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Wednesday, January 16, 2019

Catheter-Directed Therapy for PE Built on Fallacy


Tissue plasminogen activator has a notoriously checkered past within emergency medicine, and its controversial use continues with the advent of targeted therapy for pulmonary embolism. Catheter-directed administration of tPA for PE is gaining traction, and the development of multidisciplinary PE Response Teams are popularizing and advocating this therapy. (Chest 2016;150[2]:384.) The evidence for this treatment strategy, however, raises concerns about its early adoption.


Catheter-directed therapy (CDT) for PE involves placing a special catheter directly into the pulmonary artery, into or adjacent to the clot, followed by a continuous infusion of tPA. The thought is that by infusing the tPA directly into the pulmonary circulation, significantly lower doses can be used to achieve thrombolysis and to mitigate the risk of hemorrhage. Some of these catheters are specially equipped to provide ultrasound pulsations that are said to provide mechanical force to expose fibrin and improve tPA efficacy. The former is termed catheter-directed thrombolysis, the latter ultrasound-assisted catheter-directed thrombolysis. (Chest 2016;150[2]:384; Circulation 2014;129[4]:479;; Chest 2015;148[3]:667; J Vasc Interv Radiol 2018;29[3]:293;

Proponents of this therapy tout reduced doses of thrombolytics and decreased major bleeding events as compelling reasons to adopt this groundbreaking therapy. Several studies have evaluated its feasibility and efficacy for various forms of PE, but only one randomized controlled trial has been done comparing catheter-directed thrombolysis to standard care. The remainder of the literature consists largely of cohort studies with no control groups and no patient-oriented outcomes.

The Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA trial), funded by EKOS Corp., boasted a robust sample size of 59 patients with submassive PE. (Circulation 2014;129[4]:479; These patients were randomized to receive heparin or heparin plus CDT (10-20 mg of tPA over 15 hours). The CDT group demonstrated a statistically significant reduction in RV/LV diameter ratio at 24 hours (not a patient-oriented primary outcome) while the heparin group did not. No major bleeding episodes were seen in either group. (Circulation 2014;129[4]:479;

The ULTIMA study demonstrates a clear benefit in the CDT group compared with heparin alone for achieving the primary outcome of reduced RV strain. This should be no surprise because anticoagulant therapy and thrombolytic therapy have entirely different mechanisms of action. Of course, correlation does not prove causation. Patients who received CDT in the ULTIMA trial had significantly better outcomes than those receiving heparin, but the cause was likely not the sham procedure of CDT but the infusion of low-dose tPA.

No Proven Benefit
The fallacy in accepting catheter-directed therapy as effective is that clinicians conclude that the catheter delivery system is solely responsible for the improved outcomes. Two facts dispute this claim: Delivery of tPA directly into the pulmonary circulation has never been definitively proven to provide benefit compared with systemic delivery, and ultrasound therapy has not been shown to add benefit in conjunction with tPA for treating clots.

A 1988 study examined the effects of intrapulmonary tPA with standard intravenous tPA administration in a group with massive PE; clot burden and reduction in pulmonary arterial pressure were nearly identical in each group. (Circulation 1988;77[2]:353.) This makes intuitive sense based on the pulmonary physiology. The pulmonary circulation receives the entire circulating blood volume, and any medication infused peripherally will make its way into the pulmonary circulation to exert its effects.

The addition of ultrasound to catheter-directed therapy likely confers no appreciable benefit based on the results of the 2015 PERFECT trial. This study enrolled consecutive patients who had either submassive or massive PE. A portion underwent CDT without ultrasound, while others underwent ultrasound-assisted CDT. There was no significant difference between PA pressure reduction or tPA requirement between the groups. (Chest 2015;148[3]:667.) We see similar results reported in the DVT literature, where the addition of ultrasound to catheter-directed therapy does not seem to improve clot burden or reduce tPA requirement. (Circ Cardiovasc Interv 2015;8[1]:1;

A definitive trial would involve comparing catheter-directed tPA v. peripherally infused tPA at the same rate. I suspect that the outcomes would be no different and that we could start delivering effective therapy through a simple IV infusion right at the bedside, but the CDT manufacturers aren't in a hurry to fund that study.

