Serotonin Syndrome

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Written by: Jacob Stelter, MD (NUEM PGY-3) Edited by: Elizabeth Byrne, MD,  (NUEM Graduate 2017) Expert Commentary by: Patrick Lank, MD


The Case

A 21-yearold male with history of PTSD and depression presented to the ED complaining of “feeling anxious.” When evaluated, the patient was found to be anxious, continuously pacing around the room. His speech was pressured as he tangentially answered questions.  During the interview he stated that he was discharged a few days ago from a psychiatric hospital after he had intentionally overdosed on clonazepam. He then admited that two hours prior to arrival in your ED he took 30 pills of his prescribed sertraline 100mg tabs to “calm his nerves.” He denied any concurrent substance abuse. Despite the stated overdose, he denied any suicidal intent with his ingestion.

 

Physical Exam:

Vital Signs: T 98.9F oral   HR 137   BP  152/89   RR 20    Sat 99% on room air

General: Awake, alert, anxious-appearing, pacing around the room, mildly diaphoretic

Head: normocephalic, atraumatic

HEENT: PERRL,  EOMI, anicteric sclera, mydriatic pupils b/l, 8mm

Cardiac: tachycardic,  regular rhythm, no MRG

Resp: clear to auscultation, nonlabored, no crackles appreciated

Abd: Soft, not distended, not-tender to palpation, +bowel sounds

Extremities: well perfused, 2+ radial and DP pulses b/l, mildly diaphoretic

Neuro: AAOx3, 5/5 strength in all 4 extremities, +ankle clonus, hyperreflexia on patellar reflexes.

Psych: Cooperative but anxious with pressured and tangential speech., no HI , SI, hallucinations/delusions

 

Pertinent Labs:

WBC 12.5, Hgb 15.8, electrolytes within normal limits,  LA of 1.7.

Urine drug screen was positive for amphetamines and benzodiazepines. Acetaminophen, salicylate, and ethanol concentrations were below detection limits.

 

ECG:

Sinus tachycardia, QTc 457, no abnormal morphology of the QRS complexes

 

Diagnosis?

Serotonin Syndrome due to SSRI overdose.


Serotonin Syndrome

Overview

Serotonin syndrome is a disorder that is precipitated by excess serotonin. It is classically described as having a combination of hyperautonomic hemodynamic changes, neuromuscular derangements, and a change in the patient’s mental status. [1]  Serotonin syndrome is a medical condition seen only in patients with exposure to serotonergic medications and has been more recently appreciated since the advent of serotonergic drugs used to treat depression and anxiety. However, in addition to pharmaceuticals, botanicals and recreational drugs of abuse can also be serotonergic.  Causative substances increase the amount of circulating serotonin in the bloodstream, which leads to an increased propensity to develop serotonin syndrome [2].  This is not a rare diagnosis; there are approximately 7,300 cases per year results in about 100 deaths [1].

Clinical Presentation

Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20.

The diagnosis of serotonin syndrome will often manifest around the time of a dose increase, addition of another serotonergic agent or an overdose on a serotonergic agent [3]. Serotonin syndrome will typically manifest within 24 hours of exposure to the serotonergic agent [4]. Symptom presentation  can be separated into three main categories: cognitive, autonomic and neuromuscular. Cognitive symptoms range from restlessness and anxiety to agitation and altered mental status [2].  Autonomic signs and symptoms include tachycardia, mydriasis, hyper- or hypotension, hyperthermia and diaphoresis [2]. Neuromuscular symptoms are also usually observed, ranging from akathisia to muscle rigidity, hyperreflexia and myoclonus [2].  Serotonin syndrome can be a life-threatening condition if not promptly recognized and treated as it can progress to seizures or shock [1]. 

Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20.

Treatment

The most important initial step to the treatment of serotonin syndrome is to remove exposure to the offending agent. Use of activated charcoal to assist with gastrointestinal decontamination can be considered in the setting of a recent ingestion [1].  Following this, the cornerstone of therapy of serotonin syndrome is symptom based supportive care, with benzodiazepines being one of the most important components of treatment [1, 2]:

  • Obtain an ECG to evaluate the QTc and QRS durations.
  • Begin IV fluid rehydration and resuscitation.
  •  If the patient is hyperthermic, especially greater than 40 ºC, begin active external cooling.
  • Antipyretics are not useful for the treatment of hyperthermia secondary to serotonin syndrome. This is because the hyperthermia is due to increased muscle activity and not secondary to change in the hypothalamic temperature set point.
  • Benzodiazepines improve numerous symptoms of serotonin syndrome, especially agitation and are one of the most important elements of treatment.
  • Use easily titrated medications like nitroprusside or esmolol for severe hypertension.
  • If needed, vasopressors should be used for refractory hypotension.
  • A recent study has suggested the potential utility of dexmedetomidine to treat serotonin syndrome (5).
  • Cyproheptadine, a serotonin antagonist, has long been proposed anecdotally for the treatment of serotonin syndrome.  However, multiple studies suggest that it does not change outcomes and may only help temporarily control symptoms (6).

Unless the clinical features are very mild, these patients will likely need monitoring in an ICU setting for at least 24 hours after being initially managed in the Emergency Department (ED).  As always, especially in the case of an intentional overdose, contacting the local Poison Control Center is a valuable resource in helping to treat these patients.

What about Neuroleptic Malignant Syndrome?

One of the disorders that can present similarly to serotonin syndrome is neuroleptic malignant syndrome (NMS).  Pathophysiologically, NMS is related to an inherited genetic mutation in skeletal muscle and is provoked in the presence of certain neuroleptics [7]. Neuroleptic malignant syndrome often occurs after exposure to drugs that affect the central dopaminergic system, such as haloperidol. There are inherent differences between NMS and serotonin syndrome. Serotonin syndrome tends to present within 24 hours of exposure to the offending agent, whereas NMS will often be more delayed, presenting after 7 days of starting the neuroleptic [4]. Patients with serotonin syndrome will often be agitated and delirious while NMS patients will often have dysphagia, incontinence and increased secretions [4]. NMS will often have extrapyramidal side effects, muscle rigidity and rhabdomyolysis compared to the mydriasis, clonus and hyperreflexia of serotonin syndrome [4].


Return to the Case

As noted above, the patient in this case exhibited all the hallmark signs of serotonin syndrome, including agitation, restlessness, diaphoresis, mydriasis, hyperreflexia and clonus.  In the emergency department, this patient was treated with multiple rounds of lorazepam and boluses of saline which helped to control his symptoms.  This patient was admitted to the medical ICU and monitored for an additional 24 hours.  After his symptoms and vital signs normalized, he was transferred to the floor and received the psychiatric evaluation and treatment that he needed.  His hospital course was uncomplicated and he was transferred to an inpatient psychiatric treatment facility for further care.


Take Home Points

  1. Serotonin syndrome can be a life-threatening condition. Keep a high suspicion for this in patients on serotonergic agents.
  2. The hallmark signs and symptoms of serotonin syndrome are anxiety and restlessness, diaphoresis, mydriasis, clonus, hyperrflexia, tachycardia and hypertension.
  3. Treatment is mainly supportive care and includes intravenous fluids, benzodiazepines titrated to symptom control and blood pressure control as needed.
  4.  Serotonin syndrome is often confused with NMS.  Remember, NMS is in the setting of exposure to neuroleptics and tends to present later on with symptoms of extrapyramidal side effects, muscle rigidity and increased secretions.
  5. Local poison control centers are a great resource in helping manage the treatment of patients with serotonin syndrome and most will require at least 24 hours in an ICU setting after ED diagnosis and management.

Expert Commentary

Dear Dr. Stelter,

Thank you again for yet another exciting tox blog post! This case has a tremendous amount to dissect, but I want to focus on a few things.  For this case, let’s talk about the tox history, the tox physical exam, and the “supportive care” recommendation. Really, this is the definition of bread and butter medical toxicology.

The patient history described above is incredibly common, and that makes sense! Patients with a known history of psychiatric disease have higher risk of having psychiatric emergencies and have access to psychiatric medications. So whether by misunderstanding the purpose of their medication or by intentionally trying to harm oneself, it is common that we as medical toxicologists have to consider the effect a patient’s psychiatric medications have had (or will have) on their current clinical state. So what I want to know out of this patient is what all he could have been exposed to and when. Here are examples of questions I ask:

  •  “When did you take this medication?” (Looking at the clock) “Ok. It’s 3pm. You took it 2 hours ago, so at 1pm you sat down and swallowed 30 pills?” In essence, I want the patient to describe exactly how he was exposed – this can also clue me into his intent.
  • “Did you take anything else?” (Answer is commonly “no” – always dig deeper) “Are you on any other medication? When is the last time you took that medication? When you started to feel sick before you came into the emergency department, did you take anything else to help with your symptoms?”
  •  “This may sound silly to you, but I also care about anything else you are taking. Are you on any vitamins or diet pills or herbals or cleanses? Is there anything you have purchased and taken in the last week which was not food or a prescription medication we have already talked about?”
  • “Do you do any drugs?” I purposely leave the word “illicit” out. I don’t really care about legality. I just want to make them better. “I have seen many patients use all sorts of things that make them feel as sick as you feel now. Is there anything you can think of that you’ve taken which could make you this sick?”

This physical examination gave you your diagnosis! Usually we are clued into these diagnoses based on hyperthermia, which this patient frustratingly did not have. But that “hot tox” differential is something all emergency physicians should be aware of and facile in differentiating between. It includes serotonin syndrome, NMS, sympathomimetic toxicity (including cocaine, amphetamines, MDMA, cathinone derivatives, etc.), anticholinergic toxicity, and severe salicylate toxicity just to name a few.  Although this patient did not have hyperthermia, he did have almost every other finding associated with serotonin syndrome with the most specifically-associated being clonus. Once I see clonus, I take a step back and see if serotonin syndrome fits into the clinical picture.

Finally, I greatly appreciate your description of symptom-focused supportive care in this clinical scenario. As you have displayed, “supportive care” is not super simple. It is nuanced and multifaceted and very frequently life-saving. Before fellowship I was frustrated that there wasn’t necessarily a specific antidote or procedure we could do to reverse toxicity in all poisoned patients. With time, however, I have gained great respect for “supportive care” – regretting when it is not performed adequately and truly appreciating when it is life-saving.

So in this single case you have touched on the key major aspects of the specialty of medical toxicology. I hope some of my points were helpful to you in further appreciating the stellar medical care you provided this sample patient.

