Haldol v Olanzapine in the ICU for treatment of delirium

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In the ICU this month, I’ve been frequently running into the problem of patients who become delirious and agitated during their ICU course. This syndrome has been associated in multiple studies with increased mortality, and in my experience seems to often result in secondary harms such as oversedation, and even re-intubation / mechanical ventilation, which is itself associated with mortality. We are frequently advised against using benzodiazepines in these patients for sedation, given the association between the use of benzos and ICU-acquired delirium. We are then left with very few effective treatments for agitated delirium — many turn to Seroquel, some like the old standby of Haloperidol, and recently I was asked whether there was any evidence about using the newer, increasingly-popular atypical agent Olanzapine.

In this study by Skrobik et al from an ICU in Montreal, a relatively small number (73) of patients were enrolled in an RCT comparing treatment with Haldol to treatment with Olanzapine. The end result was that improvement in delirium symptoms was essentially the same. Haldo was often given early as an IV dose (despite the lack of FDA approval, though this study was done in Canada) and subsequently as enteral medications. They didn’t have IV Olanzapine, so this was always given PO/FT. The only significantly different endpoint between the two groups was the rate of extrapyramidal symptoms, which occured in 6 of the patients receiving Haldol and none of the patients receiving Olanzapine.

Downsides of this study included asymmetric distribution between the groups and a lack of blinding, alongside the small sample size. That said, I think this showed that for patients with a contraindication to the use of Haldol, Olanzapine seems to be effective at reducing delirium symptoms. Further research is needed into delirium generally, especially into coming up with effective treatments for delirium that we failed to prevent the development of.

References

Skrobik YK1, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med. 2004 Mar;30(3):444-9. PMID: 14685663. [PubMed] [Read by QxMD]

PGY-3 Coming Up + Two Book Reviews

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I really need to get back to posting on here, if only to cultivate a source of teaching points as I transition into our PGY-3 role where we’re supposed to teach the oncoming team something at the beginning of every shift. So, with that in mind, will try to re-dedicate myself to producing some content.

Until then, I wanted to post a brief review of two great books that I spent my “Educational Stipend” fund on this spring and have finished most of:

1.) Avoiding Common Errors in the Emergency Department – Amal Mattu  et al.

This is the second edition of a book that I originally found in medical school. The revised edition is significantly-expanded compared the original, with almost a complete rewrite of the content. There are 365 unique, short chapters focusing on “common errors” in the management of emergent conditions — I liked this book a lot because of the focus on high risk diagnoses or chief complaints in the error-prone, high decision density environment of the ED. While many of the topics are things that will be familiar to most clinicians, it never hurts to be reminded of an approach to troubleshooting post-intubation hypotension, or of the risk for abdominal compartment syndrome (though not typically an ED diagnosis) alongside instructions for how to measure abdominal compartment pressure. There are sections on things like cardiology, e.g. “Know the Mimics of Ventricular Tachycardia” and also critical care, with a great chapter on “How to Care for the ICU Boarder in Your ED” by none other than Josh Farkas who writes the PulmCrit blog I like so much. There are sections on upcommon presentations and pitfalls therein, such as “Normal Diagnostic Studies Do Not Rule Out Shunt Malfunction” and more medico-legal focused (clinical medicine is the overarching focus of the book, but I found this helpful) and clinical practice ares such as crowding, consultant communication / documentation and how to handle a deposition request. All in all, very readable, brief chapters that you could very easily read one of every day and learn something new, and well-written by authors respected in their fields. A bargain, and comes with an eBook for free — maybe useful for picking some above mentioned teaching points. 🙂

2.) Emergency Department Resuscitation Of The Critically Ill, 2nd Ed.

This book just came out, and I won’t pretend to have read through all of it yet, but what I have read is good enough to merit a positive review. This is also the second edition of a great book, featuring revised and rewritten chapters from authors such as Michael Winters, Peter DeBlieux, Evie Marcolini, Scott Weingert, and other EM-CC heavyweights. It focuses on best practices in the initial management of several varieties of critically ill patients (mostly on adults, but does have chapters on neonatal and pediatric resuscitation) including specific chapters on less-common but important areas such as Pulmonary Hypertension, Morbidly Obese patients, Anaphylaxis (going beyond the usual steps), various toxicology scenarios, and updates on the management of cardiac arrest and the post-cardiac arrest syndrome — something we often forget about after ROSC, unfortunately. Each chapter is around 10-12 pages, so a bit more expansive than the above-mentioned book without being too much like a typical CCM textbook. The chapters are well-referenced, and up to date in their recommendations. There are brief discussions about mechanical circulatory support (including one by Zack Shinar on ECMO and John Greenwood) including LVADs and IABPs, with a biomedical engineer contributing a great chapter on VAD malfunction and troubleshooting. This is a great book for a mid-level resident, or presumably practicing clinicians who have an interest in critical care in the ED and beyond. I feel like if you read this book and absorbed most of it, you would have caught yourself up on the last decade’s worth of developments in the world of critical care as it relates to the first several hours of patient’s hospitalizations — for anyone who isn’t throughly enmeshed in the world of FOAMed, many of the topics might be new, and for those who are, it’s a great review and dives a bit deeper than many of the podcasts and blogs out there. Totally worth checking out.