The lack of high-quality evidence in the form of large patient populations, randomized controlled trial design, and long-term patient-oriented outcomes makes adopting catheter-directed therapy for pulmonary embolism questionable at best. Yet despite the dearth of quality data, the Society of Interventional Radiology actually considers catheter-directed thrombolysis an acceptable treatment for massive PE in "carefully selected" patients. (J Vasc Interv Radiol 2018;29[3]:293;

The evidence for systemic thrombolytics in PE, especially submassive PE, is still fraught with controversy. The introduction of a costly, invasive, and poorly studied therapy such as CDT just serves to muddy the already murky waters in which we wade while caring for patients suffering from PE. Until more rigorous, methodologically sound research is presented, catheter-directed therapy is far from prime time, but it seems that the horse has already left the barn.

Dr. Mondie is the chief resident of emergency medicine at Newark Beth Israel Medical Center.

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Wednesday, January 9, 2019

Physostigmine Doesn't Live Up to Its Unsafe Reputation


The antidote physostigmine was first used to treat anticholinergic toxicity in 1864, and by the 1970s, clinicians were commonly administering it for many indications, including poisoning from pure anticholinergic agents and tricyclic antidepressants (TCAs). Some even advocated that emergency physicians include physostigmine as part of the so-called coma cocktail for any patient with significantly decreased mental status.

But things changed. The use of physostigmine had virtually disappeared by the 1990s, and the Association of United States Poison Centers reported in 1997 that only two percent of more than 7,000 patients treated that year for anticholinergic toxicity received physostigmine. What happened?

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First off, the clinical abandonment of physostigmine was somewhat surprising because it is one of the most effective and specific antidotes. It is a short-acting carbamate that increases levels of the neurotransmitter acetylcholine in synapses and at muscarinic receptors, overcoming the receptor blockade caused by antimuscarinic agents such as benztropine and scopolamine.

Unlike similar drugs like neostigmine, physostigmine readily crosses the blood-brain barrier, reliably reversing central and peripheral manifestations of the anticholinergic toxidrome. (See table.) Recent research indicates physostigmine is much more effective in controlling anticholinergic-induced agitation and delirium than benzodiazepines are while avoiding oversedation and the need for endotracheal intubation. (Ann Emerg Med 2000;35[4]:374.)

And It's Gone
So why did physostigmine nearly vanish? This can be traced to a 1980 paper describing two patients who experienced bradycardia and then asystole shortly after receiving physostigmine for severe TCA toxicity, standard treatment at the time. (Ann Emerg Med 1980;9[11]:588.) One patient was resuscitated and recovered; the other apparently suffered hypoxic encephalopathy and died.

These cases were unusual. Both patients had taken massive overdoses of tricyclics and quickly developed seizure activity. Neither was treated with sodium bicarbonate, a now-standard intervention that can prevent or treat TCA-induced dysrhythmias. Despite the authors' contention that physostigmine caused asystole in these cases, it seems more likely this represented the natural evolution of severe TCA overdose. In any case, many clinicians developed a fear of physostigmine after the paper was published, and use of the antidote cratered.

This fear has abated somewhat recently as physostigmine's safety and efficacy in treating anticholinergic agitation and delirium has been studied more, including some research presented at the recent 2018 North American Congress of Clinical Toxicology meeting in Chicago. Sean Boley, MD, of the Minnesota Poison Control System, found that 65 (46%) of 141 patients with antimuscarinic toxidrome treated with physostigmine were significantly less likely to require intubation or ICU admission than those who were not. His three-year single-center retrospective chart review also found no significant differences in adverse events such as vomiting, bradycardia, and seizures between the two groups. Dr. Boley concluded that physostigmine was useful and safe, but noted that the retrospective design made that conclusion less than robust.

