treatment has also been well described.   Although not exactly clear why, some speculate that it occurs for one of 4 reasons. 1) because the half life of FabAV is shorter than that of the venom, or 2) because the venom is initially stored in the soft tissues and then slowly released over time or 3) because the venom has a late onset component, or lastly, 4) there is delayed dissociation of the venom-antivenom complexes.  Regardless of the mechanism, late onset coagulopathy can be treated with FabAV.

Jeff:  Luckily, bleeding associated with coagulopathy and bleeding associated with late onset coagulopathy are both extremely rare.  

Nachi:  Moving on to coral snakes.  Coral snake bites should be treated with NACSA or North American Coral Snake anti-venom.  This antivenom halts or at least limits the progression of muscle paralysis and shortens the clinical course.

Jeff:  Most experts recommend NACSA treatment with the first signs of systemic toxicity and not for all comers.  This recommendation is backed by the literature as in one observational study those treated with prophylactic NACSA did less favorably as compared to those who got it only after symptoms onset.  This is probably because NACSA doesn’t reverse neuromuscular weakness and only limits progression.

Nachi:  And it’s not like you are just sitting by and watching while doing nothing – focus your initial treatment on wound care, pain control, and then observation for the development of systemic symptoms.  The exact length of observation will depend on the snake, but should be somewhere between 8 and 24h.

Jeff:  As for dosing – the initial NACSA dose is 3-5 vials IV for both peds and adults with a repeat dose if the initial symptoms don’t improve.

Nachi: Side effects and adverse reactions occur somewhere between 8-11% of the time with dermal reactions being most common and anaphylaxis being the most severe.

Jeff: There is also one last anti-venom to be aware of – Coralmyn, for coral snake envenomations.  Coralmyn is a polyclonal antivenom F(ab’)2 coral snake antivenom, developed because the current lot of NACSA has technically expired although the date has been extended numerous times.  It’s currently in a phase 3 trial, so keep your eyes out.

Nachi:  Other non-antivenom treatments that have been tested include acetylcholinesterase inhibitors and trypsin at the bite site – both should be considered experimental at this point.

Jeff:  To wrap up the treatment section, let’s talk exotic snakes.  You may recall from the intro that these have a higher morbidity and mortality compared to native species.

Nachi:  You will have to rely on your local poison control center or toxicologist for advice and you may even need to turn to the zoo or aquarium for antivenom, if it exists at all.  Patients with bites from exotic snakes should be monitored, likely in the ICU, for up to 24 hours as toxicity from some venom may have a delayed onset of up to 20 hours.

Jeff:  Scary stuff, hopefully the patient knows which type of exotic snake they own and you don’t have to sort through a million google images to try to get to the bottom of this.  Anyway, there are 3 special populations to discuss.  First are pregnant patients.

Nachi:  The authors cite a 1.4% incidence of snake bites in pregnant patients.  They note that this is low, but from my perspective, this seems shockingly high – why would a pregnant person ever get anywhere near a snake, seems just ill advised…

Jeff:  haha, true.   But regardless, treatment is the same with antivenom as needed for all the same indications.  With fetal demise rates as high as 30%, in addition to maternal monitoring, the fetus should also be monitored.

Nachi:  That number may seem high, but keep in mind that that’s from studies in other countries with more venomous snakes, so it’s likely to be lower in the US.  But the point remains, that antivenom is generally recommended to be given if the mother has indications for treatment, as poor fetal outcome is tied directly to the severity of envenomation in the mother.

Jeff: Continuing right along, the next special population to discuss are pediatric patients.  Because dosing is based on the amount of venom delivered and not on patient specific factors, dosing is the same for peds and adults.

Nachi:  How rare – so few meds seem to be the same for peds and adults.  The last population to discuss are anticoagulated patients.  Patients on antiplatelet or anti-coagulants are at increased risk of bleeding after pit viper envenomations and therefore should have their coags checked every 2 days following the last dose of FabAV.

Jeff:  I think we’ve at least mentioned most of this months controversies, but it’s probably worth quickly reviewing them since they mostly dispel common myths.

Nachi:  Good idea.  Incision and suction of snake bites is nearly universally not recommended.

Jeff:  In the absence of ischemia, fasciotomy for snake bites is not recommended, even with elevated compartment pressures.  Instead treat compartment syndrome with anti-venom and save the fasciotomy for true cases of ischemia refractory to antivenom.

Nachi:  With a known or suspected coral snake envenomation, due to shortages of NACSA, wait until the patient develops symptoms instead of empirically treating all bite victims.