That’s all for now. More posts soon.

Goal-directed Hemostatic Resuscitation of Trauma-induced Coagulopathy: Time for TEG?

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Along with the usual suspects in the world of emergency medicine / FOAMed podcasts, I’ve tried to start listening to the educational podcasts being generated by those outside of our specialty — the Eastern Association for the Surgery of Trauma, EAST, recently had a great episode of their podcast (“Traumcast”) that featured Dr. Gene Moore, chief of trauma at Denver Health reviewing a single-center RCT comparing the use of viscoelastic coagulation assays to traditional coagulation testing such as INR and PTT in guiding resuscitation of trauma patients.

I went to medical school in Houston and did my clinical rotations at Memorial Hermann, where John Holcomb did his work looking at the use of rotational thromboelastography, including the development of a very robust system for getting TEG results to the trauma team within 15 minutes of the arrival of a patient to the trauma bay. The system they developed also provided automated guidance for the administration of specific blood products based off of the TEG assay, and is described in the second article linked below from Blood: How I treat patients with massive hemorrhage, on which Dr. Holcomb is the coordinating author.

I felt like this made a ton of sense — in the often coagulopathic trauma patient, we have shown over and over again that saline is not the resuscitative fluid of choice, and have more recently demonstrated in large, prospective, pragmatically-designed trials the superiority of using more physiologic (or “balanced”, as many surgeons refer to them) protocols for transfusing bleeding patients. Why not use more dynamic information to help inform the choice of which product goes first to fix the specifically broken link in the cascade of coagulation, as these viscoelastic testing assays seem to offer?

In this study, patients requiring massive transfusion activation were randomized in a block fashion to either have transfusion of blood products guided by TEG or by traditional coagulation assays. MTP activation was based on the Resuscitation Outcome Consortium criteria: SBP <70 mm Hg or SBP 70–90 mm Hg with heart rate > 108 beats/min, in addition to any of the following injury patterns: penetrating torso wound, unstable pelvic fracture, or FAST suspicious of bleeding in more than one region.

One hundred eleven patients were included in an intent-to-treat analysis, evenly split between the groups. Survival in the TEG group was significantly higher than the conventional MTP group (log-rank P = 0.032, Wilcoxon P = 0.027); 20 deaths in the control group (36.4%) compared with 11 in the TEG group (19.6%) (P = 0.049). Most deaths occurred within the first 6 hours from arrival (21.8% CCA group vs 7.1% TEG group) (P = 0.032).

Keeping in mind that TEG is a diagnostic tool rather than a treatment, and the relatively small numbers in this single central study, I don’t know that anyone could definitively say that the use of TEG is responsible for the increased survival seen here, but the results are impressive. Given the additional information conveyed by the TEG or other functional coagulation assays, I think that more broad deployment (including outside the OR, as they have at Memorial Hermann, where the TEG is the first test run off of the trauma activation patient, and where the results– along with a computerized interpretation of the graph with a recommendation for transfusion– print off on a laser printer in the trauma bay automatically) makes a lot of sense.

We should all be learning how to interpret these assays, especially in EM where we are often initiating the massive transfusion and resuscitation of these sick trauma patients (or other exsanguinating patients — I think it stands to reason that functional clotting assays would be much more useful in patients with other kinds of coagulopathy, e.g. liver failure or and sepsis) — I think this is now reaching a broader audience, as just recently Josh Farkas covered the use of TEG in sepsis-induced coagulopathy on PulmCrit and an article in EM Resident magazine covered the basics of TEG. Hopefully as more and more people learn about these technologies, we’ll see wider deployment and utilization, resulting in better care and smarter transfusion strategies.