A separate study by Dr. Boley and his colleagues found that 57 (34%) of 154 patients with antimuscarinic delirium who were treated with physostigmine experienced more frequent and more rapid control of delirium than those who were not. The one-year prospective analysis also saw no difference between the groups in adverse events, though physostigmine was not associated with a reduced incidence of intubation as in his other review. (Clin Toxicol (Phila) 2018 June 29;

Rachel Gorodetsky, PharmD, of D'Youville School of Pharmacy in Buffalo also found that 12 (5%) of 231 patients who received physostigmine had adverse events, including vomiting (8 patients), seizures (3), and bradycardia (1). Her five-year retrospective chart review saw no significant sequelae in the three patients with seizures, and the patient who developed bradycardia did not require any intervention. Forty-eight patients in the study were treated with physostigmine in the surgical recovery room for nonspecific post-anesthetic delirium not related to antimuscarinic exposure. The authors concluded that it is likely unwarranted to avoid physostigmine as an antidote because of concern for adverse effects.

Still, the antidote must be used with caution. Keep these important clinical points in mind:

  • Physostigmine is contraindicated in the seizing patient because it has not demonstrated safe or effective.
  • No real consensus exists, but I believe physostigmine should be avoided for significant cardiac conduction delays (AV block, prolonged QRS interval) and bradycardia.
  • A good response to physostigmine can be diagnostic and avoid the need for additional tests such as CT scan and lumbar puncture in a patient with delirium thought to be caused by exposure to an anticholinergic agent.
  • The adult dose of physostigmine is 0.5-1.0 mg IV given slowly over five minutes and repeated if needed every 15 minutes for a maximum total dose of 2 mg over the first hour.
  • The local poison center should be consulted on any patient who is treated with physostigmine.

Dr. Gussow is a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Read his blog at, follow him on Twitter @poisonreview, and read his past columns at 

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Wednesday, January 2, 2019

Hoopla Aside, hs-cTnI is Not Catching Missed MIs


We have been searching for a tool to identify myocardial infarction patients who are truly safe for discharge ever since Pope, et al., found that we were discharging two percent of patients with MIs from the emergency department. (New Engl J Med 2000;342[16]:1163; Many have anointed the high-sensitivity troponin assay (hs-cTnI) for this role. The added sensitivity would identify a subset of ACS patients who would otherwise remain occult during their ED stay—in theory.

Such a sensitivity could come with a loss of specificity, a heavy price when the incidence of disease is low. Despite the theoretical advantages of hs-cTnI, evidence supporting its use is inconsistent at best. Now, with the recent publication of a cluster-randomized controlled trial by Shah, et al., we have evidence demonstrating the clinical consequences of high-sensitivity assays on patient care. (Lancet 2018;392[10151]:919;

Credit: Mustafahacalaki/

The authors performed a stepped-wedge, cluster-randomized controlled trial in 10 EDs. Patients presenting with signs and symptoms concerning for ACS underwent an evaluation during which a standard troponin and a high-sensitivity assay were drawn. The study was divided into the validation phase, in which the hs-cTnI was drawn with results not divulged to the treating clinicians, and the implementation phase, during which the hs-cTnI was incorporated into clinical decision-making. All sites underwent at least six months of a validation phase after which they were randomly assigned to an immediate implementation phase or a delayed implementation phase following an additional six months of the validation.

The authors enrolled 48,282 patients over three years, and 18,978 (39%) were enrolled during the validation phase and 29,304 (61%) during the implementation phase. A total of 10,360 (21%) patients had an hs-cTnI value that was above the 99th percentile. The majority of these patients (83%) also had an elevated contemporary troponin assay, with only 17 percent reclassified using the hs-Tn. The authors found no difference in their primary outcome—the rate of subsequent myocardial infarction (type 1 or type 4b) or cardiovascular death within one year following the initial presentation to hospital (6% vs 5% in the validation and implementation phases, respectively).

Patients who were reclassified using the hs-cTnI were more likely than those who had congruent negative troponin assays to suffer a subsequent myocardial infarction or death. Despite this increased risk of adverse events, clinician awareness of the elevations in hs-cTnI did not improve patient-oriented outcomes. Hs-cTnI was a predictor of a sicker subset of the population, but it did not identify a group of patients who benefited from a more aggressive treatment strategy.

Not Much Has Changed
Despite our hopes, it would appear that the introduction of hs-cTnI added very little to the workup of patients presenting with symptoms concerning for ACS. In fact, the utilization likely led to a significant degree of overdiagnosis, downstream testing, and overtreatment. The use of hs-cTnI increased the number of patients diagnosed with myocardial injury by 17 percent, but only a third of these patients had a diagnosis of type 1 myocardial infarction.