 

Patrick_Lank-04.jpg

Sincerely,

Patrick Lank, MD

Associate Program Director Northwestern Emergency Medicine 

Assistant Professor of Emergency Medicine

 


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How to cite this post

[Peer-Reviewed, Web Publication] Stelter J,  Byrne E (2017, Nov 13). Serotonin Syndrome [NUEM Blog. Expert Commentary By Lank P]. Retrieved from http://www.nuemblog.com/blog/serotonin-syndrome


References

  1. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20.
  2.  LoVecchio F, Mattison E. Atypical and serotonergic antidepressants. In Tintinalli’s emergency medicine: A comprehensive study guide. J Tintinalli (Ed.) (pp. 1219-24). 2016. New York, NY: McGraw-Hill.
  3. Pedavally S, Fugate JE, Rabinstein AA. Serotonin syndrome in the intensive care unit: Clinical presentations and precipitating medications. Neurocrit Care 2014;21:108-13.
  4. Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: A brief review. Can Med Assc J 2003;168:1439-42.
  5.  Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacotherapy 2014;14:1651-4.
  6.  McDaniel WW. Serotonin syndrome: Early management with cyproheptadine. Ann Pharmacother 2001;35:870-3.
  7.  Keck PE, Caroff SN, McElroy SL. Neuroleptic malignant syndrome and malignant hyperthermia: End of a controversy? J Neuropsychiatry Clin NeuroSci 1995;7:135-44.

Posted on November 13, 2017 and filed under Toxicology.

My Brain Hurts: Applying Cognitive Load Theory to Emergency Medicine Handoffs

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 Written by: Danielle Miller, MD (NUEM PGY-3) Edited by: Matt Klein, MD,  (NUEM PGY-4) Expert Commentary by: Holly Caretta-Weyer, MD


Introduction:

Have you ever been on a shift in the Emergency Department and thought: “My brain hurts,” or, “If I put one more detail in my brain, my brain may explode?”

Emergency Medicine requires synthesizing large amounts of data in a short amount of time for multiple patients. Think of your last busy post-overnight sign-out, when multiple patient-care-plans needed to be safely communicated from one team to the other. Why are these handoffs so difficult for us? Is there some theory that may illuminate this phenomenon and provide ways to improve?


What is Cognitive Load Theory:

Cognitive load theory (CLT)  was initially developed in the 1980s from research in cognitive psychology that concluded that there are multiple elements that can overload the learner and reduce problem solving (1,4,7).

In cognitive load theory, human memory is divided into three subsystems:

  •  Sensory Memory
  •  Long Term Memory
  •  Working Memory

Sensory memory encompasses brief visual and auditory inputs such as faces/colors/environments, but lasts only 1-2 seconds and generally does not reach consciousness.

Long term memory is a permanent form of memory that utilizes meaningful connections between information elements, and thus can easily be recalled.

Working memory is memory for operating a current task (4). Working memory holds information for a few seconds, with almost all information lost after about 20 seconds, unless the information is rehearsed (1).  Working memory is limited  and can hold no more than five to nine information elements (think of memorizing a phone number, ie. seven plus or minus two)(1).  Working memory is critical to completing a successful handoff, but can easily be overwhelmed.


What Impacts Working Memory:

Working memory is impacted by 3 different types of cognitive load:

  • Intrinsic load
  • Extrinsic load
  • Germane load

Intrinsic load  is the load associated with performing the task itself, such as communicating the names, comorbidities, and plans for the patients at signout.

Extraneous load is the load associated with non-essential aspects of the task, such as what is happening in the environment at signout or what is happening in someone’s personal life that may be affecting the handoff.

Germane load is the load to develop strategies to facilitate learning (3). In general, when the cognitive load associated with a task exceeds the learner’s working memory capacity, performance is impaired (3).


How Does This Apply to Handoffs:

Appreciating the limits of working memory can help identify the challenges of handoffs.

One proposed framework for handoffs is to create a “shared mental model between the giver and receiver” (4). There are multiple factors that prevent the sender and receiver from developing the shared mental model, and this concept is explored through cognitive load theory. These factors can be analyzed by the type of cognitive load that they encompass: intrinsic, extrinsic, germane.  

So What Can We Do to Improve Working Memory and Create Good Handoffs? 

The goal in handoff is to:

  • Manage intrinsic load
  • Reduce extraneous load
  • Optimize germane load (4).

Managing Intrinsic Load in the Emergency Department Handoff:

Intrinsic load  is the load associated with performing the task, or in this case, the load associated with performing the process of a handoff itself.

There are four elements that influence intrinsic load: 

First, the number of information elements influences intrinsic load (4). For example, learning about five patients and their comorbidities during sign-out causes a greater load than two. In the Emergency Department, the number of patients that we must signout is difficult to control, but we could reduce this cognitive load by discharging individuals prior to signout and listing only the critical comorbidities for each patient.

Second, the amount of time available for a task influences intrinsic load (4). For example, the need for rapid handoff and decision making consumes more working memory. Again, this is difficult to control in the Emergency Department, but allowing sufficient time for signout is key.

Thirdly, element interactivity, or how information elements interact with each other, influences intrinsic load (4). The goal, then, during handoff in the Emergency Department would be to attempt to limit uncertainty and give contingencies. For example, one could say, “If the lumbar puncture is unremarkable, I would then consider other causes of mild fever with recent travel such as pulmonary embolism.”  

A fourth determinant that influences intrinsic load is the experience of  the learner (4). As expected, the intrinsic load of a handoff is reduced when learners are more advanced, as the advanced learner has well defined illness scripts that he or she can implement and not bog-down working memory. Again, this cognitive load is difficult to control in the Emergency Department, as we cannot age the learner, but it may be helpful to simply be aware that signing out to someone of different training level requires slightly different information to diminish cognitive load.

Reducing Extraneous Load in the Emergency Department Handoff:

Extraneous load is the load associated with non-essential aspects of the task.  

Extraneous load is influenced by  three components: the physical environment, the personal environment, and how information is presented.

First, the physical environment influences extraneous load during handoffs. It is difficult to control the physical environment and distractions of the ED, but having a culture of limiting interruptions during handoffs may decrease this load.

Secondly, extraneous load is influenced by the personal environment. For example, personal distractions such as home life can increase extraneous load during handoffs. Included in this category is learner fatigue or “burnout,” which is a type of extraneous load that decreases working memory capacity and can affect handoffs (4). Focusing on wellness outside of work may limit this factor.

Thirdly, how information is presented influences extraneous load. For example, when information necessary for the handoff is distributed in space (ie, requiring the sender and receiver to access multiple different databases for information), then extraneous load is increased. Thus, having a cohesive tracking board with all pertinent information in one place, as opposed to having to click through multiple screens for information, would decrease extraneous load during handoffs in the ED. Additionally, combining auditory and visual elements during signout decreases extraneous load.

Optimizing Germane Load in the Emergency Department Handoff:

Germane load  is associated with the load to develop strategies to facilitate learning.  Strategies associated with optimizing germane load include asking clarifying questions and summarizing what has been heard. In the Emergency Department, encouraging clarifying questions during handoff would be a way to improve handoffs. Additionally, having the receiver give a summary to the sender at the end of signout, may also prove useful.


Conclusion:

Cognitive load theory gives a framework for illuminating why handoffs can be challenging in the Emergency Department. We largely use working memory during handoffs, which is a limited and influenced by intrinsic, extrinsic, and germane cognitive loads.  By implementing strategies to manage intrinsic load, reduce extraneous load, and optimize germane load, we can create more successful handoffs.


Commentary

Dr. Miller has done an excellent job of laying out the various factors at play contributing to cognitive load in the Emergency Department and specifically how these factors contribute to making sign-out such a potentially dangerous time.

I want to highlight a few key reasons sign-out conveys such a critical mass of cognitive load and then emphasize some “hacks” to reduce the various contributing factors.

A substantial amount of the critical mass is the product of the nature of the Emergency Department flow, from patient volume to case complexity. I often hear residents say at the beginning of each shift that they want to “work on efficiency.” I would challenge you to take that a step or two further and define the specific type of efficiency in light of considering the various aspects of cognitive load. Do you want to work on your ability to formulate an “if/then” dichotomous decision plan when you walk out of the room to expedite your discharge process? Do you want to further develop your illness scripts by seeing as many patients as possible and discussing where they fit into your bell curve to improve your pattern recognition? Thinking about the various aspects of cognitive load will greatly aid in defining where your efficiency bottlenecks are and how you can improve them, while also improving your knowledge, skills, and personal patient flow for future practice.

Sign-out is the culmination of an entire shift’s worth of cognitive load. It combines both cognitive fatigue from seeing patients and making decisions with physical fatigue from long hours spent working hard and potentially not eating or using the restroom. Cognitive residue from issues outside of work or on cases from previous shifts that you feel could have gone better may also contribute to the cognitive load you experience, and all of this occurs while you try to distill complex patient cases from a crazy shift into concise presentations with understandable dichotomous decision trees for the oncoming team.

I would like to emphasize a few of Dr. Miller’s key points here and add some tips with which I have had or seen significant success.

Tips for reducing cognitive load for handovers:

1.     Be disposition-oriented at all times. If you consistently walk out of the room with a dichotomous decision pathway and know whether the patient will be discharged or admitted, you will have an easier time communicating a concise “if/then” plan to another provider backed up by your decision process. Consistently remaining in this mindset will keep you in “sign-out” mode, especially as you wrap up your shift.

2.     Limit uncertainties (with the caveat that every patient should be reassessed). Providing the oncoming team with decision branch points such as “if the CT is negative, the patient can be discharged” or “this patient will need a sober re-evaluation in two hours at 9:00 AM” makes it easy for them to understand rate-limiting steps. It also allows for you to set time points for reevaluation, and if things are not following the dichotomous decision that was laid out, the receiving team should have a low threshold to take a step back and this should trigger the pursuit of a new pathway. 

3.     Find a system that works for you to reduce your cognitive load and use it! What do I mean by this? Take some of the load in your actual brain and put it into some form of external brain to reference as opposed to having to recall everything. Use old-fashioned paper and pencil with checkboxes for what needs to be done in your decision-tree or using electronic medical record hacks such as the notes section to come back to with the rate-limiting steps when you run your board. Using the EMR to communicate also has the added bonus of letting the nursing staff and others know what the rate-limiting steps for a given patient are and helps relieve some of the cognitive load off of your shoulders.
 

4.     Have a shared mental model for sign-out such as the I-PASS system. The I-PASS system is a mnemonic that stands for conveying the illness severity (for example: stable, watcher, or unstable), patient summary, action items (dichotomous if/then plan), and situational awareness for potential pitfalls and contingency planning for the them. The final S stands for synthesis by the receiver, which can be done for each individual patient, for all patients signed out, or both. By telling the oncoming provider how sick you feel the patient is and their brief presenting history and relevant past history you paint a picture of the patient for the team taking over. Once they have a mental picture of the patient, you give them your dichotomous decision tree and areas where you could foresee this breaking down. Finally, the other team should run the board back after they receive sign-out and ask clarifying questions. This also allows you to get a fresh perspective on cases if you need it. This is the one time we get to really bounce things off one another as a team – take advantage of it!
 