Jeff:  Maintenance dosing of FabAV continues to be debated.  The manufacturer recommends 2 doses every 6 hours for 3 doses while some experts recommend only maintenance dosing as needed.  It’s therefore probably safest to punt this to whatever poison control center or toxicologist you speak with.

Nachi:  I feel like we are plugging the poison center a lot, but it’s such a good free, and usually very nice consult to have on your team.

Jeff: Nice consultant – what a win!  Moving on to the cutting edge.  There is a new Crotalidae antivenom called Crotalidae Immune F(ab’)2 or, more simply, Anavip.  It should be available in the next few months.  The dosing will be 10 vials up front over 60 minutes followed by an additional 10 vials if the symptoms having been controlled.  4 more vials may be given for symptom recurrence.  Patients must be observed for a minimum of 18 hours after initial control of symptoms.

Nachi: This would be a really nice development as Anavip has a longer half life and therefore should reduce the rates of late coagulopathy and decrease the need for maintenance dosing, follow up, and repeating coags.

Jeff:  And finally, like we mentioned before, injection of the trypsin has been tried as a bridge to antivenom, as has carbon monoxide, which may mediate degradation of fibrinogen dependent coagulation.

Nachi:  Alright, so let’s talk about the disposition next. Victims of pit viper envenomations should be monitored for 8-12 hours from the time of the bite.  They will need baseline labs and repeat testing ever 4-6 hours.  IF there is no progression of the symptoms and repeat testing is normal, the patient can be discharged.

Jeff: Victims of coral snake bites should be admitted and observed for 12-24 hours regardless of symptoms.

Nachi: Victims of rattle snake envenomations who initially develop hematologic abnormalities and are treated with FabAV should have repeat testing done in 2-4 days and 5-7 days.

Jeff:  Wounds should also be closely followed to avoid complications and long term disfigurement and disability.  PT/OT may be necessary as well.

Nachi:  Perfect, let’s round this episodes out with a review of the key points and clinical pearls from this month’s issue.

• There are about 10,000 ED visits in the US for snake bites each year, and 1/3 of these involve venomous species.
• Pit vipers produce a predominantly hemotoxic venom. Both local and systemic effects can occur. Systemic effects include tachycardia, tachypnea, hypotension, nausea, vomiting, weakness, and diaphoresis.
• In general, venomous snakes have a triangular or spade-like head, elliptical pupils, and hollow retractable fangs. In contrast, non-venomous snakes have a rounded head, round pupils, lack fangs, and can have a double row of vertical scales on the tail.
• Venomous North American coral snakes often have adjacent red and yellow bands, whereas their nonvenomous counterparts usually have a characteristic black band between the red and yellow bands.
• For prehospital care in the US, the following strategies are not recommended: incision or excision, use of venom extraction devices, tourniquets, chill methods, and electroshock therapy -- and they can all actually worsen outcomes.  Prehospital providers should focus on rapid transport.
• Be cognizant of compartment syndrome, but measure compartments when possible, as some envenomations present similarly but have only subcutaneous hypertension.
• Neurologic effects can be delayed up to 12 hours after coral snake envenomations. Symptoms can include a descending paralysis.
• For diagnostic testing, consider a CBC, coags, fibrinogen level, electrolytes, cpk, creatine, glucose, and urine studies.  All patients with envenomation should be observed for at least 8 hours. Mark the site of envenomation circumferentially to monitor for changes.
• Management of patients with snake bites should be treated with supportive care, pain control, and specific antivenom when indicated.
• FabAV or CroFab is the antivenom of choice for pit viper envenomations. Although FabAV will reduce the duration and severity of symptoms and lab abnormalities, it will not reverse tissue necrosis and may not reverse neurologic effects.
• Be aware of the possibility for a hypersensitivity reaction or serum sickness to FabAV. Treat with steroids, antihistamine, IV fluids, and epinephrine as appropriate.
• Coral snake envenomations can be treated with NACSA, which halts or at least limits the progression of muscle paralysis and shortens the clinical course.  Side effects to NACSA include dermal reaction as the most common -- and anaphylaxis as the most severe.
• Patients with bites from exotic snakes should be monitored, likely in the ICU, for up to 24 hours as toxicity from some venom may have a delayed onset of up to 20 hours. You may have to turn to your local zoo for help with anti-venoms here.
• Management of pregnant patient\s is the same as nonpregnant patients with regards to snake envenomations.
• Dosing of antivenom is based on the amount of venom. Dosing is the same regardless of the age of the patient.
• All patients requiring antivenom or with suspected envenomation should be admitted.  Seek consultation with your regional poison center and local toxicologist

Jeff: So that wraps up the September 2018 episode of Emplify.