Patients reclassified by the high-sensitivity assay were more likely to undergo coronary angiography in the implementation phase compared with the validation phase, (11% in the implementation phase v. 4% in the validation phase), and more frequently received prescriptions for antiplatelet agents, dual-antiplatelet agents, statins, and beta-blockers, all without improving important patient outcomes. The full extent of the overdiagnosis is likely understated in this dataset because the authors utilized the hs-cTnI as their diagnostic gold standard when ascertaining which patients experienced an MI during the one-year follow-up.

These results should not come as a surprise. They are simply the consequence of using a more sensitive assay. How many patients will be falsely diagnosed with ACS and suffer the downstream consequences of such a diagnostic burden? Despite many years of progression in the understanding of ACS, a host of novel biomarkers, and a brand new high-sensitivity troponin assay, not much has changed since the publication of the infamous Pope trial. We are still missing one to two percent of MIs following a negative ED workup.

It would seem that the introduction of the hs-cTnI has not changed that number. This study is far from perfect. The one-year outcome that was selected as the primary endpoint is less than ideal for evaluating the downstream consequences of a diagnostic strategy from the ED, and small differences in outcomes could have been missed because of the study design. Despite these shortcomings, the results from Shah, et al., should give us pause before we anoint hs-cTnI as the diagnostic savior in evaluating chest pain patients.

Dr. Spiegel is a clinical instructor in emergency medicine and a critical care fellow in the division of pulmonary and critical care medicine at the University of Maryland Medical Center. Visit his blog at, follow him on Twitter @emnerd_, and read his past articles at

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Wednesday, December 19, 2018

'Allergic Reactions' to Fish Usually Aren't


A patient reporting facial flushing, urticaria, abdominal pain, diarrhea, headache, and palpitations within 20-30 minutes of eating fish would lead most emergency physicians to diagnose a classic seafood allergy. Other symptoms might include flushing of the neck and torso, nausea, vomiting, dry mouth, and occasionally wheezing. The symptoms are ameliorated or resolve with basic treatment for an acute allergic reaction, and everyone is convinced that the patient has a fish allergy and should avoid the offending agent in the future.

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This is a common scenario, but many such cases are not actually allergic reactions, and are caused by excess histamine in the fish, otherwise known as scombroid poisoning. Scombroid poisoning is the most common cause of ichythyrotoxicosis in the world, but scombroid poisoning, unlike a true allergy caused by an IgE-mediated reaction, is simply due to the deterioration of histidine resulting in excess levels of histamine in poorly stored fish.

Histamine (Scombroid) Fish Poisoning: A Comprehensive Review
Feng C, et al.
Clinic Rev Allerg Immunol

This review discusses the cause, clinical symptoms, treatment, and implications of scombroid poisoning. Scombroid fish include mackerel, bonito, albacore, skipjack, sardines, bluefish, and occasionally salmon, but the majority of scombroid cases are attributed to tuna and mahi mahi. The disease has only been reported in the United States since 1968, but has been reported in homes, restaurants, cafeterias, schools, army barracks, and at medical conferences.

The toxicity is due to a variety of bacteria converting histidine, commonly found in fish, to the toxin, histamine. The process is caused by inadequate storage, particularly inadequate freezing. About 80 percent of fish consumed in the United States is imported from other countries, and one can see how this could occur. Ensuring safety standards, particularly avoiding seafood storage in warm environments, is key to prevention.

The symptoms of histamine poisoning are similar to those of an allergic reaction, and often the process is misdiagnosed as a straightforward IgE-mediated allergy. It has been estimated that scombroid poisoning may cause up to 40 percent of seafood-associated outbreaks that are incorrectly diagnosed as classic allergic reactions.

