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Thursday, March 27, 2014

Emergency Medicine Digest

Selected publications of interest

1. Does a higher MAP target in septic shock confer lower mortality target?
No. A target mean arterial pressure of 80 to 85 mm Hg conferred no mortality benefit over the standard 65 to 70 mm Hg target.

Asfar P et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014 Mar 18; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa1312173)

The surviving sepsis campaign 2012 recommends a maintenance of mean arterial pressure (MAP) target of at least 65 mm Hg as part of a sepsis bundle. However, the guideline does not mention whether a higher MAP target might improve mortality and decrease end-organ dysfunction. Neither does the guideline specify an optimal range of MAP.  The guideline simply says "at least" 65 mm Hg.

In a 29-center French study, a group of researchers compared the outcomes in 776 patients with septic shock who were randomized to MAP targets of either 65 to 70 mm Hg or 80 to 85 mm Hg.

They found that there was no significant differences between the lower-target versus the higher-target groups in 28-day mortality (34% and 37%), 90-day mortality (42% and 44%) and even the median intensive care unit length of stay (8 days in both groups).

However, consistent with other previous studies, the higher-target group had a lower incidence of doubling of the blood creatinine level and hence were less likely to require dialysis.

Previously, Dunser et al (2009) showed in a large, retrospective study, that a MAP of more than 75 mm Hg may be required to maintain kidney function. (Ref: Dunser MW, Takala J, Ulmer H, et al. Arterial blood pressure during early sepsis and outcome. Intensive Care Med 2009;35:1225-1233). This notion was later confirmed in another small, prospective, observational study. (Ref: Badin J, Boulain T, Ehrmann S, et al. Relation between mean arterial pressure and renal function in the early phase of shock: a prospective, explorative cohort study. Crit Care 2011;15:R135-R135).

Why?  Why did the higher-target group were less likely to require dialysis? The postulated basic physiological mechanism is that chronic arterial hypertension causes a rightward shift in cerebral pressure-flow autoregulation, resulting in a higher targeted mean arterial pressure to maintain organ perfusion (Ref: Strandgaard S, Olesen J, Skinhoj E, Lassen NA. Autoregulation of brain circulation in severe arterial hypertension. Br Med J 1973;1:507-510).

Unfortunately, although the higher-target group were less likely to require dialysis, this benefit seemed to be offset by a significant increased risk of developing atrial fibrillation.

Why? First of all, septic shock per se is a major risk factor for atrial fibrillation (Ref: Walkey AJ, Wiener RS, Ghobrial JM, Curtis LH, Benjamin EJ. Incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis. JAMA 2011;306:2248-2254).

But the high-target group received significantly higher doses and longer duration of vasopressor catecholamines infusion, and this was postulated by the researchers to be related to the higher incidence of atrial fibrillation. Nonetheless, this postulation remains to be verified in future trials.

2. Fixed D-dimer cutoff of 500 µg/L, versus age-adjusted D-dimer to rule out pulmonary embolism

Measurement of plasma d-dimer allows pulmonary embolus (PE) to be ruled out when clinical suspicion is low or moderate, but interpretation is complicated by the fact that d-dimer levels rise normally with age. In a multicenter European study, investigators prospectively evaluated the accuracy of an age-adjusted d-dimer cutoff in 2898 patients with low or moderate clinical probability for PE. - See more at: http://www.jwatch.org/na34001/2014/03/18/age-specific-cutoffs-d-dimer-rule-out-pulmonary-embolus#sthash.Gj3B1o3b.dpuf
Righini M, Van Es J, Den Exter PL, et al. Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism: The ADJUST-PE Study. JAMA. 2014;311(11):1117-1124. doi:10.1001/jama.2014.2135.
Measurement of plasma d-dimer allows pulmonary embolus (PE) to be ruled out when clinical suspicion is low or moderate, but interpretation is complicated by the fact that d-dimer levels rise normally with age. In a multicenter European study, investigators prospectively evaluated the accuracy of an age-adjusted d-dimer cutoff in 2898 patients with low or moderate clinical probability for PE. - See more at: http://www.jwatch.org/na34001/2014/03/18/age-specific-cutoffs-d-dimer-rule-out-pulmonary-embolus#sthash.Gj3B1o3b.dpuf

Measurement of plasma d-dimer can be used to rule out pulmonary embolus (PE) when the pre-test probability using Well's score or revised Geneva score is low but PERC score cannot rule out PE clinically (see a blog post here and here).

Unfortunately, because several studies in the past have shown that D-dimer levels increase normally with age, using a fixed cut-off value of D-dimer to rule out PE is not very useful in the elderly.
For example,  in a previous study, D-dimer test was able to rule out PE in 60% of patients younger than 40 years, but in only 5% of patients older than 80 years. This results in a lot of unnecessary costly investigations being subjected to these older and often fragile patients.

(Ref: Righini  M, Nendaz  M, Le Gal  G, Bounameaux  H, Perrier  A.  Influence of age on the cost-effectiveness of diagnostic strategies for suspected pulmonary embolism. J Thromb Haemost. 2007;5(9):1869-1877.)

In this current multicenter European study (involving 19 centers in Belgium, France, the Netherlands, and Switzerland), investigators prospectively evaluated the accuracy of an age-adjusted d-dimer cutoff (defined as age × 10 in patients 50 years or older) in 2898 patients with low or moderate clinical probability for PE as compared to a fixed the cutoff at 500 µg/mL.

