Category Archives: Pulmonary

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]

Pulmonary Embolism in Pregnancy

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The diagnosis of pulmonary embolism in pregnant patients is one made difficult by many factors, including a normal elevation in serum d-dimer levels (see below) as well as the additional concern regarding exposure of a developing fetus to the high levels of radiation and contrast associated with CT pulmonary angiography. It is well-known that exogenous estrogen is a risk factor for thromboembolic disease, and while it seems from the data discussed below that pregnancy is not as scarily-high-risk for PE as we might think, we certainly know that pregnancy is a time when homones are running high Add to this the fact that in pregnancy, women are both tachypnic and tachycardic due to normal changes in cardiovascular and respiratory physiology — making a clinical diagnosis that much more difficult.

In these sequentially-published review articles by the PE guru Jeff Kline et al., the authors review the diagnostic dilemma presented by these patients and present the following algorithm:

Microsoft Word - jem_10231_JEM10231.edt

Note the inclusion of the trimester-stratified quantitative d-dimer for patients without a high pretest probability who are PERC negative — this goes against the conventional wisdom that the d-dimer is a worthless test in pregnant women due to the normal elevation found intrapartum. Similar to the way we have begun “age-adjusting” the threshold value of the quantitative d-dimer in non-pregnant patients, they propose that the threshold be “adjusted according to the trimester of pregnancy, as follows: first trimester, 750 ng/mL; second trimester, 1000 ng/mL; third trimester, 1250 ng/mL (assuming a standard cutoff of 500 ng/mL). If the patient has a non-high-pretest probability, has no high-risk features, is PERC negative, and the bilateral ultrasound is negative, and the D-dimer is below the trimester-adjusted values, PE can be ruled out to a reasonable degree of medical certainty.”

They acknowledge the limitations of this approach, including that it hasn’t been prospectively validated, and they do not present any data showing its performance as they’ve been using it, but in cases like this expert opinion is the best we have (so far). He discussed this approach on an episode of ER Cast, and explains it a little bit more in terms of the integration into clinical practice, as well as the role that gestalt can play in risk stratification. 

What I found interesting about this was the idea that the post-partum period is the most risky period of time for women in terms of pulmonary embolism — this echoes what we know about cardiovascular disease in the post-partum period, i.e. when women are autotransfused and their cardiopulmonary physiology is rapidly and massively altered, this presents the highest risk in terms of women with heart failure, valvular abnormalities, or disease entities like peripartum cardiomyopathy. According to the data presented by Kline et al, while the risk increases throughout a pregnancy, 70% of all peripartum PEs occur post partum, and the risk during pregnancy is low (OR 0.4-0.8, depending on trimester) — though, as the authors note, this may not actually reflect that pregnancy is protective against PE but instead suggest that we overtest women for pulmonary embolism during pregnancy, perhaps because of the clinical changes described above. The also cite a large meta-analysis of 23 epidemiologic studies that found PE occuring in only 3 of 10,000 pregnancies.

Another thing that stood out to me while reviewing this article was that for a patient to PERC out of these algorithms, their vital signs must be normal throughout their entire ED stay — normalization of vital signs during an ED visit does not lower the risk of PE, as specifically stated by the authors.

 

References

Kline JA1, Kabrhel C2. Emergency Evaluation for Pulmonary Embolism, Part 2: Diagnostic Approach. J Emerg Med. 2015 Jul;49(1):104-17. PMID: 25800524. [PubMed] [Read by QxMD]
Kovac M1, Mikovic Z, Rakicevic L, Srzentic S, Mandic V, Djordjevic V, Radojkovic D, Elezovic I. The use of D-dimer with new cutoff can be useful in diagnosis of venous thromboembolism in pregnancy. Eur J Obstet Gynecol Reprod Biol. 2010 Jan;148(1):27-30. PMID: 19804940. [PubMed] [Read by QxMD]
Kline JA1, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem. 2005 May;51(5):825-9. PMID: 15764641. [PubMed] [Read by QxMD]

Age-Adjusted D-Dimer

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Pulmonary embolism is a commonly-investigated diagnosis in the world of emergency department risk stratification — the presentation of these patients is varied, the ultimate impact on patients of the disease entity itself is questionable when it comes to the less sick end of the spectrum, and the tools we have for diagnosis are associated with significant amounts of radiation and contrast. However, in a practice environment with a low tolerance for missed diagnoses (however questionable the risk:benefit balance of the intervention that would have been performed), we continue to strive to balance the risks and costs of diagnostic testing with the very real risk of progressive disease.