5.     Limit interruptions during handovers. Call the communication system to have them hold your phone calls. Have the other team take traumas and critical patients. Bring your charge nurse into sign-out to expedite workups and dispositions. Do sign-out where you can't hear each other. The key is to limit distractions that take up part of your attentional capacity so that you can efficiently communicate the status and plan for each patient without omitting any important details.
 

6.     Finally, make sure you clear the deck and take care of yourself. Make sure you debrief difficult cases in real-time if you are able to in order to reduce the cognitive residue that this may contribute to the rest of your shift and sign-out. Additionally, make time to eat and use the bathroom on shift to reduce physical stress and improve cognitive processing by taking a short break every hour or two. This allows you to be at your full functional capacity and ensures you are giving your best to each patient and your colleagues once sign=out rolls around.
 

As emergency physicians, cognitive load is everywhere and inherent to our job. How you deal with it will define your “efficiency” on shift and over a long career. Developing functional strategies to manage your cognitive load early will give you the tools you need to have a long and healthy career in emergency medicine.

Holly Caretta-Weyer, MD

Instructor, Department of Emergency Medicine, OHSU                              Education Fellow, Department of Emergency Medicine

 


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How to cite this post

[Peer-Reviewed, Web Publication] Miller D,  Klein M (2017, Oct 30). My Brain Hurts: Applying Cognitive Theory to Emergency Medicine Handoffs?  [NUEM Blog. Expert Commentary By Caretta-Weyer H]. Retrieved from http://www.nuemblog.com/blog/cognitive-load


References:

  1. Van Merriënboer, Joroen JG, and Sweller, John. Cognitive load theory in health professional education: design principles and strategies. Medical Education. 2009 Dec; Vol 44, 85-93.16.
  2. Wilson EA, Wolf MS. Working memory and the design of health materials: a cognitive factors perspective. Patient Educ Couns. 2009 Mar; 74(3):318-22 
  3. Young JQ, Van Merrienboer J, Durning S, Ten Cate O. Cognitive load theory: implications for medical education. Med Teach. 2014 May; 36(5): 371-84
  4. Young JQ, Ten Cate O, O'Sullivan PS, Irby DM. Unpacking the Complexity of Patient Handoffs Through the Lens of Cognitive Load Theory. Teach Learn Med. 2016; 28(1):88-96.
  5. . Patterson ES, Roth EM, Woods DD, Chow R, Gomes JO. Handoff strategies in settings with high consequences for failure: Lessons for health care operations. International Journal for Quality in Health Care. 2004; 162:125–32.
  6.  Young JQ, O'Sullivan PS, Ruddick V, Irby DM, Ten Cate O. Improving handoffs curricula: Instructional techniques from cognitive load theory. Acad Med. 2017 Mar; DOI: 10.1097.
  7. Sweller, J . Cognitive load during problem solving: Effects on learning. Cognitive Science.1988 Jun;12 (2): 257–285.
  8.  Paas, Fred G. W. C.; Van Merriënboer, Jeroen J. G. The efficiency of instructional conditions: An approach to combine mental effort and performance measures. Human Factors: the Journal of the Human Factors and Ergonomics Society. 1993. 35 (4): 737–743.

Posted on October 30, 2017 and filed under Cognitive Theory.

The ATACH-2 Trial: Blood Pressure Control in ICH

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Written by: Jessica Bode, MD (NUEM PGY-3) Edited by: Michael Macias, MD,  (NUEM class of 2017) Expert Commentary by: Andrew Naidech, MD, MSPH


Introduction

Hemorrhagic stroke is the second-leading cause of strokes (behind ischemic strokes). The 30-day mortality from intracerebral hemorrhage (ICH) ranges from 35 to 52 percent, with one-half of these deaths occurring within the first two days[1]. A 2010 systematic review estimated that only between 12 and 39 percent of patients go on to achieve independent function[2]. Somewhat intuitively it has long been thought that aggressive blood pressure (BP) control may improve outcomes by limited hemorrhage expansion.

The INTERACT2 study examined the efficacy of intensive systolic blood pressure (SBP) reduction to a goal of <140 mmHg over the course of 1 hour and within a 6 hour window of symptom onset as measured by death and disability. While initially touted as a positive study further examination of the methodology revealed significant differences in the two arms only with ordinal analysis. When comparing this aggressive intervention to the standard treatment SBP goal of <180, the 2013 study found no significant difference between treatment arms. [3]

The 2016 ATACH-2 study sought to reexamine this question: Does aggressively lowering blood pressure lead to decreased death or disability at 90 days?


Study

Qureshi AI et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage (ATACH-2 Trial). NEJM 2016. PMID: 2726234


Study Design

  • Randomized, multicenter, two-group, open-label trial (took place in 110 sites in the US, Japan, China, Taiwan, South Korea and Germany)

Population

  • Age 18-90
  • Intracerebral hemorrhage (< 60 cm3) seen on CT scan with NIHSS score 4 or greater
  •  GCS ≥5 
  •  Presenting within 4.5 hours of symptom onset (initially within 3 hours but later extended)
  • At least one reading of SBP of 180 mmHg or more between symptom onset and the initiation of intravenous antihypertensive treatment

Exclusion Criteria

  • Time of symptom onset not reliably established
  • Previously known AVM, neoplasm or aneurysm
  •  Intracerebral hematoma considered to be related to trauma.
  • lCH located in infratentorial regions such as pons or cerebellum
  •  IVH associated with intraparenchymal hemorrhage and blood completely fills one lateral ventricle or more than half of both ventricles
  • Subject is considered a candidate for immediate surgical intervention by the neurosurgery service
  • Pregnancy or parturition within previous 30 days or active lactation
  •  Any history of bleeding diathesis or coagulopathy
  • Use of warfarin within the last 5 day
  • A platelet count less than 50,000/mm3
  • Known sensitivity to nicardipine
  • Pre-morbid mRS of 4 or greater
  • Subject’s living will precludes aggressive ICU management

Ultimately 8532 patients were screened, 1000 were randomized


Intervention Protocol

Patients were assigned to aggressive (SBP goal <140) or standard (SBP goal <180) arms with BP control achieved via nicardipine or, alternatively, via labetalol or diltiazem. Strict control within these parameters was maintained for 24 hours.

Outcome Measures

Primary

  • Modified Rankin scale of 4-6 (death or disability) at 3 months after randomization

Secondary

  • European Quality of Life–5 Dimensions (EQ-5D) scores at 3 months
  • Visual-analogue scale (VAS) at 3 months
  • Proportion of patients with 33% or more expansion in volume of hematoma on 24h delta scan
  • Safety outcomes (fall in GCS by 2 or increase of NIH Stroke Score by 4)
  • Incidence of serious adverse events within 72 hours

Results

“In conclusion, our results do not support the notion that acute reduction to a target systolic blood pressure of 110 to 139 mmHg in patients with intracerebral hemorrhage is more effective in improving functional outcomes than a reduction to a target systolic blood pressure of 140 to 179 mm Hg.”
 
 

Aggressive SBP reduction to a target of 110-139 mmHg did not result in lower rate of death or disability compared to the standard treatment goal of 140-179 mmHg. There was no difference between groups in mRS of 4-6 at 3 months (38.7% in intervention arm, 37.7% in control arm).


Interpretation

 Strengths

  •   Multi-centered trial
  •  Clinically meaningful outcomes

 Weaknesses

  • During the trial, ATACH-2 expanded enrollment from patients who presented within 3 hours to those who presented within 4.5 hours. As the authors acknowledge in the paper, this could mask a time-dependent loss of benefit but they deem this unlikely as subgroup analyses of INTERACT2 data did not demonstrate this phenomenon.
  • Intracerebral hemorrhage grouped as a single entity
  • Primary treatment failure (inability to achieve target BP within 2 hours) was seen in 12.2% of patients in the intensive-treatment group vs just 0.8% in the standard-treatment group. It’s difficult to interpret its impact on treatment effect.
  • 56.2% of patients were Asian making it difficult to generalize to primarily European populations though when subgroups extracted out again no clinically significant benefit to aggressive therapy was found.

The Bottom Line

As mentioned above, ATACH-2 serves as a rebuttal to the purported positive results of the INTERACT2 trial. On further analysis, the interpretation of INTERACT2 results was somewhat flawed and many experts have ultimately come to view it as a negative trial, consistent with ATACH-2. Dr. Rory Spiegel discusses this in more depth here.

As it stands, decisions should be made in conjunction with neurology and neurosurgery at your institution, but the literature at present does not support aggressive BP control and in fact this practice may lead to harm in the form of decreased cerebral perfusion. Standard SBP target of <180 mmHg should probably be maintained.


Expert Commentary

Intracerebral hemorrhage (ICH) is the most deadly form of stroke and has no FDA approved treatment . This is not to say nothing can be done, and the lack of specific therapies has heightened the importance of optimizing the management. Protocols to improve diagnosis, obtain appropriate imaging, obtain subspecialty care, screen for dysphagia, ensure rehabilitation assessments and accredit Stroke Centers are important. Within these broad strokes, hypotheses about which specific management strategies are likely to improve biomarkers and, subsequently, patient outcomes, can be rigorously tested.

Severe hypertension is both a risk factor and a cause of ICH. Hypertension is plausibly linked to growth of the hematoma, a proximate cause of worse patient outcomes. Thus, it is reasonable to test the hypothesis that lowering blood pressure reduces hematoma growth and, subsequently, improves patient outcomes.

INTERACT2 was negative for its primary endpoint of improved odds of good outcome with a dichotomous ordinal scale, while statistically significant for ordinal regression (a method to determine if there is a shift along the score) and health-related quality of life (HRQoL). ATACH-2 found no evidence of overall benefit to rapid blood pressure lowering, and an increased rate of renal failure. There was no evidence that rapid lowering of blood pressure reduced hematoma growth, which makes the potential mechanism of improved outcomes conjectural.

These studies highlight another problem: Outcomes assessment in clinical trials may be too crude to show meaningful differences between groups. Since INTERACT2 and ATACH-2 were designed, NIH has created, normed, and distributed new benchmarks for HRQoL, the Patient Reported Outcomes Measurement Information System (PROMIS) and Neuro-QOL. We have previously validated PROMIS and Neuro-QOL against ordinal scales, and found they highlight facets of HRQoL that are important, but not as well measured by ordinal scales while being more statistically powerful [4].  They are now generally accepted as pivotal outcomes for clinical research [5]. 

Aggressive blood pressure lowering is likely to be of some benefit; a target of 140 – 160 mm Hg systolic is reasonable for patients with systolic blood pressure <220 mm Hg pending the next update of evidence based guidelines. Going forward, accurate assessment of patient outcomes with sensitive, powerful scales will make clinical trials more meaningful, and more likely to be positive.