References

Gonzalez E1, Moore EE, Moore HB, Chapman MP, Chin TL, Ghasabyan A, Wohlauer MV, Barnett CC, Bensard DD, Biffl WL, Burlew CC, Johnson JL, Pieracci FM, Jurkovich GJ, Banerjee A, Silliman CC, Sauaia A. Goal-directed Hemostatic Resuscitation of Trauma-induced Coagulopathy: A Pragmatic Randomized Clinical Trial Comparing a Viscoelastic Assay to Conventional Coagulation Assays. Ann Surg. 2016 Jun;263(6):1051-9. PMID: 26720428. [PubMed] [Read by QxMD]
Johansson PI1, Stensballe J2, Oliveri R3, Wade CE4, Ostrowski SR3, Holcomb JB4. How I treat patients with massive hemorrhage. Blood. 2014 Nov 13;124(20):3052-8. PMID: 25293771. [PubMed] [Read by QxMD]

Buffalo Chest

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The American Bison is one of my favorite mammals, so it is no surprise that I found this interesting and a good teaching point last year while working along with the V.A. thoracic surgery service: http://www.nejm.org/doi/full/10.1056/NEJMicm010281#t=article — This article presents a case which illustrates a concept known as a “buffalo chest”, or absence of anatomical separation of the two hemithoraxes, secondary to genetics, trauma, or iatrogenesis. I saw these in patients who had undergone median sternotomies for various cardiothoracic procedures. It’s also a physiology seen in trauma patients, patients with cancer who have had resections, people with various kinds of primary pulmonary disease, or just randomly by genetic bad luck (I imagine, though the article doesn’t list this as a specific cause). This is known as a buffalo chest because the American Bison (or at least according to the article, some) has a single, contiguous pleural space. While I would never use the word “easy” to describe the hunting of buffalo, particularly with bows from horseback, this facilitated the killing of them for food (or sick entertainment in the case of some poor buffalo shot by settlers off a train), as a GSW or penetrating arrow would to their broad sides could lead to a tension physiology.

Consider this possibility in the crashing patient with tension pneumothorax that doesn’t resolve with a unilateral chest tube, especially if any of the risk factors described. I agree with something described (and criticized by some)  in the FOAMed trauma world — nobody should die of traumatic arrest without decompression of the bilateral chests. I think this supports the empiric decompression of the contralateral chest in the positive pressure-ventilated patient in undifferentiated cardiac arrest where pneumothorax is wanting to be ruled out, and would really like to see more research on better ways to manage it in the acute setting.

Faking it: How to detect malingered psychosis

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This was an amusing and interesting article shown to me by one of our consulting psychiatry faculty — in it, the authors Drs. Resnick and Knoll lay out their approach to determining whether someone might be feigning madness for secondary gain. This is, sadly, something we see very frequently in the emergency department — not so much specifically the faking of psychosis, but more often things like suicidality, which some patients (whose unfortunate lives are such that they would prefer being stuck in the emergency department on an “involuntary” hold to being out in the streets, or often those who were just arrested and are now on their way to jail) will endorse knowing that it results in a cascade of CYA consultations that result in a longer LOS and often a sandwich / sometimes psychotropic medications, or alcohol withdrawal. In the case of arrested patients, sometimes they can avoid a trip to jail by diverting to the hospital which will lead the officer to write them a ticket instead of arrest them. Sometimes this population also endorses psychotic symptoms such as command hallucinations, and the subjective nature of these complaints makes them very difficult to determine as being organic or not.

Malingering, defined by the authors as “the intentional production of false or grossly exaggerated physical or psychological symptoms, motivated by external incentives” is obviously a diagnosis of exclusion, particularly in our most vulnerable populations such as the homeless or incarcerated. However, one must also consider the patients whose care is being delayed by beds occupied by those without true illness, and the resources allocated to sussing out those actually at risk from those who are angling for secondary gain. There is also a very strong “Peter and the Wolf” phenomenon that can result from dealing with the same patients every day who come in claiming suicidality, only to recant after they sober up, or who are found to have conditional suicidality that hinges on things like being fed, housed, or given controlled substances such as pain medications or benzodiazepines — meaning, there is a risk that it could both degrade one’s index of concern for true suicidal ideation, and one’s empathy for other patients presenting with concern that they are a danger to self.

So what do they recommend? Some highlights:

Asking about improbable symptoms, which are rarely seen even in the most severely disabled patients, e.g. “When people talk to you, do you see the words they speak spelled out?” or (my personal favorite) “Have you ever believed that automobiles are members of an organized religion?”

Focusing on incongruities between the way they are presenting or endorsing symptoms and the circumstances they were in before arrival, or the way they behave when the examiner is not present, e.g. endorsing having active auditory and visual hallucinations yet showing no evidence of being distracted or attending to internal stimuli.

Critically evaluate reported hallucinations, particularly visual ones which are less often seen in true psychosis than reported in malingering. True visual hallucinations also are usually of “normalized people” and seen in color, rather than dramatic or atypical things such as giant monsters or devils, or flashes of light/color, which is more associated with neurologic disease or drug intoxication than psychosis.