Nachi: As always - the address for this month’s credit is ebmedicine.net/E0918, so head over there right away to get your credit.  Remember that the  you heard throughout the episode corresponds to the answers to the CME questions.

Jeff: And don’t forget to grab your free issue of Synthetic Drug Intoxication in Children at ebmedicine.net/drugs specifically for emplify listeners. Feel free to share the link with your colleagues or through social media too. Next month we are talking sepsis and the ever frequently changing guidelines so it’s not something you want to miss.  Talk to you soon

Most Important References

4. *Lavonas EJ, Ruha AM, Banner W, et al. Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop. BMC Emerg Med. 2011;11:2-227X-11-2. (Consensus panel)

6. *Bush SP, Ruha AM, Seifert SA, et al. Comparison of F(ab’)2 versus Fab antivenom for pit viper envenomation: a prospec­tive, blinded, multicenter, randomized clinical trial. Clin Toxicol (Phila). 2015;53(1):37-45. (Randomized controlled trial; 121 patients)

7. *Gerardo CJ, Vissoci JR, Brown MW, et al. Coagulation parameters in copperhead compared to other Crotalinae envenomation: secondary analysis of the F(ab’)2 versus Fab antivenom trial. Clin Toxicol (Phila). 2017;55(2):109-114. (Ran­domized controlled trial; 121 patients)

8. *American College of Medical Toxicology, American Acad­emy of Clinical Toxicology, American Association of Poison Control Centers, European Association of Poison Control Centres and Clinical Toxicologists, International Society on Toxinology, Asia Pacific Association of Medical Toxicology. Pressure immobilization after North American Crotalinae snake envenomation. Clin Toxicol (Phila). 2011;49(10):881-882. (Position statement)

10. *Wood A, Schauben J, Thundiyil J, et al. Review of eastern coral snake (Micrurus fulvius fulvius) exposures managed by the Florida Poison Information Center Network: 1998-2010. Clin Toxicol (Phila). 2013;51(8):783-788. (Retrospective; 387 patients)

48. *Cumpston KL. Is there a role for fasciotomy in Crotalinae envenomations in North America? Clin Toxicol (Phila). 2011;49(5):351-365. (Review)

75. *Walker JP, Morrison RL. Current management of copper­head snakebite. J Am Coll Surg. 2011;212(4):470-474. (Retro­spective; 142 patients)

81. *Kitchens C, Eskin T. Fatality in a case of envenomation by Crotalus adamanteus initially successfully treated with polyvalent ovine antivenom followed by recurrence of defibrinogenation syndrome. J Med Toxicol. 2008;4(3):180-183. (Case report)

118. *Hwang CW, Flach FE. Recurrent coagulopathy after rattle­snake bite requiring continuous intravenous dosing of anti­venom. Case Rep Emerg Med. 2015;2015:719302. (Case report)

Show Notes

Disclaimer: This is the unedited transcript of the podcast. Please excuse any typos.

Jeff:  Welcome back to Emplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. I’m Jeff Nusbaum, and I’m back with my co-host, Nachi Gupta and we’ll be taking you through the August 2018 issue of Emergency Medicine Practice.

Nachi: This month’s topic is one that Jeff has significant personal experience with from his college days. We’re reviewing Cannabinoids -- and emerging evidence in their use and abuse.

Jeff: Um… that is definitely not true. I was actually a varsity rower in college... Are we still reviewing talking points together before we start recording these episodes?

Nachi: Sometimes…

Jeff: This month’s issue was authored by Mollie Williams, who is the EM residency program director at the Brooklyn Hospital Center. It was peer-reviewed by Joseph Habboushe, assistant professor at NYU and Nadia Maria Shaukat, director of the emergency and critical care ultrasound at Coney Island Hospital in Brooklyn, New York.

Nachi: We’re going to be talking about the pathophysiology of cannabinoids, clinical findings in abuse, best practice management, differences between natural and synthetic cannabinoids, and treatment for cannabinoid hyperemesis syndrome. So buckle up and get ready.

Jeff: As you’re listening through this episode, remember that the means that we are about to answer one of the CME questions from the end of the print issue. If you’re not driving while listening, be sure to jot down these answers and get your CME credit when we’re going through this issue..

Nachi: As of June 2018, there are 31 states, the District of Columbia, and 2 US territories that possess state and local-level laws allowing the use of cannabis medicinally or in recreational formulations. Marijuana actually maintains the highest lifetime use of an illicit drug used within the US.

Jeff: There are a shocking 22 million past-month users of marijuana in the US, followed by pain relievers at 3.8 million, and cocaine at 1.9 million. Clearly, an important topic worth discussion, especially as synthetic products have become more widely available.