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Andrew Naidech, MD, MSPH

Professor of Neurology (Stroke and Neurocritical Care), Anesthesiology, Medical School Sciences, Neurological Surgery, and Preventive Medicine (Health and Biomedical Informatics), Northwestern University

 

 



References

  1. Flaherty ML, Haverbusch M, Sekar P, et al. Long-term mortality after intracerebral hemorrhage. Neurology 2006; 66:1182.
  2. van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010; 9:167.
  3. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368:2355.
  4. Naidech AM, Beaumont JL, Berman M, Francis B, Liotta E, Maas MB, Prabhakaran S, Holl J, Cella D.Dichotomous "Good Outcome" Indicates Mobility More Than Cognitive or Social Quality of Life.  Crit Care Med. 2015 Aug;43(8):1654-9. doi: 10.1097/CCM.000000000000108
  5. Salinas J, Sprinkhuizen SM, Ackerson T, Bernhardt J, Davie C, George MG, Gething S, Kelly AG, Lindsay P, Liu L, Martins SC, Morgan L, Norrving B, Ribbers GM, Silver FL, Smith EE, Williams LS, Schwamm LH.An International Standard Set of Patient-Centered Outcome Measures After Stroke.  Stroke. 2016 Jan;47(1):180-6. doi: 10.1161/STROKEAHA.115.010898. Epub 2015 Nov 24.

Posted on October 16, 2017 and filed under Neurology.

The PESIT Trial: Do All Syncope Patients Need a PE Workup?

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Written by: Alex Ireland, MD (NUEM PGY-2) Edited by: Josh Zimmerman, MD,  (NUEM class of 2017) Expert Commentary by: D. Mark Courtney, MD


Syncope is defined as a transient loss of consciousness and postural tone caused by cerebral hypoperfusion. This chief complaint is familiar to most emergency physicians given it accounts for more than 1-2 million patient visits in the US annually.[1]  The differential diagnosis is broad and crosses multiple organ systems, including, but not limited to, cardiovascular, neurovascular,  and hemorrhagic/hematologic causes.  Pulmonary embolism (PE) is one cardiovascular cause that is considered to be infrequent. This is because when associated with syncope, it is often made more clinically apparent by signs and symptoms such as dyspnea, chest pain, tachycardia, hypotension, and hypoxemia.  The American Heart Association consensus statement on the evaluation of syncope gives little attention to diagnostics for PE, instead focusing on arrhythmia, ischemia, and structural heart disease. [2]  We know from a San Francisco Syncope Rule validation trial that when adverse events occur in the minority of patients with generalized syncope, they are related mostly to cardiac arrhythmias, followed by MI- not PE. [3] Previous studies have cited the prevalence of pulmonary embolism as a cause of syncope in hospitalized patients as low as 1.6%. [4]  But are we underestimating and under-diagnosing this potentially lethal condition? The PESIT study sought to systematically assess the prevalence of pulmonary embolism in patients admitted for syncope. [5] 


Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope. Paolo Prandoni, M.D., Ph.D., Anthonie W.A. Lensing, M.D., Ph.D., Martin H. Prins, M.D., Ph.D., Maurizio Ciammaichella, M.D., Marica Perlati, M.D., Nicola Mumoli, M.D., Eugenio Bucherini, M.D., Adriana Visonà, M.D., Carlo Bova, M.D., Davide Imberti, M.D., Stefano Campostrini, Ph.D., and Sofia Barbar, M.D., for the PESIT Investigators*. N Engl J Med 2016; 375:1524-1531. October 20, 2016

What was the PESIT trial? 

Figure 1. Inclusion and Exclusion Flowchart

Figure 1. Inclusion and Exclusion Flowchart

    The PESIT trial was a cross-sectional study of patients older than 18 years of age who were hospitalized for a first episode of syncope. This was a multicenter trial, taking place in 11 hospitals (2 academic, 9 nonacademic) in Italy. There were several important exclusion criteria to this study including patients on anticoagulation, pregnant patients, and those with previous syncopal episodes.   Most importantly, however, the study excluded all patients discharged and solely focused on those admitted for an inpatient evaluation (Figure 1). 

 

    All included patients were subjected to a standardized history aimed at suggesting the cause of syncope and identifying risk factors for pulmonary embolism (Figure 2). They then underwent mandatory chest radiography, electrocardiography, arterial blood gas testing, and routine blood testing, including a D-dimer assay. Further diagnostic workup for causes other than pulmonary embolism was not standardized and varied between patients based on attending physician discretion.

Figure 2. Standardized History Questions

    The presence or absence of PE was assessed with a validated algorithm based on pretest clinical probability and the result of the D-dimer assay. The pretest clinical probability was defined according to the simplified Wells score, which classifies PE as being “likely” or “unlikely” (Table 1). In patients who had a high pretest clinical probability, a positive D-dimer assay, or both, computed tomographic pulmonary angiography or ventilation-perfusion lung scanning was performed.

 


Outcomes

    The primary outcome of the PESIT trial was to measure the prevalence of pulmonary embolism in patients admitted to the hospital for syncope. Secondarily, the thrombotic burden was assessed by measuring the most proximal location of embolus or the percentage of perfusion defect area.

    In 58.9% (339/560) of patients, PE was ruled out by low pre-test probability and a negative D-dimer. Of the remaining patients, 42.2% (97/229) had a pulmonary embolism. In the entire cohort, the prevalence of PE was 17.3% (97/560). Thus, the authors concluded that nearly one of every six patients hospitalized for a first episode of syncope has a pulmonary embolism (Figure 3, Table 2).

Figure 3. Results Flowchart

Figure 3. Results Flowchart


Strengths and Weaknesses of the Study

    The major strength of the PESIT trial is the systematic approach with which PE's were diagnosed. ALL admitted patients underwent consideration of and testing for PE based on risk factors and pretest probability. Even if, for example, the initial ECG suggested an arrhythmia as the cause of syncope, if they did not rule out for PE, they went on to get a scan. This ensured a complete and thorough investigation. Furthermore, their results were internally valid, as the prevalence of PE was consistently 15-20% across all 11 centers.

    Additionally, the population studied is also fairly representative of those who most emergency medicine physicians would admit to the hospital with syncope. Reasons for admission included trauma, severe comorbidities, failure to identify a cause in the ED, and a high probability of cardiac syncope. While we don’t commonly site the EGSYS score that they used, the components such as palpitations, heart disease, and an exertional component to syncope, are all considerations that factor into our clinical gestalt for admission.

    A glaring problem with this study is the significant variation in diagnostic workup beyond PE. Other potential explanations for syncope were much more likely to be undetermined in those with confirmed embolism (see table 2). Because further workup was left to the discretion of individual physicians, alternative and perhaps more causative causes of syncope may have been under-diagnosed or underreported.

    Furthermore, this study has limited external validity when used to assess our ED population as a whole, given the exclusion criteria of all patients discharged from the ED. When recalculating the prevalence based on all patients who presented to the ED, only 1 in 26 (97/2584 = 3.8%) patients were diagnosed with a PE, far fewer than their conclusive 1 in 6. A major contributing factor is likely age. As expected, the mean age of patients discharged was much younger at 54 years (range 16 to 79). These patients are much less likely to develop PE based on currently available decision rules such as the PERC Rule.

    We commonly use tools such as the PERC Rule or the Wells score to quantify our pretest probability because they include characteristics known to be associated with PE. As seen in the clinical characteristics described in table 2, patients diagnosed with pulmonary embolism had a high prevalence of symptoms commonly associated with PE, such as hypoxemia and tachycardia, or clinical manifestations of DVT. They were also far more likely to have a history of previous venous thromboembolism or to have active cancer. A large proportion of PESIT patients diagnosed with PE presented exactly as we would expect patients with a PE to present. These  data strengthen support for current clinical practice, which for most physicians means only entering the diagnostic pathway for pulmonary embolism when history and physical exam suggests it as a potential diagnosis.

    Lastly, the PESIT trial spends significant effort quantifying radiographic burden of pulmonary embolism across all their positive cases. As mentioned earlier, all patients were evaluated for PE, regardless of clinical gestalt. However, we must remember that degree of radiographic filling defect does not necessarily correlate with clinically significant pulmonary embolism. In 40% of patients with PE, the extent of pulmonary vascular obstruction was at the segmental or subesegmental level or was less than 25% of total lung area. Some of these may have been clinically insignificant, not likely to have caused the syncopal event, and perhaps were discovered incidentally. A better predictor for the severity of PE might have incorporated factors such as heart rate, systolic blood pressure < 100 mmHg, elevated BNP, and elevated troponins, which are used in the simplified PE Severity Index and a subsequently developed composite score to predict mortality from PE. [6,7}


Take Home Message

    In summary, Pulmonary embolism is an important “must-not miss” cause of syncope, but it is likely an uncommon diagnosis in patients who pass out, recover, and appear well – the main way that most patients in the US with syncope present. Overall, 1 in 26 patients who present to the ED with first time syncope may have a PE. A large portion of these may be clinically insignificant and not causative of syncope. Those with symptoms and signs of PE are more likely to have a significant PE and should be evaluated as such. Thus, we should not change our current clinical practice based on the results of the PESIT trial.


Expert Commentary

Internal validity:

Dr. Ireland’s review of the Prandoni study reviews it’s methods and results quite well.  He also points out the important ways in which we as consumers of literature should address a study.  The first is with respect to internal validity (how well the authors measured what they in fact intended to measure).  This takes into account potential for bias, or systematic ways in which error could be introduced into the measurement.  Dr. Ireland does not seem to identify many problems with this study from that standpoint.   In general I agree with this, if the goal of measurement of this study was to exhaustively test all patients who are admitted largely at the discretion of their doctors after a first event of syncope.  If so, then the methods of this paper seem to have resulted in reasonable internal validity.  However if the goal of the paper is to identify the prevalence of symptomatically significant PE among ALL patients with first time PE, then it is quite possible that there is bias due to the methods of inclusion.  Specifically, the fact that only admitted patients were included, and those admitted had a fairly large degree of comorbid conditions may have resulted in a measurement of PE that is higher than what would be expected for in general “syncope.”

External validity:

The second key question for a consumer of medical literature to ask is, simplistically, “are these patients like mine?”  The answer to this is probably no.  The patients included are different than a typical US ED "undifferentiated passing out patient" not just because they are Italian, but also because they had a high prevalence of symptoms to suggest PE such as history of PE/DVT,  or history of malignancy. In the US, we would probably not consider many of these patients to be “undifferentiated syncope.” Rather, we would consider them to be possible symptomatic PE patients and simply test them.  Dr. Ireland points this out in his evaluation of table 2.  It is not a novel finding that many of the patients with these comorbidities, signs, and symptoms went on to have PE when tested (Courtney Annals of EM Annals of Emergency Medicine 2010;55(4):307–315).