The D-Dimer level is a test used in patients with a low to moderate pretest probability of DVT or PE (and possibly aortic dissection?) — if negative, it will virtually rule out PE, and can help you avoid further testing with CT pulmonary angiography. If positive, further testing is required. So why do emergency physicians hate the D-Dimer? Because while elevation in D-Dimer levels is sensitive for pulmonary embolism or DVT, it is not specific — particularly with cutoff levels of ~ 500 ng/dL, which is the conventional cutoff for a positive test. Elevated D-Dimer levels occur for a multitude of reasons, including liver disease, inflammation, malignancy, trauma, pregnancy, and– most complicating of all– advanced age.

The first of the studies I read this weekend, the ADJUST-PE study, a group of authors had previously retrospectively derived and valid the value of a progressive D-Dimer cutoff adjusted to age in 1712 patients — the optimal age-adjusted cutoff was defined as patient’s age multiplied by 10 in patients 50 years or older. The ADJUST-PE study represented their attempt to prospectively validate the adjustment and to assess its impact on patients in real life. In this multi-center study which enrolled 3324 patients, the age adjusted D-Dimer cut off did very well — only one patient who had a D-Dimer between 500 ng/dL and their age-adjusted cutoff (in other words, someone who would have gotten scanned if they weren’t using the new tool) was found at three month follow up to have a PE, and this was non-fatal. The age adjusted level allowed for safe discharge of patients that might otherwise have been exposed to the costs/potential harms associated with CTPA or treatment of non-hemodynamically significant emboli.

The second study takes the same approach and retrospectively applies the cutoff to 31,094 suspected pulmonary embolism patients presenting to an emergency department in the community. They report data for all ED visits for Kaiser Permanente Southern California members older than 50 years, from 2008 to 2013, who received a D-dimer test after presenting with a chief complaint related to possible PE such as chest pain or dyspnea (due to their focus on PE rather than DVT). The authors excluded patients who underwent ultrasound imaging for DVT for the same reason. What they found was a sensitivity of 92.9% and a specificity of 63.9% for the age-adjusted D-Dimer threshold applied to this population — this compares to 98.0% and 54.4% for the traditional threshold of 500 ng/dL. This is not unsurprising — what I thought was interesting about the second paper was its expansion of the discussion of this testing strategy to include estimates for other harms beyond symptomatic PE that might be missed — specifically, they discuss the incidence of contrast-induced nephropathy, and how changes in testing strategies translate into potential benefits there that may outweigh the harms done by missing clots. These are statistical models, and need to be taken with a grain of salt, but they predict that  “using an age-adjusted D-dimer threshold would miss or delay diagnosis of 26 more pulmonary embolisms than the current standard, but it would prevent 322 cases of contrast- induced nephropathy, 29 cases of severe renal failure, and 19 deaths related to contrast-induced nephropathy in this sample.”

So what will I do with this information? Probably try for better shared decision making and try to avoid CTPA in patients with D-Dimers below the age-adjusted cutoff. I think sharing these numbers with our patients in a comprehensible way, and talking to them about the potential harms associated with testing is the best way forward– this will require further work in terms of identifying the best way to communicate these risks and odds to patients, and as always, trying to balance advocacy for patients, and our ultimate goal of keeping them safe, alive and functional, with the fear of missing a diagnosis or sending someone home with a nebulous non-diagnosis and the possibility of clinical deterioration.

References

Righini M1, Van Es J2, Den Exter PL3, Roy PM4, Verschuren F5, Ghuysen A6, Rutschmann OT7, Sanchez O8, Jaffrelot M9, Trinh-Duc A10, Le Gall C11, Moustafa F12, Principe A13, Van Houten AA14, Ten Wolde M15, Douma RA2, Hazelaar G16, Erkens PM17, Van Kralingen KW18, Grootenboers MJ19, Durian MF20, Cheung YW15, Meyer G8, Bounameaux H1, Huisman MV3, Kamphuisen PW21, Le Gal G22. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA. 2014 Mar 19;311(11):1117-24. PMID: 24643601. [PubMed] [Read by QxMD]

Duration of symptoms of respiratory tract infections in children

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From the BMJ, we have a very interesting systematic review evaluating the duration of symptoms in children seen in the ED (or A&E, if you will) for fairly minor complaints: otitis media, acute cough, sore throat, and common cold. In my time in the pediatric ED, I’ve noticed that a not-insignificant number of visits are repeat visits for persistent symptoms in well-appearing children who were seen and discharged from the ED within the last week or so. The parents are often concerned that the cough has still not gone away, or that the child’s breathing at night still sounds funny to them — these are not different symptoms than the child was originally evaluated for, but I thought it was possible that better anticipatory guidance in terms of the duration of symptoms parents could expect might result in fewer of these “bounce
backs”.