Nachi: And worth noting -- Colorado, where medicinal and recreational marijuana use has been decriminalized and later legalized, has shown a nearly 2-fold increase in the prevalence of ED visits, which may be related to marijuana exposure.

Jeff: Medicinally, cannabinoids are currently used in the treatment of chronic pain syndromes, complications of multiple sclerosis and paraplegia, weight loss due to appetite suppression in HIV/aids, chemotherapy-induced nausea and vomiting, seizures, and many other neuropsychiatric disorders. In fact, cannabis use has been documented for medical use dating as far back as 600 BC in West and Central Asia.

Nachi: All of that being said though, there is an absence of high-quality reviews and evidence to support the use of cannabinoids for any of the indications you just mentioned. And the US DEA maintains cannabis as a Schedule I substance.

Jeff: This DEA designation limits the ability to do research and obtain federal funding for such research. General lack of federal regulations on chemical content also leads to product variation, which may be a cause of increased incidences of accidental overdoses.

Nachi: To attain the most up to date information for this article, Dr. Williams searched the PubMed and Cochrane Databases from 1950 to 2018. This produced predominantly case reports and retrospective studies. There were just a few randomized prospective studies -- not surprising.

Jeff: Let’s get started with the pathophysiology. There are 3 cannabis species to be aware of: Cannabis sativa, cannabis indica, and cannabis ruderalis. Within these species, over 545 active cannabis-derived components have been described.

Nachi: There are ten main constituents of cannabis sativa. Of these, 9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD) are found in the greatest quantities. The neuropsychiatric and addictive properties of cannabis are due primarily to the delta-9-THC.

Jeff: THC and other cannabis derivatives work through the endocannabinoid system and other neuroregulators. The endogenous cannabinoid system has 4 components: (1) endogenous endocannabinoids, (2) receptors, (3) degradation enzymes, and (4) transport mechanisms.

Nachi: There are two endogenous endocannabinoids to know about: anandamide (AEA) and 2-arachidonoyl-glycerol.

Jeff: Cannabinoid receptors are broadly dispersed through the central nervous system, and to a lesser degree, also to other organ systems.

Nachi: Because CB receptors are concentrated within the central nervous system, they exert the majority of their effects on the neuropsychiatric systems. And   -- yes that’s a double ding -- the cannabinoid 1 (or CB1) receptor is most responsible for cannabis-induced neuropsychiatric effects.

Jeff: Interestingly, the anti-emetic effects and possible palliative properties of cannabis derivatives are thought to be secondary to the inhibitory effects on serotonin receptors and the excitatory effects on the transient receptor potential vanilloid 1 (or TRPV1).  More on TRPV1 later...

Nachi: So far we have been talking about cannabinoids from the cannabis plant, but with cannabis being illegal in many states, there has been a growing emergence of synthetic cannabinoids. Synthetics were initially developed in the 1980s largely for research purposes.

Jeff: Because the current DEA controlled substances schedule designations are based on original chemical names, synthetics have gained popularity as manufacturers are able to produce newer compounds and circumvent DEA designation as well as routine urine drug screening tests.

Nachi: You may be familiar with some of the street names for synthetics -- like spice, K2, scooby snacks, black mamba, kush, and kronic. These can often be purchased over the internet or through specialty smoke shops.

Jeff: Scooby Snacks, what a fantastic name, mooovingggg on… Synthetic cannabinoids often have greater affinity for the CB1 receptor than naturally occurring cannabinoids -- and synthetics can produce 100 times the effect. As a result, the presenting symptoms with synthetic intoxication can be difficult to differentiate from crystal meth or bath salt abuse.

Nachi: Manufacturers sometimes use solvents and other contaminants. Clusters of toxic ingestions and deaths have occurred. Emergency clinicians need to be aware of this and should report suspicious events immediately.

Jeff: For more on synthetic intoxications in the ED, be sure to take a look at the recent May 2018 issue of Pediatric Emergency Medicine Practice on Synthetic Drug Intoxication in Children if you haven’t already read it. Also, just a quick FYI - If you’re not a current subscriber to Pediatric Emergency Medicine Practice, we’re giving away a free copy of the issue specifically for our listeners. Just head over to ebmedicine.net/drugs for the PDF of the issue.

Nachi: A free issue for our listeners, that’s nice! Let’s move on to a discussion about current indications for cannabinoids. So, there is no clear consensus on these indications, but there is some research of varying quality that supports the treatment of some chronically debilitating diseases with cannabinoids.

Jeff: A systematic review and meta-analysis from 2015 found low-quality evidence to support cannabis therapy for appetite suppression in HIV and aids patients; moderate-quality evidence for treatment of chronic pain and spasticity; and also moderate quality evidence for some chronic debilitating diseases.