Another way to examine generalizability is to examine the course of these syncope patients and ask if this is similar to the course that would be taken in the US. Of the 2584 ED syncope patients in this study, 1867 were discharged. Are we discharging 72% of our syncope patients?  Whether or not we should be is another question.  However,  it is likely that the US ED environment has a much lower threshold for admission for syncope than the Italian setting, similar to the way that the US ED environment has a much lower threshold for testing for PE than the European setting.  Therefore, it is highly likely that, at least to some extent, these Italian syncope patients are more ill than the average US ED syncope patient.  This is supported by the elderly median age in the Prandoni study of 80….meaning half of all their patients were over 80 years of age!  Also note that of the 717 remaining patients not discharged, a further 157 were excluded.  So this sample really is a unique selected group…..making it difficult to generalize this study to the average US ED patient with syncope.  

Dr. Jeff Kline and I explored the possible external generalizability of this report in a re-examination of the PERC dataset which included 7940 patients from 12 US emergency departments, all of whom had  symptoms prompting testing for PE.  Among 466 PE positive patients, 6.6% reported syncope, while among 7474 PE negative patients 6.0% reported syncope (95% CI for difference, -1.7 - 3.0).  This suggested syncope was not a predictor of PE. We also noted in the Prandoni study a mean age of 75 and a high prevalence of main pulmonary artery clot (42%), something we have not found in US studies of undifferentiated PE patients where median percent obstruction was 9%.

Bottom line: 

In elderly syncope patients with some combination of tachycardia, tachypnea, hypotension, active cancer, and perhaps especially those without a clear suspected cause of syncope, PE should be a consideration that warrants testing.  Perhaps this should be considered even when patients do not have the more traditional symptoms of PE such as dyspnea or chest pain.  However, we would caution clinicians NOT to interpret this study as rationale for widespread testing on all or nearly all US ED syncope patients.  The outcome of such a simplistic interpretation of this study would undoubtedly result in further radiation and contrast burden and harms for our patients.

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D. Mark Courtney, MD

Associate Professor of Emergency Medicine and Medical Social Sciences, Northwestern Emergency Medicine


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How to cite this post

[Peer-Reviewed, Web Publication] Ireland A,  Zimmerman J (2017, Sep 27). The PESIT Trial: Do All Patients Need a Syncope Workup?  [NUEM Blog. Expert Commentary By Courtney DM]. Retrieved from http://www.nuemblog.com/blog/PESIT


Resources

1. Syncope Evaluation in the Emergency Department Study (SEEDS): A Multidisciplinary Approach to Syncope Management. Win K. Shen, Wyatt W. Decker, Peter A. Smars, Deepi G. Goyal, Ann E. Walker, David O. Hodge, Jane M. Trusty, Karen M. Brekke, Arshad Jahangir, Peter A. Brady, Thomas M. Munger, Bernard J. Gersh, Stephen C. Hammill and Robert L. Frye. Circulation. 2004;110:3636-3645.

2. AHA/ACCF Scientific Statement on the evaluation of syncope: from the American Heart Association Councils on Clinical Cardiology, Cardiovascular Nursing, Cardiovascular Disease in the Young, and Stroke, and the Quality of Care and Outcomes Research Interdisciplinary Working Group; and the American College of Cardiology Foundation: in collaboration with the Heart Rhythm Society: endorsed by the American Autonomic Society. Strickberger SA, et. Al. American Heart Association Councils on Clinical Cardiology, Cardiovascular Nursing, Cardiovascular Disease in the Young, and Stroke; Quality of Care and Outcomes Research Interdisciplinary Working Group. American College of Cardiology Foundation.; Heart Rhythm Society.; American Autonomic Society. Circulation. 2006 Jan 17;113(2):316-27. No abstract available. Erratum in: Circulation. 2006 Apr 11;113(14):e697.

3. Prospective validation of the San Francisco Syncope Rule to predict patients with serious outcomes. Quinn J, McDermott D, Stiell I, Kohn M, Wells G.. Ann Emerg Med. 2006 May;47(5):448-54.

4. Etiology of syncope in hospitalized patients. Saravi M, Ahmadi Ahangar A, Hojati MM, Valinejad E, Senaat A, Sohrabnejad R, Khosoosi Niaki MR. Caspian J Intern Med. 2015 Fall;6(4):233-7.

5. Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope. Prandoni P, Lensing AW, Prins MH, Ciammaichella M, Perlati M, Mumoli N, Bucherini E, Visonà A, Bova C, Imberti D, Campostrini S, Barbar S; PESIT Investigators. N Engl J Med. 2016 Oct 20;375(16):1524-1531.

6. Jiménez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170:1383.

7. Jiménez D, Kopecna D, Tapson V, et al. Derivation and validation of multimarker prognostication for normotensive patients with acute symptomatic pulmonary embolism. Am J Respir Crit Care Med 2014; 189:718.


Posted on September 26, 2017 and filed under Cardiovascular.

The Waiting Game: Biphasic Anaphylaxis

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Written by: Kumar Gandhi, MD, MPH (NUEM PGY-2) Edited by: Andrew Moore, MD, MS (NUEM PGY-4) Expert Commentary by: Aaron Kraut, MD


Case Scenario

18 y.o. female with history of asthma and multiple food allergies presents with rash and
shortness of breath following ingestion of assortment of cookies at a Halloween party. A diffuse erythematous pruritic rash started fifteen minutes following the ingestion of cookies. Associated symptoms include tingling in the back of the throat and wheezing. The patient reports one prior episode requiring use of an EpiPen, but she never refilled her prescription.


Vitals: HR: 90, RR: 25, BP: 105/70, Temp: 98.6, SpO2: 97% on room air


Pertinent findings on physical exam include:

  • Mild pharyngeal edema with no uvular deviation.
  • Moderatewheezing in bilateral lung fields
  • Diffuse abdominal tenderness
  • Blanching (urticarial) rash on the back,nabdomen, axilla, femoral creases, and posterior legs.

An Epi-Pen injection in the right thigh, coupled with concomitant 125mg of methylprednisolone IV Push, 25mg of Benadryl IV push [1] results in decreased wheezing and resolution of the urticarial rash.


Now that the patient is stable we need to ask ourselves a few important questions:

  1. Was this an allergic reaction or anaphylaxis?
  2. When can we discharge the patient?

Anaphylaxis: Overview


Anaphylaxis is a life-threating systemic hypersensitivity reaction. Pathophysiology includes [1]:

  • IgE-mediated Type 1 hypersensitivity reaction
  • Degranulation of mast cells releases vasoactive mediators including histamine, prostaglandins, and leukotrienes
  • Histamine mediates systemic vasodilation, cardiac contractility, and vascular permeability
  • Leukotrienes mediate vascular permeability and in combination with prostaglandins cause bronchoconstriction

 

Common Triggers:

Screen Shot 2017-09-11 at 10.10.23 AM.png
  • Foods: Peanut, tree nut, shellfish, finned fish, milk, egg
  • Insects: Insect stings and Insect bites
  • Medications: Antibiotics, Aspirin, and NSAID’s
  • Biologic materials: Monoclonal antibodies, chemotherapy, vaccines
  • Physical Factors: Exercise, cold, heat
  • Iatrogenic: Latex and radiocontrast agents

 

Signs and Symptoms of Anaphylaxis [2]:

  • Skin and mucosal symptoms occur in 90% of episodes
  • Respiratory symptoms and signs occur in up to 70% of episodes
  • GI symptoms such as nausea, vomiting, and diarrhea occur in 45% of episodes
  • Cardiovascular symptoms such syncope, dizziness, and tachycardia can occur in 45% of episodes

 


NIAID/FAAN Criteria for the Diagnosis of Anaphylaxis [3]

Diagnosis of Anaphylaxis:

  • Anaphylaxis is primarily a clinical diagnosis.
  • Diagnosis of anaphylaxis is made when any one of three NIAID/FAAN diagnostic criteria are fulfilled.

A 2012 retrospective cohort study of the NIAID/FAAN criteria demonstrated 97% sensitivity and 82% specificity for the diagnosis of anaphylaxis in 214 ED patients [3].

 

 

What is Biphasic Anaphylaxis?

Biphasic anaphylaxis is an anaphylactic episode followed by an asymptomatic period with return of anaphylactic symptoms in the absence of further exposure to the triggering antigen [4]. Incidence of secondary reaction following primary anaphylactic reaction can range from 1% to 23%, and
occurs in up to 23% of adults and up to 11% of children. [4] [5] [6]. The time interval from primary to secondary reaction ranges from 1 to 72 hours, though predominantly occurs within 8 hours of primary event [6].


Risk Factors for Biphasic Anaphylaxis


Predicting the occurrence of a biphasic reaction poses a diagnostic challenge. Previously studied risk factors for the development of biphasic anaphylaxis include [4]:

  • Severity of the primary anaphylactic reaction
  • Time from exposure of antigen to development of the primary response
  • Presence of hypotension or laryngeal edema
  • History of a previous biphasic reaction or asthma
  • Time to delivery of epinephrine for primary anaphylaxis [7]
  • Initial dosing of epinephrine in treatment of primary anaphylaxis [8]

 

How long should we watch patients?


Previous Practice
World Allergy Organization 2011 guidelines recommend an individualized approach, ranging from at
least 4 hours for patients with moderate respiratory or cardiovascular compromise to up to 8-10 hours or
longer if indicated for a protracted anaphylactic response. [9]


Often referenced in the anaphylactic observation time conundrum, Ellis et al. performed a 3-year
prospective study in a Canadian tertiary hospital, which found 103 cases of true anaphylaxis with a
19.4% occurrence of biphasic reactivity and an average time of secondary reaction onset of 10 hours.
Biphasic reactivity occurred in 60% cases before 10 hours [8]. The increased prevalence of biphasic reactions in this study is likely secondary to inclusion of all biphasic reactivity, including recurrent minor reactions and reactions that were not truly biphasic requiring epinephrine. [8] [10].


Current Literature
New literature indicates a much lower prevalence of clinically significant biphasic anaphylaxis. Gruanau et al. performed a retrospective chart review of 2,819 adult ED patients at two large urban ED’s
over a five-year span. 496 patients were classified as anaphylactic, of the total number of anaphylactic
patients evaluated only 5 (0.18%) had clinically significant biphasic reactions and zero mortality. Of the 3
patients that actually left the ED, the biphasic reaction occurred up to 6-days post-discharge, indicating
these reactions could occur at any time after discharge. This study concluded given such a low prevalence
of biphasic anaphylaxis, zero mortality, and variability in time to the secondary reaction it is unnecessary
to observe patients following resolution of symptoms [10] [11] [12].