U.S. fish consumption has markedly increased since the 1980s; average seafood consumption per person is more than 16 pounds a year, and histamine fish poisoning is paralleling the rise in consumption. It often occurs in outbreaks where a number of individuals are affected by the same source. Scombroid poisoning has been reported throughout the world, and the process is annoying, but no deaths have been reported in the United States. Histamine poisoning is usually mild, has a short duration, and is self-limited. Symptoms usually occur within 20-30 minutes of eating histamine-contaminated fish, are ameliorated by antihistamines, or resolve spontaneously within six to eight hours. The symptoms most commonly seen include urticaria, flushing, headache, nausea, vomiting, and lightheadedness. Hypotension, bronchospasm, throat swelling, and respiratory distress may occasionally accompany this process.

Scombroid Poisoning Facts

  •  Occurs when fish are improperly stored in warm temperatures. Only a few hours are required to produce the toxin.
  •  Histidine normally found in fish is converted to histamine by histidine decarboxylase, an enzyme found in many bacteria normally residing in fish.
  •  Toxic levels of histamine can accumulate within two or three hours of storage at temperatures 68°F (20°C) or higher.
  •  Histamine is not broken down by cooking, freezing, or subsequent refrigeration.
  •  Fish usually appears fresh, but may have a peppery or metallic taste when eaten.
  •  Symptoms occur within one hour of eating histamine-contaminated fish.
  •  Most common symptoms are flushing of the head/neck, feeling of warmth, urticarial rash, and headache.
  •  Hypotension, bronchospasm, and cardiac arrhythmias occur rarely.
  •  Symptoms are impossible to differentiate clinically from a true allergy. Identifying the same symptoms in other individuals who consumed the same product can confirm scombroid poisoning.
  •  A seafood/fish allergy does not develop in adults who have not had symptoms in the past.
  •  Evaluation by an allergist can uncover true fish allergy.
  •  Treatment consists of H1- and H2-blocking antihistamines, but occasionally epinephrine may be required.

Bacterial Enzyme
This is a relatively new toxicity: Histamine was not proven to be the culprit of scombroid poisoning until 1991. It was previously thought that orally ingested histamine could not be absorbed in sufficient amounts to cause symptoms.

Bacteria that normally reside in fish contain an enzyme, histidine decarboxylase, which converts benign histidine to histamine. A variety of bacteria have histidine decarboxylase activity. The exact type and composition of these bacteria vary according to geographic location, fish feeding habits, water temperature, and the handling process. Once the histamine has been formed, it is resistant to cooking, smoking, freezing, canning, and subsequent refrigeration; none of these can prevent histamine fish poisoning. The fish will smell or appear fresh, but those with scombroid poisoning might report that it tasted metallic, peppery, spicy, or bubbly.

Fortunately, scombroid poisoning is self-limited and has no long-term complications. It has been reported that individuals taking isoniazid or monoamine oxidase inhibitors, which inhibit histamine metabolism, may be more vulnerable to scombroid poisoning and may have prolonged and severe symptoms. The duration of various scombroid poisoning generally depends upon the amount of contaminated fish that was consumed.

The best way to protect against the production of histamine is to keep the product at a temperature of 0°C (32°F) or lower. Histidine decarboxylase is inactivate and bacteria can't grow at these temperatures. When stored at temperatures above 20°C (68°F), it only takes a few hours for enough histamine to be formed to cause symptoms.

True Allergy
Evaluating a patient for possible histamine fish poisoning begins with a history that includes the type of fish, when it was eaten, and if symptoms have occurred in the past, suggesting true allergy. Importantly, it should be noted that it is rare for fish allergy to develop in adults spontaneously. A true allergy is unlikely if someone has tolerated fish in the past. Spoiled fish does not have a specific appearance or odor that would aid in the diagnosis. Even fish with high histamine levels appears fresh. The best historical clue is ascertaining whether others who consumed the same food become similarly ill.

An allergist can confirm a true fish allergy by evaluating for specific immunoglobulin IgE via testing and food challenges. It is unlikely that the offending fish can be found or tested, but histamine levels can be measured. Skin prick testing can help diagnose histamine fish poisoning, though obviously it is not available in the ED.

Antihistamines are the mainstay of treatment for scombroid poisoning and fish allergy. H1 blockers such as diphenhydramine are generally effective. H2 blockers, such as cimetidine and ranitidine, are also beneficial and can be added if symptoms persist or are severe. The symptoms should completely resolve a few hours following antihistamine administration. The use of IM epinephrine can be considered in severe cases, or if the patient is hypotensive or wheezing. Methylprednisolone is often incorporated in the treatment, but the value is controversial.