They close by advising clinicians to “avoid direct accusations of lying, and give the suspected malingerer every opportunity to save face. For example, it is preferable to say, ‘You haven’t told me the whole truth'”, rather than directly confront them as malingering or lying.

All in all, this was an interesting diversion regarding a very difficult population and a sad phenomenon seen in the ED. Worth the 10 minutes it takes you to read, even if it doesn’t ultimately stop you from consulting psychiatry.

 

Transient Hypotension in the Emergency Department

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An interesting technicality in the use of the PERC rule to rule out pulmonary embolism is the tachycardia component — it asks not whether the patient is tachycardic at the time of the application of the rule, or whether tachycardia was sustained throughout the emergency department stay, but instead whether the patient had (as described by Jeff Kline in his great review article on PE diagnosis and risk stratification): “3. Pulse <100 beats/min during entire stay in ED”.  Meaning, even transient tachycardia may suggest a life-threatening diagnosis, even if it resolves while the patient is in the emergency department, and we’re probably PERCing out a whole bunch of patients inappropriately, at least according to Kline (who, notably, testifies a whole bunch as an expert witness in cases of missed pulmonary emboli).

I recently had a handful of patients in whom concerning blood pressures were measured and documented, which then resolved when vital signs were re-checked or after a small quantity of fluid or repositioning. I was wondering whether anyone had looked at the prognostic significance of ED hypotension, and whether these momentary dips in blood pressure should be something that concerns me. I did a quick search and found two studies that addressed this question in two different populations:

First we have, from the Rick Bukata school of title writing: “Emergency department hypotension predicts sudden unexpected in-hospital mortality: A prospective cohort study.”  This study, by Alan Jones and Jeff Kline out of (and formerly out of) Carolinas, prospectively enrolled 4,790 adult ED patients admitted to the hospital for reasons other than trauma. Patients were divided into those with and without systolic BPs below 100 mmHg at any time during their ED visit and followed through their hospitalization for the primary outcome of in-hospital mortality. Secondary outcomes included “sudden and unexpected death”, the relationship between the degree and the duration of hypotension measured and mortality, and the test characteristics of hypotension as a test for predicting in-hospital mortality.

Their conclusions are illustrated well in this graph:

hypotension

As they concisely summarize in the article’s conclusion:

Patients exposed to hypotension had a threefold increased risk of in-hospital death and a 10-fold increased risk of sudden, unexpected in-hospital death. Patients with any one SBP < 80 mm Hg had a sixfold-increased incidence of in-hospital death, and patients with a SBP < 100 mm Hg for > 60 min had almost a threefold-increased incidence of in-hospital death.

The second article from the same group echoes this conclusion in a different population of patients. This article, “The significance of non-sustained hypotension in emergency department patients with sepsis” is a secondary analysis of the above data set which looks specifically at the prognostic value of non-sustained hypotension defined as one or more occurrence of SBP < 100 mmHg in patients with sepsis as defined by the receipt of antibiotics in the ED + at least two SIRS criteria.

774 patients met their inclusion criteria for sepsis, and after 74 were excluded for “overt shock” (sustained hypotension or use of pressors). They examined the remaining patients for a primary outcome of in-hospital death.  They found, as one might expect, that hypotension predicts worse outcomes in this sub-population of patients — including when patients had non-sustained hypotension. Again, there seemed to be a “dose-dependent” relationship, with an inverse relationship between the nadir of the ED SBP and the frequency of in-hospital death, as shown here:

sepsishypotension

Another important finding (though taken in context of a fairly small sample) was the statistically similar incidence of the primary outcome in both the groups with transient and sustained hypotension. Both groups of patients had a 2.5-3x higher risk of in-hospital mortality when compared to patients without any hypotension.

Without belaboring the point, these two studies underscore the prognostic significance of even transient hypotension in the undifferentiated emergency department patient, and (as is better known to have implications in terms of severity) in patients diagnosed with sepsis. Like the previous post regarding lactate, or the well-known pearl about tachycardia at discharge, this is a number that should get your attention and which demands evaluation and possible intervention / escalation of care.