Rohacek M et al. also performed a retrospective chart review 1,334 adult ED patients in a Swiss tertiary
care hospital over a 12-year span. 495 patients met the diagnosis of anaphylaxis, of which only 12 (2.3%)
were clinically significant anaphylactic reactions, with only 2 (0.36%) occurring in the hospital. Similar to
the Gruanau et al. study there were no deaths during the 10-day follow-up period. The study also
demonstrated no difference in the biphasic response rate for those patients watched for less than 8-
hours vs greater than 8 hours. [10] [13].


The new literature indicates a prevalence of 0.18%-2.3% clinically significant biphasic anaphylactic
reactions and zero mortality over the 4100 patients who were included in both studies. This indicates it is
likely safe to discharge patients home following resolution of their anaphylactic episode.


Recommendations/Take Home Points


Consider 1-hour observation period following resolution of symptoms for those patients [10]:

  • Promptly and adequately treated with Epi-Pen and demonstrate early resolution of symptoms
  • Patients who can be trusted with strong return precautions and with ability to access medical interventions should a biphasic response occur and demonstrate competence with utilizing an Epi-Pen at home [9]
  • 1-hour observation period is to ensure no recurrence of anaphylaxis following complete metabolism of epinephrine [10]

Consider observation time of 4-8 hours for those patients with:

  • Previous episodes of biphasic anaphylaxis or history of asthma [4]
  • Anaphylaxis with severe features including refractory hypotension, laryngeal edema, and respiratory compromise [4]
  • Patients who may have experienced significant delays in treatment with epinephrine or received a subtheraputic initial dose of epinephrine [7] [8]

Anaphylaxis Discharge Instructions
The discharge process presents a critical opportunity to educate patients about the signs and symptoms of a potential biphasic episode of anaphylaxis as well as provide the necessary education and tools for a patient to quickly intervene should a future episode of anaphylaxis occur. Per World Allergy Organization guidelines for the assessment and management of anaphylaxis, discharge management should include [9]:

World Allergy Organization Discharge Management Guidelines [9]


Expert Commentary

This is a great summary of an important and controversial topic. In my relatively short career as an emergency physician, I’ve probably heard 17 different answers to the seemingly simple question of how long to observe someone with anaphylaxis in the ED.  

You did a very nice job of summarizing the best available evidence to guide our practice as emergency physicians. A few key points I’ll highlight again for emphasis:

  1.  Not all allergic reactions are anaphylaxis- in a nutshell, you need multisystem organ involvement (usually skin/mucosa +respiratory or GI) or skin/mucosal involvement and hypotension to have anaphylaxis.

  2.  Severe biphasic responses are RARE and vary greatly in their time to onset

One of my biggest take homes on this topic comes from the Grunau 2014 Annals of EM article.  In that study, all of the severe/clinically significant biphasic anaphylactic reactions occurred in patients who did not meet the diagnostic criteria for anaphylaxis on their initial ED visit.   In my mind, this represents a huge opportunity for education and preemptive intervention in our emergency department patients who present with moderate/severe allergic reactions in general.

If I treat a patient for a moderate/severe allergic reaction with diphenhydramine and steroids, I universally discharge that patient with a prescription for an EpiPen and an explicit warning about the rare event of a biphasic reaction. Ideally, if they are one of those rare few who has a biphasic reaction because of an ‘inadequately treated’ initial reaction (one of the risk factors for a biphasic reaction), I’d like them to be able to administer life-saving epinephrine before they arrive back to the ED.

As far as the question of how long to observe once we’ve pulled the trigger on IM epinephrine in the ED, there is still no magic formula despite the several well-conducted studies you’ve reviewed here.

For me, it comes back to patient education. Since we know we cannot reliably predict the time to onset of biphasic symptoms, I do not put a strict time limit on patient observation after Epi administration. However, I will offer several criteria that a patient must meet before I’m comfortable with discharge.

  1. Objective airway findings must be resolved (uvular, lip/tongue edema, change in voice)
  2. Skin findings must be stable or improving
  3. Hemodynamics must be normal

Some patients may satisfy those criteria 45 minutes after Epi administration, while others may take 120 minutes or longer.  If my patient has worsening skin findings or continued objective airway findings at >120minutes, I will usually admit them for close monitoring and consideration of repeat epi dosing. 

If a patient meets the aforementioned discharge criteria, then it’s time for the education piece. If I know that the patient understands the signs and symptoms of a recurrent or biphasic anaphylactic reaction, has an Epi-Pen and knows how to use it, and understands that he/she must return to the ED immediately if he/she uses the Epi-Pen, I will discharge the patient as early as 40min-1hr after ED arrival. My thought is that there isn’t much to be gained from observation, where any worsening of symptoms would prompt re-administration of epinephrine (which the patient can accomplish themselves). The key, however, is that the patient understands the necessity of immediately returning to the ED upon re-dosing of epinephrine.

Finally, I am not personally a fan of the 4-8 hour observation, as I don’t believe there is much to be gained by keeping a patient in the ED for that amount of time. Either they respond to epinephrine and rapidly improve, or they do not respond and require repeated dosing or close airway monitoring/intervention for continued objective airway involvement. I’ll decide to admit many of these patients within the first 15 minutes of their ED stay. These rapid “decision to admit” patients also include those with anaphylactic shock (persistent hypotension or altered mental status/end-organ dysfunction), or severe objective airway findings (e.g. stridor, hypoxemia) on ED arrival.

And with that, you have an 18th different answer to the question of how long to observe someone with anaphylaxis in the ED. But do remember that biphasic anaphylaxis can also occur in patients who did not present with frank anaphylaxis on their initial ED visit. Be mindful of your discharge instructions for all allergic reactions and consider prescribing Epi-Pens to those whom you treat with diphenhydramine and steroids.

Screen Shot 2017-09-11 at 9.55.17 AM.png

 

Aaron Kraut, MD

Assistant Professor, Assistant Program Director, University of Wisconsin Emergency Medicine


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How to cite this post

[Peer-Reviewed, Web Publication] Gandhi K,  Moore A (2017, Sep 12). The Waiting Game: Biphasic Anaphylaxis.  [NUEM Blog. Expert Commentary By Kraut A]. Retrieved from http://www.nuemblog.com/blog/anaphylaxis


References

  1. Adams, James “immune System Disorders. “Emergency Medicine: Clinical Essentials. Philadelphia, PA: Elsevier/Saunders, 2013 924-28. Print.
  2. Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis--a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115:341.
  3. Campbell RL, Hagan JB, Manivannan V, et al. Evaluation of national institute of allergy and infectious diseases/food allergy and anaphylaxis network criteria for the diagnosis of anaphylaxis in emergency department patients. J Allergy Clin Immunol 2012; 129:748
  4. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol. 2005;95:217e226. III
  5.  Rohacek, M, H Edenhofer, A Bircher, and R Bingisser. 2014. Biphasic anaphylactic reactions: occurrence and mortality. Allergy, no. 6 ( 12). doi:10.1111/all.12404. 
  6. Tole JW, Lieberman P. Biphasic anaphylaxis: review of incidence, clinical predictors, and observation recommendations. Immunol Allergy Clin North Am 2007;27:309–326.
  7.  Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000; 106:762.
  8. Ellis AK, Day JH. Incidence and characteristics of biphasic anaphylaxis: a prospective evaluation of 103 patients. Ann Allergy Asthma Immunol 2007; 98:64.
  9. Simons FE, Ardusso LR, Bilo MB, El-Gamal YM, Ledford DK, Ring J et al. World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 2011;4:13–37.
  10. Swaminathan, Anand, and Salim Rezaie. "REBELcast Episode 1." Audio blog post. REBEL E.M. N.p., 1 July 2014. Web.
  11. Grunau BE et al. Incidence of Clinically Important Biphasic Reactions in Emergency Department Patients with Allergic Reactions or Anaphylaxis.
  12. Swaminathan, Anand. "SGEM#57: Should I Stay or Should I Go (Biphasic Anaphylactic Response)." Blog post. N.p., 13 Dec. 2013. Web.
  13. Rohacek, M, H Edenhofer, A Bircher, and R Bingisser. 2014. Biphasic anaphylactic reactions: occurrence and mortality. Allergy, no. 6 ( 12). doi:10.1111/all.12404. 

Posted on September 11, 2017 and filed under Pharmacology.

Inguinal Hernia Imaging and Reduction

Written by: Jesus Trevino MD, MBA (NUEM PGY-3) Edited by: Samia Farooqi, MD (NUEM 2016 Graduate) Expert Commentary by: Adriana Segura Olson, MD


Case

Mr. FJ is a 84 year old male with history of bilateral inguinal hernias status post repair with mesh 26 years ago who presents with constipation.  Five days ago, he suffered from a profuse diarrheal illness that also affected his household members.  Two days ago, he developed constipation with gradually progressive abdominal bloating, belching, and today bilious emesis.  On exam, he is afebrile, hemodynamically stable with moderate abdominal distention and right inguinal swelling that is tender, non-mobile and without overlying skin changes.

A CT abdomen and pelvis revealed a small bowel obstruction secondary to a right-sided incarcerated inguinal hernia!


Types of abdominal hernias

Abdominal hernias can be classified based on etiology (i.e., congenital vs acquired) and location (Adams): 

A retrospective review of 2510 hernia repairs from a single institution in Scotland (1985-2008) found the following distribution of abdominal hernias by location (Dabbas):

  • Inguinal (70.7%)

  • Umbilical (13.9%)

  • Epigastric (6.6%)

  • Incisional (4.7%)

  • Femoral (3.7%)

  • Spigelian/other (0.4)

Of inguinal hernias, the indirect form account for 65% of cases (Adams).

Clinical presentation and physical exam findings

Patient characteristics associated with an increased risk of abdominal hernia include (Fitzgibbons):

  • Male sex

  • Lower BMI

  • Family history of abdominal hernia

  • COPD

  • Smoking

  • Collagen vascular disease

  • Thoracic or abdominal aortic aneurysm

  • Open abdominal surgery

  • Peritoneal dialysis

On presentation, patients typically complain of abdominal or scrotal pain with or without superficial abdominal wall swelling that may worsen with maneuvers that increase intra-abdominal pressures (Adams).  There may be a preceding event involving heavy lifting, coughing or other form of straining.  (Adams).  Symptoms such as nausea, emesis, constipation, and abdominal distention raise concern for small bowel obstruction.

On exam, inspection may reveal swelling in a ventral, umbilical, inguinal or femoral location.  Often, the swelling can be reduced with gentle pressure - a reducible hernia; those that cannot be reduced at bedside are classified as incarcerated hernias.  Tenderness to palpation and overlying skin changes, such as red, purple or blue coloration, increases suspicion for strangulated hernia.

Imaging

CT abdomen and pelvis is a good imaging modality to assess for abdominal hernia, especially when there is concern for acute incarceration or strangulation.  CT findings include a “zone of transition” depicting a change in diameter of small bowel from dilated to a normal or decreased diameter such as the “pinch point” seen in the case image.  Signs concerning for strangulation include engorged vessels within incarcerated hernia, fat stranding and thickened bowel wall (Strange).