Nachi: While talking about evidence-based medicine here, another review by the National Academies of Science, Engineering, and Medicine on possible associations between cannabis and cancers arising in the lungs, head, and neck, or testicles -- showed no statistically significant associations exist.

Jeff: So in case that wasn’t clear - the overall evidence to support cannabis therapy, in general, is weak. Also, be aware that there are various formulations of cannabis that allow for different routes of administration. We’re talking oils, tinctures, teas, extracts, edibles like candies and baked goods, parenteral formulations, eye solutions, intranasal, sublingual, transmucosal, tablets, sprays, skin patches, topical creams, rectal suppositories, and capsules -- just to name, a few.

Nachi: A few! That seems pretty complete to me. Basically, any way you can imagine, it seems like a route of administration has been explored. But of importance, these formulations have different absorption times -- as you might expect. The shortest duration to peak plasma levels of delta-9-THC is through the inhalation route, which can produce effects within 3 minutes. On the longer end, rectal cannabis administration can take up to 8 hours to reach peak plasma concentrations.

Jeff: Let’s talk about some of the clinical findings and systemic effects associated with cannabis use. First up is the link between cannabis use and stroke or TIA. Cannabis users who smoked at least once weekly had a 3.3 times higher risk of stroke or TIA.

Nachi: And there is moderate quality evidence that this link may be dose-dependent. Larger amounts of cannabis use lead to cerebral vasospasm and a reduction in cerebral blood flow.

Jeff: In terms of psychiatric effects, several low-to-moderate quality studies have shown statistically significant associations between psychosis and self-reported cannabis use. Some association between high potency cannabis or synthetic cannabinoid use with new-onset psychosis or relapse in previous psychiatric disorders has also been found. Lastly, there is weak data supporting a correlation between cannabis use and depression.

Nachi: From a cardiovascular standpoint, cannabis use is associated with increased resting heart rate, hypertension, and decreases in the anginal threshold for patients with chronic stable angina. A 2001 study described an augmented risk of myocardial infarction within the first hour of cannabis use and found an almost 5-fold increase in those who reported smoking cannabis at least weekly when compared to those who smoked monthly or less.

Jeff: Dysrhythmias, qt prolongation, av blocks, myocarditis, and sudden death have all been reported with cannabinoids.

Nachi: In terms of pulmonary effects, these are not really related to cannabis use directly, but rather the smoke inhalation and combustion materials of synthetic cannabinoids. Effects from chronic use can be seen.

Jeff: Renally speaking, acute kidney injury and rhabdomyolysis are associated with synthetic cannabinoids and have been observed in several case reports. The rhabdo is believed to be due, in part, to associated seizures, muscle tremors, and agitation.

Nachi: Among metabolic abnormalities, patients can present with hyperthermia, hypoglycemia, hypokalemia, hyponatremia, and metabolic acidosis.

Jeff: Orally and dentally, dry mouth is the most common finding in acute cannabis toxicity. Chronic use has also been linked to severe periodontitis.

Nachi: And ophthalmologically, there is, of course, the commonly seen conjunctival injection. Cannabis has also been found to decrease intraocular pressure when used topically -- and of note, there have also been rare reports of acute angle closure glaucoma and central retinal vein occlusion.

Jeff: While talking about clinical findings and systemic effects of cannabis use, we certainly need to go over cannabinoid hyperemesis syndrome (or CHS), which is -- quite simply put -- associated with frequent visits to the ED in chronic users. It presents with nausea, vomiting, and abdominal pain.

Nachi: CHS is commonly misdiagnosed as cyclical vomiting syndrome. After the legalization of marijuana in Colorado, it was reported that nearly twice as many patients had presented for what was thought to be cyclical vomiting syndrome. And ironically, though cannabis has been used as an anti-emetic, chronic use can cause the opposite reaction, leading to CHS, which is typically refractory to traditional anti-emetics.

Jeff: And the etiology of CHS is not well understood. Similarly, the exact criteria for CHS are poorly defined. It presents as a recurrent and relapsing disorder that can be divided into 3 phases: prodromal, hyperemetic, and recovery.

Nachi: In the prodromal phase, patients complain of early morning nausea without vomiting, and they can have mild abdominal discomfort. This can last from months to years. In the hyperemetic phase, patients complain of severe, unremitting abdominal pain with repeated episodes of vomiting and retching. This is often associated with an inability to tolerate po.

Jeff: The hyperemetic phase lasts 24-48 hours and can lead to dehydration, electrolyte abnormalities, and weight loss. Patients may learn to relieve symptoms by compulsively bathing in hot water.