Symptoms of Scombroid Toxicity

  •  Cutaneous flushing of the face and neck, uncomfortable feeling of intense warmth
  •  Erythematous and urticarial rash, often most prominent on the face and upper torso
  •  Perioral burning, itching, or edema
  •  Abdominal cramping, nausea, vomiting, and diarrhea
  •  Headache
  •  Dizziness
  •  Tachycardia
  •  Palpitations
  •  Chest tightness with shortness of breath
  •  Peppery or metallic taste to the fish
  •  Blurry vision
  •  Hypotension (distributive shock)
  •  Bronchospasm and respiratory distress (rare)
  •  Cardiac arrhythmias (rare)

Comment: Up to two percent of individuals in this country are actually allergic to seafood. Seafood allergy is the most common food allergy in adults and one of the most prevalent food allergies in young children. Symptoms after eating seafood would prompt most to conclude that an allergic reaction has occurred. A true allergy is an immunologic response to the proteins in food that is IgE-mediated. Interestingly, the highest rate of seafood allergy occurs in African Americans, with shellfish being reported as a leading cause. Fish and shellfish allergies can vary from mild to severe, and death can occur.

Many fish, especially those with dark meat, such as tuna, mahi mahi, bluefish, and mackerel, will produce histamine at higher temperatures by bacteria normally present in the fish. Interestingly, an individual who has an allergy to a finned fish would not necessarily have an allergy to shellfish because the allergens are different. The specific treatment for allergy and scombroid poisoning is relatively straightforward, and it's best to refer all patients to an allergist. Those with a true allergy should carry an epinephrine pen because true allergy can be life-threatening. Scombroid poisoning does not appear to be life-threatening.

The proper handling of commercial fish is important, but scombroid poisoning can occur from fish caught by individuals. Anglers often eat tuna, mahi mahi, mackerel, or skipjack. Catching a fish in the morning and storing it in the warm environment of a boat for the day can certainly produce enough histamine to cause a reaction. Toxic histamine levels can accumulate within a few hours via bacterial action. A number of bacteria are responsible, including Escherichia coli, Vibrio, Proteus, Klebsiella, Clostridium, Salmonella, and Shigella. Curiously, scombroid poisoning can also occur by eating Swiss cheese; bacteria contaminate the raw milk prior to processing.

Identifying individuals with similar symptoms who ate the same fish is the best way to confirm scombroid poisoning. Characteristically, patients improve promptly with antihistamine administration. Patients with mild symptoms or those who respond immediately can generally be discharged from the ED after a short period of observation. Some clinicians suggest a day or two of an oral antihistamine, such as loratadine or cetirizine. Those with severe symptoms such as airway edema, bronchospasm, or hypotension should be observed for 12-24 hours.

The treatment of true fish allergy and scombroid poisoning are the same in the ED, and referral to an allergist is recommended because labeling a person with a seafood allergy can have significant consequences to his diet. It would be unfortunate if someone were told in the ED that he has a seafood allergy, eschewing all seafood in the future, when it was benign scombroid poisoning.

Dr. Roberts is a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, PNP, at, and read his past columns at

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Wednesday, December 12, 2018

Cricoid Pressure Nothing More than Medical Nostalgia


The use of cricoid pressure is a polarizing issue. It is not uncommon for experts in emergency airway management to come close to blows when discussing the efficacy of Sellick's famous maneuver. Until recently, there has been a paucity of data to support or discredit its use, but the publication of the IRIS trial represents the first large, high-quality empiric examination of this historic piece of airway dogma.

The IRIS (Sellick Interest in Rapid Sequence Induction) trial examined using cricoid pressure in surgical patients undergoing rapid sequence induction (RSI) at 10 centers across France. (JAMA Surg 2018 Oct 17. doi: 10.1001/jamasurg.2018.3577; The authors enrolled 3,472 adult patients requiring RSI for any type of surgical procedure under general anesthesia who were considered to have a full stomach (less than six hours of fasting) or at least one risk factor for pulmonary aspiration. Patients were randomized to receive a sham procedure or true cricoid pressure, defined as an expected pressure equivalent to 30 newtons applied using the first three fingers on the cricoid cartilage. Operators were trained to apply the procedure correctly before being permitted to participate in the study.