References

Marchick MR1, Kline JA, Jones AE. The significance of non-sustained hypotension in emergency department patients with sepsis. Intensive Care Med. 2009 Jul;35(7):1261-4. PMID: 19238354. [PubMed] [Read by QxMD]
Holler JG1, Bech CN1, Henriksen DP2, Mikkelsen S3, Pedersen C4, Lassen AT1. Nontraumatic hypotension and shock in the emergency department and the prehospital setting, prevalence, etiology, and mortality: a systematic review. PLoS One. 2015 Mar 19;10(3):e0119331. PMID: 25789927. [PubMed] [Read by QxMD]

Hyperlactatemia in the Emergency Department

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Much has been made over measurement of serum lactate over the last several years– primarily focusing on whether we should be measuring it in the first place, and what the significance (and etiology) of elevations in serum lactate is, and what role it should play in diagnosis and risk stratification. Back in 2010, Scott Weingert was organizing the New York Sepsis Collaborative, and produced this podcast covering the basics of lactate measurement, with a particular bent towards sepsis. He did a great job covering the essential take-home of the data that existed thus far, and addressed a lot of points of confusion many people have about lactate — namely, the idea that it results from hypoxia/hypoxemia or anaerobic respiration, and covers some of the alternative etiologies of hyperlactatemia, i.e. any beta agonist, whether endogenous catecholamines or exogenous, such as albuterol or epinephrine being used as a vasopressor. The takeaway from this, echoed in sepsis care guidelines issued by many other organizations since and in the policies and protocols in many hospitals and emergency departments, is that elevated lactate is a marker of increased mortality, and may be an early alarm that someone is in septic shock or headed towards it.

I wanted to cover two studies — one by Shapiro et al. (a big name in sepsis research), and the other by del Portal et al– that looked at this question in the ED. These were prospective and retrospective cohort studies respectively, and both looked at over 1,000 emergency department patients and evaluated the prognostic significance of elevated venous lactate measurements. In the first study by Shapiro et al, they evaluated all patients admitted to the hospital with an infection-related diagnosis. In the second study, they looked at older adults admitted to the hospital with any diagnosis, though a very large proportion of patients were excluded. Reasons for exclusion (they excluded >14,000 of 16,886 total admissions , so I think this really affects the robustness of this paper) were things like being a sick trauma patient, transfers out, LWBS or leaving AMA — those are all reasonable, but they also excluded all patients in whom a lactate was not drawn in the ED. Without providing the numbers to break this down, it’s tough to say how generalizable these conclusions are, or if lactates were only obtained in patients that the providers thought were sick/potentially septic in the first place (which was the protocol at the hospital conducting the study by Shapiro et al.).

As one might expect, both studies found that hyperlactatemia correlates with badness in the form of increased mortality. The relationship is linear, and statistically significant. The authors also stratified the mortality by time — in Shapiro et al. by 28d in-hospital v. death within 3 days (top graph), and in del Portal’s study by in-hospital, 30 day and 60 day mortality (bottom):

lactateshapirolactatedelcar

Note the similar trend and the steep upward trajectory of the relationship — these results have been paralleled in the critical care literature, and have led to the commonly-accepted idea that a lactate > 4.0 is a threshold above which one should be concerned for hypoperfusion or shock, even in the absence of hypotension. These studies do not, and no studies have, established a causal relationship between lactate elevation and increased mortality– nor have they shown that trying to “clear” lactate will lead to better outcomes than trending alternative markers of perfusion (though several studies have looked at this question, without any definite conclusions). They also did not establish that one need only be worried about lactate > 4.0 — multiple studies including this one have shown that infected patients with lactate in the 2.0–3.9 mmol ⁄ L range have a risk of mortality that is approximately twice that of patients with a lactate level of < 2.0 mmol ⁄ L. They also have not established that we need not be worried about patients without hyperlactatemia — so-called “occult” sepsis.

More recent studies have questioned the relationship between hyperlactatemia and hypoperfusion per se by looking at changes in microcirculation, but I think it’s safe to say that an elevated lactate in a patient with suspected infection should still ring alarm bells in your head. Having these mortality “buckets” in mind when mentally risk stratifying patients or prioritizing them for workup or interventions can also help — particularly when these patients might otherwise look well and thereby fly under the radar.

In my mind, an elevated serum lactate must be explained — sometimes, the explanation is that they just got a nebulizer treatment, are in alcoholic ketoacidosis (which along with the production of ketones, leads to an accumulation in reduced nicotinamide adenine dinucleotide (NADH), which then results in impaired conversion of lactate to pyruvate or preferential conversion of pyruvate to lactate, both resulting in increased lactic acid level), or seized. But these are diagnoses of exclusion, and one must assume until proven otherwise that this represents their body’s sympathetic accelerator pedal being pushed to the floor and that they are needing resuscitation and provision of care with the mentality that this is a sick patient.