Nachi: Resolution of symptoms is seen when the patient stops using cannabis. This is during the recovery phase, which can last from days to months. But this can be short-lived if the patients begin using cannabis again.

Jeff: On that note, we should also touch on cannabis withdrawal. Termination of heavy and habitual use can lead to withdrawal syndromes within 48 hours. Symptoms here include irritability, anxiety, restlessness, sleep difficulty, seizures, and aggression. Medications that can be helpful include benzodiazepines, neuroleptic agents, and quetiapine in refractory cases.

Nachi: Moving on to the next sections in the article, let’s talk about differential diagnosis and prehospital care. The differential for acute cannabinoid intoxication, as you might suspect, is broad, and it includes some life-threatening processes. We won’t list them here, but be sure to think broadly before deciding on cannabis as the cause of your patient’s symptoms.

Jeff: For the prehospital providers -- care here is mainly supportive. Provide airway protection as needed - gather information from the patient’s environment, looking for empty pill bottles or another empty packaging.

Nachi: Let’s move on to care once in the ED. All patients who are in distress and suspected of drug ingestion should be disrobed completely and placed on a cardiac monitor. Fully assess for trauma and place an IV in the patient. Search the patient’s clothing for drugs and paraphernalia, which may help in making the diagnosis.

Jeff: When getting a complete history from the patient, it may also be worthwhile to talk with any persons accompanying the patient to the ER for more information. In your history, be sure to ask about a pattern of use and possible co-ingestions.

Nachi: When considering cannabis hyperemesis syndrome, a detailed history and physical exam are crucial for making the diagnosis. To differentiate between other etiologies of abdominal pain and vomiting, be sure to ask about the use of hot baths for relief, resolution of symptoms after stopping cannabis use, and the predominance of symptoms in the morning hours.

Jeff: On physical exam, for cannabis intoxication, there isn’t a particular toxidrome to look for. Monitor vital signs closely, looking out for alterations in blood pressure and heart rate. A complete neurologic and mental status examination will be the key here.

Nachi: Decisions for lab testing should be dependent on the patient’s presentation. Possible tests include CBC, BMP, LFT’s, lipase, cpk, ckmb, troponin, urinalysis, urine drug screening, serum tox screens (for alcohol, aspirin, and acetaminophen), and any other drug levels for medications that the patient is taking for medicinal purposes, like phenytoin or lithium levels.

Jeff: One study supported point of care urine drug testing in the ED. However, know that acute cannabis intoxication can be difficult in the chronic user, as delta-9-THC will be present in urine for up to 24 days. Testing for synthetically derived cannabinoids is difficult due to changes in synthetic compounds.

Nachi: Interestingly, there are a number of medications that are associated with false positive cannabinoid screenings. These include ibuprofen, pantoprazole, efavirenz, and lamotrigine.

Jeff: For any patient arriving with suspected cannabis or synthetic abuse, consider checking an EKG. You’re looking for signs of ischemia, arrhythmia, and interval abnormalities. Serum and urine tox tests are not particularly helpful in the acute chest pain patient who is using synthetic marijuana.

Nachi: Not surprisingly, there are no specific diagnostic imaging modalities to help diagnose cannabis or synthetic cannabinoid intoxication. But imaging may help with assessing other disease states on a patient’s differential, so stay mindful of that.

Jeff: Now that we’ve talked about history, physical exam, and useful testing modalities, let’s talk about treatment for cannabis and synthetic cannabinoid toxicity… therapy is primarily focused on supportive care. Most ED visits only require a short stay.

Nachi: That’s right, there are no antidotes to give for treatment here. Be sure to look for and treat dehydration, acute renal failure, and rhabdo though. In severe cases of neuropsychotropic effect, give benzodiazepines, like lorazepam, to help with control.

Jeff: For GI effects, first-line treatment is traditional anti-emetics like ondansetron or metoclopramide. Recent literature and case reports have shown significant improvement with butyrophenones like haloperidol as a second-line treatment.

Nachi: While talking about treating the gastrointestinal effects of cannabis toxicity, let’s also discuss methods to control cannabinoid hyperemesis syndrome. The mainstays for treatment here are actually supportive therapy and cessation of cannabis use.

Jeff: And can you tell us more about why these patients crave hot showers and improve after? Is there a pathophysiology or mechanism to know about there?

Nachi: There is a well-studied theory here and it relates to the TRPV1 receptor that we talked about earlier. Temperatures in excess of 109 degrees Fahrenheit, acidic conditions, and compounds found in certain foods and plants (like cannabis) activate this receptor. It’s believed that intermittent and repetitive exposure to agonists of the TRPV1 receptor leads to a persistent state of nausea and vomiting. Desensitization of the receptor happens after repeated stimulation, and repetitive topical capsaicin or hot water is believed to function as an exogenous agonist.