A prospective study in Australia of patients with abdominal pain presenting to an ambulatory practice showed CT without contrast was 90% sensitive and 97% specific for the diagnosis of abdominal hernia, yielding a LR+ 26 and LR- 0.10 (Garvey). Assuming greater acuity of symptoms in the Emergency Department is associated with greater anatomical abnormalities more easily detected on CT, these test statistics can be generalized to the emergency setting.

Reduction

Bedside reduction is indicated when a hernia is incarcerated without evidence of strangulation.  Signs suggestive of necrosis of hernia contents include peritonitis and erythema or necrosis of the overlying skin (Adams).

To prepare for reduction, place the patient supine in Trendelenburg (-20 degrees) with an ice pack overlying the area of swelling (Roberts).  In addition to procedural sedation, immediate pain control soon after ED arrival facilitates abdominal wall muscle relaxation and increases likelihood of reduction success, sometimes even spontaneously when the patient is properly positioned.

Next, palpate the outline of the abdominal wall defect with the nondominant hand and place gentle inward pressure with the dominant hand at the base (i.e., the most proximal portion) of the hernia contents to slide the contents intra-abdominally.  As the hernia contents slide through the abdominal wall defect, take care to avoid completely collapsing the lumen of the trapped small bowel at the “pinch point” as this will lead the remaining trapped bowel to distend (i.e., the ballooning effect), exceed the dimension of the wall defect and reduce the chances of a successful reduction at the bedside.

Disposition

Reducible abdominal wall hernias without signs of bowel ischemia can be discharged with appropriate outpatient general surgery follow-up for elective repair.

Hernias that remain incarcerated or have evidence of strangulation require general surgery consult for eventual OR reduction.  Factors associated with difficult bedside reduction include duration of incarceration and small abdominal wall defect.


Case resolution

Bedside reduction failed; in retrospect, there was a low likelihood success based on the small “pinch point” (1.3 cm) relative to the bulk of the hernia contents.  Mr. FJ was admitted and underwent open inguinal hernia repair with small bowel resection, primary anastomosis and discharged on post-operative day 14.


Expert Commentary

This is an excellent summary by Dr. Trevino of the Emergency Department management of hernias with respect to imaging and reduction.

As mentioned in this post, it is important to determine whether an incarcerated hernia is associated with strangulation, which indicates bowel necrosis. Hernias that are clearly strangulated should not be reduced at the bedside and surgical consultation is warranted; however, these are not always easily distinguishable on physical exam. While patients with incarcerated hernias without strangulation can present with systemic symptoms including nausea and vomiting, signs of strangulation include toxic appearance of the patient, significant systemic symptoms, or pain that persists after reduction of the hernia. A lactate is often sent in cases of an incarcerated hernia, but its sensitivity and specificity is limited and therefore, when there is a high index of suspicion, a normal lactate level should not be used to rule out strangulation (Derikx). 

We often feel reassured with a normal lactate, but be wary of relying on this test and don’t let your surgical consultants rely too heavily on the lactate either!

It’s worth mentioning cases of internal hernias, which involve bowel protrusion through the peritoneum or mesentery into another compartment in the abdominal cavity. While rare, they are important to keep on the differential of undifferentiated abdominal pain as they can lead to small bowel obstruction or bowel necrosis. Internal hernias can be difficult to diagnose clinically because their presentation is often vague and intermittent, and they are not palpable on physical exam. CT scan of the abdomen and pelvis is the diagnostic modality of choice and this imaging may be normal in cases of reducible internal hernias. When diagnosed, prompt surgical consultation is indicated.

 

Adriana Segura Olson, MD

Assistant Professor, UT San Antonio Department of Emergency Medicine


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How to cite this post

[Peer-Reviewed, Web Publication] Trevino J,  Farooqi S (2017, Aug 15). Inguinal Hernia Imaging and Reduction.  [NUEM Blog. Expert Commentary By Olson AS]. Retrieved from http://www.nuemblog.com/blog/hernia-reduction


References

Adams, James. Emergency Medicine: Clinical Essentials. Philadelphia, PA: Elsevier/Saunders, 2013. Print.

Dabbas, N., K. Adams, K. Pearson, and G. Royle. "Frequency of Abdominal Wall Hernias: Is Classical Teaching out of Date?" JRSM Short Reports 2.1 (2011): 5. Print.

Garvey, J. F. W. "Computed Tomography Scan Diagnosis of Occult Groin Hernia." Hernia 16.3 (2011): 307-14. Print.

Roberts, James R., Catherine B. Custalow, Todd W. Thomsen, and Jerris R. Hedges. Roberts and Hedges' Clinical Procedures in Emergency Medicine. Print.

Solomon, Caren G., Robert J. Fitzgibbons, and R. Armour Forse. "Groin Hernias in Adults." New England Journal of Medicine N Engl J Med 372.8 (2015): 756-63. Print.

Strange, Chad D., Krista L. Birkemeier, Spencer T. Sincleair, and J. Robert Shepherd. "Atypical Abdominal Hernias in the Emergency Department: Acute and Non-acute." Emerg Radiol Emergency Radiology 16.2 (2008): 121-28. Print.

Derikx, Joep P.m., Dirk H.s.m. Schellekens, and Stefan Acosta. "Serological markers for human intestinal ischemia: A systematic review." Best Practice & Research Clinical Gastroenterology 31, no. 1 (2017): 69-74.

Adriana Segura Olson, MD. Assistant Professor, Assistant Program Director, Department of Emergency Medicine, University of Texas Health San Antonio

AAA-OK: Approach to Imaging of Abdominal Aortic Aneurysm

Around 30% of symptomatic abdominal aortic aneurysms (AAAs) are misattributed to non-vascular causes, leading to poor outcomes. This post offers an approach to imaging of symptomatic and ruptured AAA's and presents data demonstrating that bedside ultrasound is a powerful tool when this diagnosis is in the differential. 

When Our Minds Lead Us Astray: Cognitive Bias in the Emergency Department

As anyone who has spent time in the ED can attest, emergency physicians are faced with a constant stream of decisions to make. In order to help navigate this challenging milieu of constant decision making, experienced emergency physicians rely on cognitive shortcuts. This post highlights the cognitive biases that creep into medical decision making and cognitive shortcuts, and how to prevent those biases from negatively impacting patient care. 

Priapism: The ED-Focused Approach

 

Written by: Aaron Quarles, MD (EM Resident Physician, PGY-3, NUEM), Emmanuel Ogele, MS4, Northwestern University Feinberg School of Medicine ; Edited by: Meghan Quigley, MD (NEUM 2017 Graduate); Expert Commentary by: Nelson Bennett, Jr., MD


The Case

An otherwise healthy 36 year old man presents to the emergency department late on a Saturday night. You enter the exam room to find a man who appears anxious and cannot seem to get comfortable. He immediately informs you that he is in the adult film industry and they were doing a shoot earlier in the day. He states that he took Viagra, but was unable to achieve an erection as rapidly as needed. So he injected an intracavernosal prostaglandin E1 with rapid and resolute effect.

Despite the popular refrain to “seek immediate medical help for erections lasting more than 4 hours,” your patient waited until hour 9 before presenting. He was thorough, however, in his attempt to detumesce; employing such strategies as repeated masturbation, warm baths, alcohol, and even cocaine (the latter two may actually cause priapism!).

Physical exam revealed an extremely firm, fully erect penis that was painful to touch. The glans was soft and not discolored. At this point, all the patient can say is, “Please doc, you have to help me.”


A Bit About Priapism

Priapism is most commonly defined as an erection lasting longer than 4 hours and is unrelated to sexual stimulation. Between 2006 and 2009, somewhere between 5 and 8 visits per 100,000 male subjects to the emergency department (ED) in the United States were due to priapism. In adult males, erectile dysfunction drugs are the usual culprit, accounting for up to 25% of presentations. There is also a notable increase in incidence during the summer months and in patients with sickle cell disease, leukemia, pelvic tumors, & trauma [1,2,3].

What is the pathophysiology behind this condition?

Ischemic priapism occurs secondary to obstruction of venous outflow. The nitric oxide-phosphodiesterase-5 (NO-PDE5) pathway has been implicated in the pathogenesis of ischemic priapism. Dysregulation of this pathway leads to failure to control vasodilation, which in turn leads to prolonged arterial inflow and subsequent obstruction of venous outflow. This causes prolonged erection and ischemia in the penis [3,4].

Non ischemic priapism is not caused by obstruction but rather is due to extravasation of blood into the corpus cavernosum from an arterial fistula. This is less common than the ischemic variant and often happens in the setting of trauma to the perineum (think bicycle seats and other straddle injuries).

A third type of priapism, known as stuttering priapism, represents unwanted intermittent erections usually lasting 3 hours and confined mostly to the sickle cell population. Given its veno-occlusive pathophysiology, stuttering priapism is akin to a self-limited ischemic priapism. These patients are sometimes managed with self-injection of sympathomimetic agents.

How can I distinguish between the types of priapism and why is it important to do so?

It is important to distinguish ischemic from non-ischemic priapism because ischemic priapism is a urologic emergency. This is the first step in management. In ischemic priapism, microscopic changes begin to occur at 4 hours of persistent erection and irreversible fibrotic damage occurs after 24 hours. 90% of cases lasting over 24 hours develop erectile dysfunction with severe impairment in sexual function, which is why early intervention along with counseling the patient on likely outcomes is critical.

Is a physical exam necessary for patient presenting with priapism?

Although presentation is usually self-evident, a fast, focused physical examination of the genitals, perineum and abdomen are warranted. Ischemic priapism will usually present with a painful, tender and a fully rigid phallus. Non-ischemic is usually less rigid and less painful. Abdominal and perineal inspection are helpful to rule out any other traumatic injuries.


Management in the ED

Ischemic Priapism

Once the diagnosis of ischemic priapism has been made, intervention is required to prevent long term dysfunction. Underlying conditions such as sickle cell, should be considered and treated as appropriate (hydration, O2 etc), but they should not delay treatment of priapism. A general approach to management of ischemic priapism is demonstrated below:

Analgesia → Systemic Vasodilators → Direct Vasoconstrictor → Aspiration/Irrigation → Urologic surgery

 Provide oral or parenteral analgesia as appropriate. You may consider systemic vasodilators such as terbutaline (Roberts and Hedges recommends 0.25 to 0.5 mg subQ q15minutes; or 5mg PO once). However, the AUA guidelines suggest no indication for oral systemic vasodilators given limited efficacy. And let’s be honest, the next steps provide significantly more bang for your buck.

Both the European and American Urological Associations recommend cavernosal aspiration and intracavernosal sympathomimetic injection as the treatment of choice. When sympathomimetic injection was added to aspiration and irrigation there was a significant associated increase in resolving priapism [7].