 

References

Shapiro NI1, Howell MD, Talmor D, Nathanson LA, Lisbon A, Wolfe RE, Weiss JW. Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med. 2005 May;45(5):524-8. PMID: 15855951. [PubMed] [Read by QxMD]
del Portal DA1, Shofer F, Mikkelsen ME, Dorsey PJ Jr, Gaieski DF, Goyal M, Synnestvedt M, Weiner MG, Pines JM. Emergency department lactate is associated with mortality in older adults admitted with and without infections. Acad Emerg Med. 2010 Mar;17(3):260-8. PMID: 20370758. [PubMed] [Read by QxMD]

D-Dimers & Dissection

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A recent patient I saw in the emergency department was a fifties year-old woman with a family history of aortic dissections presenting with “chest pain” per the triage note. On my history and exam, she more endorsed vague neck and epigastric discomfort (which had now resolved), and had no other classic findings for a dissection (e.g. hemodynamic instability, asymmetric pulses or blood pressures, abnormal neurologic findings, etc.). She also had a a normal chest x-ray and a negative initial workup for ACS, including a normal ECG and undetectable troponin. In terms of other life-threatening diagnoses, she did not PERC out, and had a Wells score that suggested the D-Dimer would be an appropriate test to rule out pulmonary embolism.

When I discussed with her the potential utility of getting a CT scan of her chest to evaluate for an aortic dissection — she asked me about how much radiation exposure this involved, and shared her (valid and very appropriate) concerns about getting too much radiation. She had many CT scans for various reasons over the years she felt, and did not want any additional unnecessary radiation.

I talked to her more about this and tried to start some shared decision making by sharing a favorite infographic of mine about radiation amounts in diagnostic imaging, and (to myself) pondered a clinical question: If the D-dimer test was low, did that along with the low-ish pretest probability, safely decrease the likelihood of dissection enough to forego a CT scan? There is an emerging literature on the use of dimer testing to rule out aortic dissections, but how good is it? Do you use the same cut-off as in pulmonary embolism? Should that cutoff be age adjusted? And what are the test characteristics in this context? I had no idea, so that’s what today’s post-didactics reading was about.

I read through “A Systematic Review and Meta-analysis of D-dimer as a Rule-out Test for Suspected Acute Aortic Dissection” by Asha et al., which reviews the work of 30 studies and combines the data for 4 studies using a standard cutoff of 0.50 μg/mL to estimate sensitivity, specificity, and positive and negative likelihood ratios of a D-dimer. As the abstract conclusion reads:

“Overall, sensitivity and negative likelihood ratio were 98.0% (95% confidence interval [CI] 96.3% to 99.1%) and 0.05 (95% CI 0.03 to 0.09), respectively. These measurements had little statistical heterogeneity. Specificity (41.9%; 95% CI 39.0% to 44.9%) and positive likelihood ratio (2.11; 95% CI 1.46 to 3.05) showed significant statistical heterogeneity. When applied to a low-risk population as defined by the American Heart Association (prevalence 6%), the posttest probability for acute aortic dissection was 0.3%.”

So there you have it. Obviously, there’s more to it, and the actual paper is worth reading — it discusses some of the drawbacks of the included studies, specifically unanswered questions about bias and the generalizability to ED populations given the high prevalence of disease in the included cohorts. Limitations aside, basic conclusion that was in low risk patients, a negative D-dimer confers an even lower risk of acute aortic dissection, and it may be reasonable (don’t you love that phrase?) to consider using this result to inform your decision-making regarding the utility of imaging. Of course, one must also consider the rate of false positives, and the potential harms of resultant downstream testing as has been discussed regarding testing for PE.

I think that one of the more important (and potentially easily-overlooked, as when it comes to all clinical decision tools or supports, or anything that serves as a Bayesian modifier) points I took away from this review is that while this is a potentially useful test in this context, pretest probability matters. As the abstracts of some of the included studies say: “When applied to a low-risk population…”, “…in patients with low likelihood of the disease”,  “…the presence of ADD risk score 0 or ≤ 1 combined with a…” and so on. You should only really hang your hat on a negative dimer assay when you think the probability is low in the first place. Another question to consider though, is how low is the pre-test probability to suggest you *shouldn’t* order a dimer to r/o dissection? And how many people with potential dissections that might be caught and thereby managed earlier PERC’d out of receiving a test that might reveal this diagnosis (though might also subject them to an unnecessary scan for PE)?

As the full text of the article states:

It would be pertinent to comment on the many case reports of patients with confirmed acute aortic dissection but a negative D-dimer result. It should first be recognized that these cases did not have a risk-stratification applied and also that no test, no matter how good, including the reference standards for the disease, has 100% accuracy. These cases mostly represent a subgroup of patients with a thrombosed false lumen or an intramural hematoma who seem particularly likely to have a lower or negative D-dimer result. The studies in this meta-analysis included such patients, which means that the high sensitivity and excellent negative likelihood ratio were achieved with the inclusion of these problematic cases.