Jeff: In any case of repetitive emesis, be sure to consider electrolyte replacement if needed. In many cases, hydration or repletion will need to happen through an IV. Proton pump inhibitors can also help in some cases where GI symptoms are a dominating complaint of the patient.

Nachi: Recent literature supporting the use of haloperidol for nausea and vomiting has found that symptoms improve approx 1hr after administration. This can decrease the need for observation or admission.

Jeff: Haloperidol works via dopamine 2 receptor antagonism. D2 receptors are found in high concentrations throughout the nervous system and bind with high affinity to haloperidol. The suggested starting dose is 2.5mg IV with a repeat dose of 5mg IV if needed. An RCT is underway in Canada on the use of ondansetron versus haloperidol with an estimated completion of July 2019.

Nachi: Capsaicin has similarly shown promise in cannabis hyperemesis syndrome through the TRPV1 receptor as we discussed already. Currently, there are no dosing recommendations or application instructions for capsaicin. There is some evidence supporting relief within 30 to 45 minutes, and capsaicin can be applied topically to any nonmucosal surface like the abdomen, chest, or back.

Jeff: So to recap -for cannabis hyperemesis syndrome, treat with anti-emetics, PPI’s, electrolyte repletion, and IV hydration as needed. As a second line treatment, consider haloperidol and topical capsaicin applied to the chest, abdomen, or back.

Nachi: Let’s talk about some special populations next -- starting with Pediatrics. According to data from 2012, of the 130 million people reporting illicit drug use within their lifetime, 25% were children between 12 and 17 years of age.

Jeff: And according to the national poison data system, states with marijuana use laws have seen a 30% increase in calls related to marijuana use by children. From 2010 to 2011, the number of ED visits by children aged 12 to 17 years old due to synthetic cannabinoid use also has doubled.

Nachi: Many children and adults believe that synthetic cannabinoids don’t pose serious health risks, as these are not illegal to purchase. And this class of drugs is particularly attractive to adolescents since it will not readily test positive on urine drug tests. All of this is very concerning for emergency clinicians.

Jeff: There have been several recent reports of myocarditis in association with marijuana use. One case resulted in death due to myocyte necrosis after an unknown amount of edible marijuana was consumed by a toddler.

Nachi: Horrific!

Jeff: And the exact mechanism through which the myocardial necrosis happens isn’t known.

Nachi: For all children and adolescents who present to the ED with alteration in mental status, psychosis, or chest pain -- be sure to screen for cannabis or synthetic cannabinoid use.  There are case reports in the pediatric literature of STEMIs seen in patients without pre-existing cardiac disease or risk factors.

Jeff: Keep in mind that urine drug screens can be falsely positive from certain proton pump inhibitors, so if possible, assess a urine drug screen prior to starting a PPI in these patients.

Nachi: Moving on to our next special population… pregnant women. Know that it can be difficult to the differential between hyperemesis gravidarum and cannabis hyperemesis syndrome in pregnant patients. Ask specific questions regarding marijuana use before and during the pregnancy.

Jeff: It’s also worth noting that cannabis is known to cause adverse outcomes on babies such as low birth weight and more frequent perinatal ICU placement.

Nachi: Let’s move on to the final major section of the article, which is on the legal status of cannabis and cannabinoids. Much of the controversy surrounding cannabis for medicinal use relates to the absence of quality evidence. More research is needed to evaluate potential public health risks posed by variations in quality and potency, potential impact to our healthcare system, and ability to legislate for synthetic cannabinoids.

Jeff: Though marijuana and all whole-plant derivatives are schedules I controlled substances, there are a few cannabinoid-based drugs approved by the FDA for medicinal purposes -- with lower schedule designations. Dronabinol is a schedule III drug derived synthetically from delta-9-THC. It’s used in chemotherapy-induced nausea/vomiting, as well as anorexia and weight loss from AIDS/cancer.

Nachi: Nabilone, a schedule II synthetic variant of THC, has been approved in the treatment of aids-related anorexia and chemotherapy-induced nausea also.

Jeff: Nabiximols, a plant-derived cannabinoid, has been approved in Europe and Canada for multiple sclerosis induced spasticity and cancer-related pain. Nabiximols are not yet approved in the US.

Nachi: And lastly, we should mention cannabidiol, which is a schedule I controlled substance approved for treatment of seizures with 2 rare diseases -- Lennox-gastaut syndrome and dravet syndrome. Compared with placebo alone cannabidiol and other medications have shown efficacy in lowering the rate of seizures for these diseases.