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This study was technically negative, but the authors reported the sham cricoid procedure failed to demonstrate noninferiority when compared with the true Sellick technique. This is most likely an error in the authors' statistical analysis rather than any clinical benefit of cricoid pressure. The rate of primary endpoint, pulmonary aspiration (detected at the glottis level during laryngoscopy or by tracheal aspiration just after tracheal intubation), was essentially identical in both groups. It occurred in 10 patients (0.6%) in the Sellick group and in nine (0.5%) in the sham group. The rates were similar for suspected pneumonia within 24 hours of intubation (0.9% vs 0.6%), aspiration pneumonia (0.2% vs 0.2%), and severe pneumonia (0.1% vs 0.1%).

The only element that was noticeably different between the groups was the difficulty of intubation. Patients randomized to the cricoid pressure group had a higher incidence of grade 3 and 4 Cormack and Lehane views. Interruption of the maneuver also occurred more frequently in the cricoid pressure group. Abandoning these attempts more often improved the view after its release. The cricoid pressure group required longer times to intubation and more frequently experienced intubations exceeding 30 seconds. The incidence of difficult tracheal intubation did not reach statistical significance, but it was numerically higher in the cricoid pressure group (72 v. 51).

Epic Fail

This was a negative trial from a frequentist perspective because of the form of hypothesis testing utilized in the primary analysis. The authors used a noninferiority trial design, which asked a different question from the traditional superiority trials to which we are accustomed. Rather than presenting a null hypothesis that states no difference between the groups, the noninferiority trial design operates under the assumption that the novel intervention is inferior to the standard treatment. The alternative hypothesis states that the treatment options are equivalent. The novel treatment must demonstrate a nearly equal efficacy within a degree of certainty to reject the null hypothesis. This means the point estimate and surrounding 95% confidence interval must fall above an a priori selected noninferiority margin. (JAMA 2015;313[24]:2371;; Ann Intern Med 2006;145[1]:62.)

The authors in this case designated the true cricoid pressure group as the established approach and the sham maneuver as the novel comparator, and in doing so, designed a trial in which cricoid pressure could not fail. The sham group at worst would be found to be noninferior to the traditional approach. The authors chose an inferiority margin of 50 percent worse than the cricoid group, or a relative risk of 1.5. They predicted that the rate of their primary endpoint would occur in 2.8 percent of the patients in the cricoid pressure arm based on previous literature, meaning the sham control group could have a rate of aspiration no greater than 4.2 percent to be considered noninferior.

The actual rate of aspiration events in the cricoid pressure group was far lower than the authors anticipated (0.6%). The rate of aspiration in the sham control group was numerically lower at 0.5 percent and clinically equivalent due to the paucity of aspiration events, but the confidence interval surrounding this outcome was larger than anticipated. Despite the relative risk of aspiration falling in favor of the sham group at 0.9, the confidence interval surrounding this point estimate crossed the noninferiority margin (95% CI, 0.33-2.38).

We utilize frequentist statistics as a tool to estimate the risk of sampling error in any given cohort. But its single-minded dichotomous temperament at times limits our ability to interpret what is otherwise in plain sight. From a frequentist perspective in the IRIS trial, we are unable to demonstrate the noninferiority of sham cricoid pressure. A simple inspection of the results, however, demonstrated that true aspiration events are uncommon and cricoid pressure fails to prevent them.

Our futile attempts to prevent this rarity also actively thwart our own efforts to secure an airway. The applicability of these results to the ED or ICU patient population where the risk of aspiration is much higher is unclear, but given the obvious harm demonstrated in this study, the onus should now fall on us as clinicians to demonstrate its utility. Until then, it should be considered nothing more than a melancholy specimen of medical nostalgia.

Dr. Spiegel is a clinical instructor in emergency medicine and a critical care fellow in the division of pulmonary and critical care medicine at the University of Maryland Medical Center. Visit his blog at, follow him on Twitter @emnerd_, and read his past articles at

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