It is always worth remembering that rare diseases are rare, and that in a patient with a low pretest-probability of having a disease, any test can be construed as to have a high sensitivity when applied to the wrong population. For instance, I can figure out who is low risk for aortic dissection in most chest pain patients with the “Bryan” rule — I just ask if their name is Bryan, spelled with a y. If negative, they are extremely unlikely to have an aortic dissection. Of course, if they do, my test will likely miss them but the point remains. In the patient described above, even though the D-dimer was negative, this patient was not low risk by the fairly-conservative AHA acute aortic dissection risk score (pictured below), and therefore the sensitivities and specificities cited in the articles presented in this meta-analysis don’t apply to their case.

1-s2.0-S0196064415001183-gr3

In cases where acute aortic dissection is suspected as a likely potential diagnosis, a D-dimer is probably not an appropriate test to replace definitive diagnostic imaging of the aorta–  specifically, as stated by previous guidelines from the AHA: computed tomography (CT), magnetic resonance imaging (MRI), or transesophageal echocardiography. Let this inform your discussions of shared decision making in the emergency department, and document accordingly, and hopefully you’ll be able to adopt a strategy to help everyone sleep better at night.

References

Nazerian P1, Morello F2, Vanni S1, Bono A3, Castelli M1, Forno D3, Gigli C1, Soardo F3, Carbone F3, Lupia E3, Grifoni S1. Combined use of aortic dissection detection risk score and D-dimer in the diagnostic workup of suspected acute aortic dissection. Int J Cardiol. 2014 Jul 15;175(1):78-82. PMID: 24838058. [PubMed] [Read by QxMD]

Evaluation of Cervical Spine Clearance by Computed Tomographic Scan Alone in Intoxicated Patients With Blunt Trauma

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One common and vexing problem I’ve run into thus far in residency is the intoxicated patient, found down, brought in by EMS in a rigid cervical collar placed because of the presumption of possible trauma leading to an unstable cervical injury. The efficacy and necessity of cervical collars has been debated elsewhere, and I’m not looking to discuss that here — what I’m more interested is, if these patients have a negative CT scan (for better and for worse, fairly common practice in those unable to give a reliable exam, especially if they have any sign of trauma on them), can we safely remove their collar?

This study, by the “Pacific Coast Surgery Association” and published in JAMA Surgery, prospectively evaluated 1668 intoxicated adults with blunt trauma who underwent cervical spine CT scans over one year at a single Level I trauma center. Intoxication was defined based on the results of urine and blood testing, and the outcome of interest was clinically-significant cervical spine injuries that required cervical immobilization (not necessarily surgical fixation).

The authors wanted to evaluate the negative predictive value of a normal CT scan in the intoxicated patient to determine whether this would allow safe removal of their cervical collar– it is well-known that some injuries (e.g. unstable ligamentous injuries or spinal cord injuries without fractures of the vertebrae) may not be identifiable on a CT scan, and in the patient who is altered, it may be difficult to elicit exam findings that would tip a practitioner off to the presence of these injuries.

So what did they find? In intoxicated patients, the negative predictive values of a CT scan read as negative for acute injury were 99.2% for all injuries and 99.8% for unstable injuries.  There were five false-negative CTs, with 4 central cord syndromes without associated fracture. There was also one false-negative for a potentially unstable injury identified in a drug-intoxicated patient who presented with clear quadriplegia on examination. All of these were detected on MR imaging. About half of the intoxicated patients with the negative CT went on to be admitted with their cervical collar left on. None of these intoxicated patients went on to have an injury identified later, or to have any neurologic deficit, leading to a conclusion of a NPV of 100% in that cohort.

My takeaway from this paper: while there are some weaknesses, e.g. the lack of protocol-based care and the significant heterogeneity in terms of “intoxication”, it seems reasonable to take away from this that a negative CT scan done on a modern scanner and read by an experienced trauma radiologist or neuroradiologist does allow you to safely clear the collar of an intoxicated patient who does not have any gross neurologic deficits. This data lends further support to the 2015 recommendations from the Eastern Association for the Surgery of Trauma who in a systematic review and meta-analysis “found the negative predictive value for identifying unstable CSIs to be 100% and thus have made a conditional recommendation for cervical collar removal based on a normal high-quality CT scan”. Adopting this practice could help minimize unnecessary testing (including expensive MRIs that are more likely to show false positives than to identify clinically-significant injuries) , allow for earlier disposition of patients from the emergency department, increase patient comfort, and decrease the emotional and cognitive burden placed on providers who otherwise often have to continuously struggle to keep patients adherent to immobilization practices.