But first, provide local anesthesia. A dorsal penile nerve block can be achieved using a 27-gauge needle and 1% lidocaine (without epinephrine). Raise a skin wheal at the 10 and 2 o’clock positions of the penis as close to the base as possible. Inject through the wheals in a medial direction, being careful to avoid cavernous artery injury. Alternatively a subcutaneous ring block over the dorsal aspect of the penis is effective. Or simply anesthetize the skin on either side of the mid penile shaft where you anticipate entering for aspiration. Be careful to avoid superficial veins.

 
 

Next, sterilely attach a 19 or 21 gauge butterfly needle to a syringe or tubing irrigation system of your choice (a useful video demonstrating a convenient way to set up aspiration and irrigation tubing by Dr. Larry Melick ).

Direct the butterfly needle into the now anesthetized 10 or 2 o’clock position of your choice and begin to aspirate. Advance carefully until you get return of dark venous blood. The corpora communicate, so in most cases, only one side needs to be aspirated. If one side isn’t working, try the other. After about 30-60 cc’s of blood are removed, if priapism persists, irrigation with 10-20 ml aliquots of saline or a diluted phenylephrine solution may be attempted. Continue with this approach until the dark venous blood becomes bright red or until flaccidity is achieved.  

Alternatively, direct injections of phenylephrine diluted to a concentration of 100-500 mcg/mL dosed in 1 mL injections can be performed every 3-5 minutes. Treatment failure is considered after one hour of these injections. Patients should be placed on a cardiac monitor while administering these medications given the risk of systemic effects (severe hypertension, dysrhythmia). Proceed with caution in those patients with such underlying conditions.

If these methods fail, urgent urological consultation is required for possible placement of a corpus cavernosum-spongiosum shunt.

 

Pearl: Phenylephrine is less capable of binding its receptor in acidotic conditions. Thus in patients presenting with 2-3 days of sustained erection, although one should try Phenylephrine as first line, keep in mind this patient will most likely need surgery and should be moved to the OR faster. 

Pearl: For patients with a positive history of sickle cell disease, ischemic priapism is managed in the same way it is when caused by other etiologies. In addition, narcotic analgesia, IV hydration, supplemental oxygen, and alkalization is indicated. 

 

Non – ischemic Priapism

Non-ischemic priapism is not an emergency. Management consists of observation with the expectation that it will resolve spontaneously.

Pitfall: Injection of sympathomimetics is not recommended as arterial flow will distribute the drug promptly into systemic circulation. In the setting of trauma, other injuries should be managed accordingly. If non – ischemic priapism does not resolve spontaneously, it can be treated by embolization of the fistula in the IR suite [10].


Disposition

Following successful aspiration, observation is recommended. The patient may be sent home with urology follow up.


Pearls and Pitfalls:

  • A good history can often distinguish between ischemic and nonischemic priapism
  • Time is functional penis
  • Providing proper analgesia is critical, dorsal penile nerve block makes you and your patient’s life easier
  • Intracorporeal injection = intravenous injection (patients should be placed on a monitor when administering vasoactive agents & caution should be taken in severe hypertension, dysrhythmias, etc)
  •  Be mindful that this can be embarrassing and traumatic for patients so care should be taken in addressing the patient as a whole

Expert Commentary

Definition and Etiology

Table 1: Causes of Priapism

Priapism, a prolonged erection lasting more than 4 hours in the absence of sexual stimulation, is a urologic emergency that can result in ischemia, corporal fibrosis, and erectile dysfunction[15].   The duration of corporal ischemia results in variable reversible and irreversible smooth muscle and endothelial injury with histologic changes seen by 12 hours[16].  After 48 hours of ischemia, there is permanent smooth muscle cell death and erectile dysfunction[16-18].  Incidence of all-cause priapism has been reported between 0.3 per 100,000 person-years up to 2.9 per 100,000 person-years[19]

Although the etiology of priapism is not completely understood, it is believed to be a failure of detumescence[17].  Many disease states have been associated with priapism, including hematologic disorders, malignancy, neurologic disorders, trauma, infection, medications, recreational drugs (see Table 1)[15, 17].  Evaluation should include a complete history, physical exam, CBC with differential, hemoglobin electrophoresis, and urine toxicology screen.

Treatment

For the proper management of priapism, it is important to distinguish between ischemic and non-ischemic subtypes.  Ischemic priapism is comparable to a compartment syndrome causing hypoxia of the corpora cavernosa that is typically painful and requires emergent intervention to preserve erectile function.  Non-ischemic priapism is a high-flow state that is typically not painful and resolves spontaneously.  Non-ischemic priapism is more often associated with trauma.  A cavernous blood gas can be performed to differentiate the two.  Patients with ischemic priapism will have hypoxia with pH <7.25, pCO2 >60 mmHg, and pO2 >30 mmHg.  Blood gas results for patients with non-ischemic priapism will be consistent with normal arterial blood gases.  The blood gas on a detumesced penis would be consistent with a mixed venous blood gas.[15]

The practical aspects of priapism treatment deserve special comment.  Understand that the patient will be embarrassed, anxious, and in pain. Do everything needed to ensure patient comfort and privacy.

  1. Prior to performing any treatment, obtain informed consent for treatment of priapism.
  2.  Place patient on a cardiac and BP monitor.
  3. Administer a dorsal penile nerve block with 1-2% lidocaine using a 25-27G needle. 
  4. Insert the needle at the base of the penis at the 10 o’clock position. Advance the needle towards the opposite side of the shaft (2 o’clock). Make sure that you have not entered the corpora by gently aspirated.
  5. Deposit 10 mL of lidocaine into the penile shaft. Note the distention of Buck’s fascia when injecting the lidocaine. Allow approximately 10 minutes for the local anesthesia to reach full effect. 
  6. Insert a 16 or 18 gauge needle into the penile shaft and aspirate 20 to 30 mL of blood. Irrigation with a saline solution is not routinely recommended as it rarely results in faster detumescence.
  7. Next, inject 1 mL of a diluted phenylephrine concentration (100-500 mcg/ml). This phenylephrine solution may be injected in 1 mL aliquots - no less than every five minutes
    • Pay special attention to the cardiac and BP monitor as phenylephrine may cause reflex bradycardia and hypertension
    • There is no upper limit in the amount of phenylephrine that can be injected. However, practically it may take 10 to 15 mL to achieve detumescence or to decide that surgical intervention is needed.

  8. Once the penis is detumesced, it should be wrapped loosely with gauze and non-adhesive dressing (Coban).
  9. The patient should be monitored in the emergency department for at least another hour to ensure continued penile detumescence.
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Nelson Bennett, Jr, MD

Associate Professor, Department of Urology, Northwestern University, Feinberg School of Medicine 


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How to Cite this Blog Post

[Peer-Reviewed, Web Publication] Quarles A, Ogele E, Quigley M(2017, July 4). Priapism: The ED Focused Appropach.  [NUEM Blog. Expert Commentary By Bennett N]. Retrieved from http://www.nuemblog.com/blog/priapism


Resources

  1. Nationwide emergency department visits for priapism in the United States. Flum ASCashy JZhao LCMcVary KT. J Sex Med. 2013 Oct;10(10):2418-22.
  2.  Incidence of priapism in emergency departments in the United States. Roghmann F, Becker A, Sammon JD, Ouerghi M, Sun M, Sukumar S, Djahangirian O, Zorn KC, Ghani KR, Gandaglia G, Menon M, Karakiewicz P, Noldus J, Trinh QD J Urol. 2013;190(4):1275. 
  3.  Adeyoju AB, Olujohungbe ABK, Morris J, et al. Priapism in sickle-cell disease: Incidence, risk factors and complications — an international multicenter study. BJU Int 2002;90:898-902
  4.  Pryor J, Akkus E, Alter G, Jordan G, Lebret T, Levine L, Mulhall J, Perovic S, Ralph D, Stackl W Priapism. J Sex Med. 2004;1(1):116. 
  5. Arthur L Burnett Trinity J Bivalacqua. Priapism: current principles and practice. Urologic clinics of North America. 2007, Vol.34(4), p.631-42, viii
  6. Pryor JP, Hehir M. The management of priapism. Br J Urol. 1982;54(6):751. 
  7. Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton JP, Lue TF, Nehra A, Sharlip ID, Members of the Erectile Dysfunction Guideline Update Panel, American Urological Association. American Urological Association guideline on the management of priapism. J Urol. 2003;170(4 Pt 1):1318. 
  8. Salonia A, Eardley I, Giuliano F, Hatzichristou D, Moncada I, Vardi Y, Wespes E, Hatzimouratidis K; European Association of Urology. Guidelines on Priapism. Eur Urol. 2014 Feb;65(2):480-9. doi: 10.1016/j.eururo.2013.11.008. Epub 2013 Nov 16.
  9. Dittrich A, Albrecht K, Bar-Moshe O, Vandendris M.Treatment of pharmacological priapism with phenylephrine. J Urol. 1991;146(2):323. 
  10. Sullivan P, Browne R, McEniff N, Lee MJ. Treatment of "high-flow" priapism with superselective transcatheter embolization: a useful alternative to surgery. Cardiovasc Intervent Radiol. 2006;29(2):198.
  11.  Rosen’s. Genitourinary and Renal Tract Disorders
  12.  Roberts and Hedges
  13. Spycher MA, Hauri D. The ultrastructure of the erectile tissue in priapism. J Urol 1986;135(1):142.
  14. Uptodate. Priapism.
  15. Montague, D.K., et al., American Urological Association guideline on the management of priapism. J Urol, 2003. 170(4 Pt 1): p. 1318-24.
  16. Spycher, M.A. and D. Hauri, The ultrastructure of the erectile tissue in priapism. J Urol, 1986. 135(1): p. 142-7.
  17.  Bivalacqua, T.J. and A.L. Burnett, Priapism: new concepts in the pathophysiology and new treatment strategies. Curr Urol Rep, 2006. 7(6): p. 497-502.
  18. Broderick, G.A., et al., Priapism: pathogenesis, epidemiology, and management. J Sex Med, 2010. 7(1 Pt 2): p. 476-500.
  19.  Eland, I.A., et al., Incidence of priapism in the general population. Urology, 2001. 57(5): p. 970-2.


 

 

Posted on July 3, 2017 and filed under Urology.

The Use of the Angiocatheter in Central Venous Line Insertion

There are two techniques for guide wire insertion when performing central line placement. This week we compare the evidence for the two approaches and provide support for the cathether-over-needle (CON) technique which may prove useful in specific situations.  

Is High Flow Nasal Cannula Effective for Adults with Acute Respiratory Distress in the Emergency Department?

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Acute Compartment Syndrome

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To Admit or Not to Admit: Initial Results from the Intermediate-Risk Syncope (IRiS) Study

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Asplenia in The Emergency Department

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