So what did the authors at BMJ find? In 90% of children, earache was resolved by seven to eight days, sore throat between two and seven days, croup by two days, bronchiolitis by 21 days, acute cough by 25 days, common cold by 15 days, and non-specific respiratory tract infections symptoms by 16 days.

21 days of cough for bronchiolitis and 25 days for non-bronchiolitis URIs? That is way longer than what I hear when parents are being discharged — I am no less guilty of underselling the duration of symptoms than others. It’s a tough question to answer, right? “How much longer will this last?” — Prognostication is always the hardest part of medicine, whether you’re talking to the dying cancer patient or to the parents of the child with the perpetually stuffy nose and inflamed upper airways. Well, I personally intend to try to provide parents with a more evidence-based answer for the rest of this season– something along these lines: “Longer than you can possibly imagine. Most kids will have a cough for three weeks or more, and many will seem like they go the entire winter without getting better. But as long as they’re eating, drinking, pooping, peeing, moving about and more or less acting like a slightly-more-congested-and-therefore-irritable version of themselves, that’s okay!”

It’s a tough balance. You wouldn’t want to dissuade parents from seeking medical attention (ideally from their PMD) if the child doesn’t get better in a reasonable amount of time, but it’s very difficult knowing what that time is for them. Moral of the story: encourage that follow up visit with the PMD, and make sure to give thorough and explicit return precautions accounting for the myriad reasons we *do* need to see these patients back ASAP.

References

Thompson M1, Vodicka TA, Blair PS, Buckley DI, Heneghan C, Hay AD; TARGET Programme Team. Duration of symptoms of respiratory tract infections in children: systematic review. BMJ. 2013 Dec 11;347:f7027. PMID: 24335668. [PubMed] [Read by QxMD]

Bronchiolitis and the Risk of Apneic Events – Risk Stratification Tool?

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Walsh et al. published “Derivation of Candidate Clinical Decision Rules to Identify Infants at Risk for Central Apnea.” in Pediatrics in November, which attempted to derive several CDRs and compare them for identifying risk of central apnea in pediatric patients with respiratory illness. Of course, for an outcome as rare as central apnea in a population that usually does very well, almost any set of criteria you apply to patients will leave you with a rule that has a very high NPV — so what did they find?

The group analyzed 990 ED visits for 892 infants. Central apnea subsequently occurred in the hospital in 41 (5%) patients. Three candidate CDRs were generated by different techniques, and the results were analyzed and yielded the following risk factors: Parental report of apnea, previous history of apnea, congenital heart disease, birth weight ≤2.5 kg, lower weight, and age ≤6 weeks all identified a group at high risk for subsequent central apnea. All CDRs and RFs were 100% sensitive (95% confidence interval [CI] 91%-100%) and had a negative predictive value of 100% (95% CI 99%-100%) for the subsequent apnea.

Candidate clinical decision rules from Walsh et al.

Candidate clinical decision rules from Walsh et al.

The third tool, not shown above, is a computationally-intensive algorithm that used a Random Forest method to generate a risk stratification. Much like the recently-published work on sepsis using Big Data strategies, this had a better AOC than either of the above two, which are much simpler and can by applied by clinicians. This rule and others like it may have a future in the form of electronic heath record-embedded decision support, but are less amenable to being remembered and applied by the physician at the point of care when making a disposition decision.

It is important to note some caveats about this and the results — particularly the prevalence of apnea in this population, which accepted parental reports of apneic events as part of the numerator (i.e. not just monitored and captured events), but it still underscores the idea that parental concern should be your concern until proven otherwise.

Anyway, all this to say, bronchiolitis-related apnea is a terrible outcome but a very rare outcome. Admission for observation may be considered in high-risk patients, and should be discussed with parents. If a hospital doesn’t have apnea monitoring, is it still reasonable to admit these kids for observation? That’s not really germane to the studies published here, but came up recently on one of my rotations — I guess if a respiratory arrest happened, it would be better to be in a setting where a response could occur swiftly and with full capabilities, but I don’t know that such an admission is better than sending the kid home with parents who will likely be steadfast bedside observers of the child’s respiratory status throughout the night. That question will have to wait for another study, I suppose.

References

Walsh P1, Cunningham P2, Merchant S3, Walker N3, Heffner J3, Shanholtzer L3, Rothenberg SJ4. Derivation of Candidate Clinical Decision Rules to Identify Infants at Risk for Central Apnea. Pediatrics. 2015 Nov;136(5):e1228-36. PMID: 26482666. [PubMed] [Read by QxMD]