References

Bush L1, Brookshire R1, Roche B1, Johnson A1, Cole F1, Karmy-Jones R1, Long W1, Martin MJ2. Evaluation of Cervical Spine Clearance by Computed Tomographic Scan Alone in Intoxicated Patients With Blunt Trauma. JAMA Surg. 2016 Jun 15. PMID: 27305663. [PubMed] [Read by QxMD]

Thrombolytic treatment of cardiac arrest or periarrest due to suspected pulmonary embolism

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I recently saw a case in the department that led to me thinking about the role of thrombolytics in cardiac arrest patients — particularly for the purpose of trying to treat arrest from suspected PE. Thrombolytics in out-of-hospital cardiac arrest patients is something I’ve seen considerable inter-attending variability on in practice, and heard conflicting things about from the things that I’ve read and heard in podcasts. So, naturally when there are no podcasts readily accessible on the matter, I turned to PubMed and came across an excellent review article on the subject from Logan et al., “Evidence-based diagnosis and thrombolytic treatment of cardiac arrest or periarrest due to suspected pulmonary embolism”, published four years ago in AJEM.

As they write in the introduction, “This article discusses clinical features consistent with the presumptive diagnosis of PE, provides an overview of thrombolytic agents, and presents a detailed review of the literature supporting the use of thrombolysis as a treatment option for patients in cardiac arrest or periarrest due to suspected PE.” The authors do an excellent job summarizing the available (as of 2014, at least, or 2012 — this being the latest publication included) evidence and discuss strategies for considering whether to push lyrics in the cardiac arrest patient you think might have a pulmonary embolism. Note that this is a different question from lytics in patients with cardiac arrest due to coronary occlusion — though it is likely that many of those showed up in the reviewed trials of lytics in undifferentiated cardiac arrest, or PEA arrest that wasn’t necessarily thought to be secondary to an MI.

What does it boil down to?

“The above literature review shows that unstable or arresting patients experiencing massive PE will likely benefit from thrombolytic therapy. Studies with a retrospective design generally demonstrated the best outcomes, as was expected, due to the patient population having a known or high risk for PE, and possibly publication bias of positive results. Trials with a prospective design had more variation because these trials generally included a heterogeneous patient population in cardiac arrest and illustrates the potential difficulty of applying this intervention in real-time clinical practice. Analysis of the subgroup population of patients with PE in the prospective trials showed possible improved outcome after thrombolytic therapy, although these studies were not powered to look specifically at this group. This disparity emphasizes the importance of patient selection when evaluating for the efficacy of thrombolytic therapy.”

They said it best, so I won’t try to restate their conclusions — one thing I did find particularly interesting was a clinical decision making rule evaluated  in both a retrospective and a prospective trial which found the following triad to be associated with cardiac arrest secondary to massive PE: witnessed cardiac arrest, age less than 65 to 70 years, and PEA as the initial rhythm. This study found that 50% of the (admittedly fairly small n of 48) patients with this triad had a PE, which improved the diagnostic likelihood of PE when compared with the previously discussed sensitivity of 36% when only assessing for PEA rhythm in unexplained cardiac arrest.

There are robust data supporting the use of lytics in patients with hemodynamic compromise in the setting of diagnosed pulmonary embolism. Do these same data, or the data presented in this review and since support the use of it in all undifferentiated cardiac arrest patients, or in any subset of cardiac arrests? I agree with the authors — the data suggests that if the arrest is due to massive PE, lytics may benefit them and are probably worth trying, especially early on if your suspicion is high. But in the undifferentiated cardiac arrest patient, even one in PEA, I think there are many other things to consider like bedside ultrasound, duration of arrest, initial  rhythm, witnessed/unwitnessed, and cormorbid conditions / premorbid quality of life to consider before using an expensive, non-FDA-approved (for this indication) medication that has significant risks.

My next question that I still don’t have a good answer for yet, is whether someone can and should go to the cath lab after ROSC in the setting of the use of thrombolytics? And does this answer hinge on whether the lytics were given for a high suspicion of pulmonary embolism as the precipitating event? Is there ever a role for lytics in cardiac arrest where your suspicion isn’t high for PE as the etiology, but the patient is “too unstable” to go to catheterization? As I said in the last post, definitely more to come.

References

Logan JK1, Pantle H2, Huiras P3, Bessman E2, Bright L4. Evidence-based diagnosis and thrombolytic treatment of cardiac arrest or periarrest due to suspected pulmonary embolism. Am J Emerg Med. 2014 Jul;32(7):789-96. PMID: 24856738. [PubMed] [Read by QxMD]