Jeff:  Lots of interesting stuff to look out for there in cannabinoid-related medications. Alright, on to disposition -

Nachi: Most patients who present with uncomplicated acute cannabis or synthetic cannabinoid intoxication can be observed until clinically sober. Discharge home should be in the care of a sober family member or friend. Make sure that the patient knows not to operate vehicles or heavy machinery under the influence of drugs. Counsel them on drug abuse also.

Jeff:   In more rare situations, patients will require admission. Consider this particularly for patients who have end-organ damage, rhabdomyolysis, acute renal failure -- evidence of cardiovascular, cerebrovascular, or ophthalmologic insults -- intractable vomiting, or acute psychosis.

Nachi: And for cannabinoid hyperemesis syndrome, patients may require admission for IV hydration and electrolyte correction. Once the patient is tolerating PO and lab derangements have been corrected, they can be discharged.

Jeff: Let’s wrap up the episode with key points and clinical pearls…

N: Marijuana is the most commonly used illicit substance in the US. States that have legalized marijuana for medical and recreational purposes are showing increased rates of marijuana abuse and dependence.

J: When concerned with drug intoxication, search your patient’s clothing for drugs and paraphernalia on arrival.

N: The neuropsychiatric and addictive properties of cannabis are due primarily to delta-9-THC.

J: Synthetic cannabinoids have gained popularity as manufacturers are able to produce newer compounds and circumvent DEA designations as well as routine urine drug screening tests.

N: Manufacturers of synthetic cannabinoids sometimes use solvents and other contaminants, which have caused clusters of toxic ingestions and death.

J: The shortest duration to peak plasma levels of delta-9-THC is through the inhalational route. Effects can be seen within 3 minutes.

N: Cannabis users who smoke at least once weekly can have a 3.3 times higher risk of stroke or TIA.

J: The risk of myocardial infarction is increased within the first hour of use, and there is an almost 5-fold increase for individuals who smoke at least once per week.

N: Acute kidney injury and rhabdomyolysis have been noted with synthetic cannabinoid use in several case reports.

J: Cannabis intoxication is associated with many metabolic abnormalities like hyperthermia, hypoglycemia, hypokalemia, hyponatremia, and metabolic acidosis.

N: Cannabis hyperemesis syndrome, which presents with abdominal pain and vomiting, is associated with frequent visits to the ED in chronic users.

J: The mainstay for treatment of cannabis hyperemesis syndrome is supportive therapies and cessation of cannabis use.

N: Patients with cannabis hyperemesis syndrome crave hot showers because of activation of the TRPV1 receptor.

J: Topical capsaicin may also help in the treatment of cannabis hyperemesis syndrome through activation of the TRPV1 receptors.

N: Haloperidol at 2.5mg IV may help in refractory vomiting associated with cannabis hyperemesis syndrome.

J: Many children and adults do not believe synthetic cannabinoids pose serious health issues as the they are not illegal to purchase. This is incorrect.

N: Most patients with acute uncomplicated cannabis intoxication can be observed and discharged. Admit if there are any signs of end organ damage, intractable vomiting, or acute psychosis.

Jeff: So that wraps up the August 2018 episode of Emplify.

Nachi: For those of you looking for CME - the address for this months credit is ebmedicine.net/E0818, so head over there right away to get the credit you deserve.  Remember that the you heard throughout the episode corresponds to the answers to the CME questions.

Jeff: And don’t forget to grab your free issue of Synthetic Drug Intoxication in Children at ebmedicine.net/drugs specifically for emplify listeners. Feel free to share the link with your colleagues or through social media too. See you next time!

Most Important References

5. * Kim HS, Monte AA. Colorado cannabis legalization and its effect on emergency care. Ann Emerg Med. 2016;68(1):71-75. (Literature review; 21 studies)7. * Baron EP. Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: What a long strange trip it’s been …. Headache. 2015;55(6):885-916. (Review)9. * Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456-2473. (Retrospective chart review; 4 cases)64. * Tournebize J, Gibaja V, Kahn JP. Acute effects of synthetic cannabinoids: update 2015. Subst Abus. 2016:1-23. (Systematic review; 46 articles, 114 patients)83. * Wallace EA, Andrews SE, Garmany CL, et al. Cannabinoid hyperemesis syndrome: literature review and proposed diagnosis and treatment algorithm. South Med J. 2011;104(9):659-664. (Review)

Join Jeff, a former firefighter, and Nachi, a former mathematician, as they take you through the July 2018 issue of Emergency Medicine Practice: Emergency department management of dyspnea in the dying patient

Most Important References