It was shown that using the age-adjusted cutoff resulted in a 12% absolute increase and a 41% relative increase in the proportion of negative d-dimer results without the loss of sensitivity of detecting PE. In those patients with in-between values (between 500 µg/mL and their cut-off value), only one (0.3%) was found to have PE during follow-up.

Hence, from this study, it is suggested that:
  • for patients younger than 50 years old, use the fixed cut-off point for D-dimer at 500 µg/mL.
  • for patients 50 years and older, a D-dimer result was considered negative if it was less than (age in years ×10) µg/mL.
or patients aged 50 and older, a d-dimer result was considered negative if it was less than age ×10 - See more at: http://www.jwatch.org/na34001/2014/03/18/age-specific-cutoffs-d-dimer-rule-out-pulmonary-embolus#sthash.Gj3B1o3b.dpuf
Bear in mind, the usage of CTPA especially in elderly patients is not without risks. Elderly patients are more likely to present with renal impairment and to develop contrast-induced nephropathy. The use of the ventilation-perfusion lung scan is also limited by the higher number of inconclusive results obtained in this age group.

Sunday, February 09, 2014

Funnel or tapered shaped pediatric airway - where does this concept come from?

Pediatric airway, especially for those 2 years of age, has often been described as a funnel-shaped with its narrowest part at the level of the cricoid cartilage (in contrast with the cylindrical adult larynx).

But where does this concept originate from?

Ríos Medina et al (2012) in a review article (click here to download in pdf) stated that it was way back in 1951 when Eckenhoff wrote about the anatomical considerations of the pediatric larynx and their implications for anesthesia.

However, Eckenhoff's article was in turn based on descriptions made half a century before by Bayeux, who reported the findings from anatomic dissections in 15 bodies of children between 4 months and 14 years of age, together with their corresponding plaster models. In that article, Eckenhoff describes the cricoid cartilage as a rigid structure that cannot be distended in order to pass the ETT, and describes how its parts come together to form a ring around the larynx. Eckenhoff actually clearly states the danger of extrapolating such cadaver findings to live human beings. Unfortunately a number of anesthesiology textbooks picked up on these anatomical descriptions of the pediatric airway since then.

In 2003, Litman et al., in a study using MRI on 99 children under 14 years of age showed that the narrowest portion was identified at the cross-sectional diameter of the vocal cords.

Dalal et al. (2009), in another study using video bronchoscopy on 128 children under 13 years of age seems to confirm Litman's findings. Although the approaches are different, the glottis is identified as the narrowest portion and the larynx as being more cylindrical than rather than traditionally taughted to be tapered. Nonetheless, Litman observes that, although his results show that the narrowest portion of the pediatric airway is at the glottis entrance, functionally the cricoid cartilage is a rigid structure that cannot be distended, and it is still the site of the greatest risk for injury.

Although this new concept is probably still evolving,  the clinical implication is that cuffed ET tubes can be used safely just as with uncuffed tubes.

Thursday, January 02, 2014

Some updates from the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction (STEMI)

Some salient updates relevant to the emergency physicians from the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction (STEMI):

The criteria  for STEMI

1) ST elevation, of course with, of

    ≥2 mm (0.2 mV) in men or
    ≥1.5 mm (0.15 mV) in women for leads V2–V3


    for other leads, remember as usual,
    ≥1 mm (0.1 mV) in at least 2 contiguous chest leads or the limb leads

measured at the J point

2)  Finally..... finally, new or presumably new LBBB per se is no longer considered a diagnostic criteria for STEMI.  To quote the guideline,

New or presumably new LBBB at presentation occurs infrequently, may interfere with ST-elevation analysis, and should not be considered diagnostic of acute myocardial infarction (MI) in isolation.

In the online data supplement of the guideline (click here to access), the guideline uses the Sgarbossa's criteria as the diagnostic criteria in the presence of LBBB.

Note also that from that section of the online data supplement, ECG diagnosis of STEMI in the setting of RBBB as well as left anterior and posterior fascicular blocks does not require special diagnostic criteria. I've seen people apply incorrectly the Sgarbossa's criteria in the presence of RBBB.

3) Interestingly, posterior wall MI, with ST depression in ≥ 2 precordial leads (V1–V4) as well as

4) STE in "the forgotten lead" (or the "widow maker"), the aVR (with coexistent multi-lead ST depression) has been accorded special places in the diagnostic criteria of STEMI.

5) Not to forget, the hyper-acute T wave in the very early phase of STEMI before the development of STE.

Oxygen supplement in STEMI

The other interesting review from the guideline is that OXYGEN SUPPLEMENT is not for everybody. In fact, the guideline quotes a very interesting Cochrane review results:
A pooled Cochrane analysis of 3 trials showed a 3-fold higher risk of death for patients with confirmed acute MI treated with oxygen than for patients with acute MI managed on room air. ....Supplementary oxygen may, however, increase coronary vascular resistance.

Strange. Why would this updated guideline say that oxygen supplement may increase the risk of death when the same ACC/AHA in 2007 assigned Class I recommendation for oxygen use for cases where the SaO2 less than 90% and Class IIa for all patients with UA, NSTEMI or uncomplicated STEMI?

First, let's look at what are the rationale for the recommendation for oxygen use:

  • increasing arterial oxygen tension decreases the acute ischemic injury and the eventual infarct area and
  • the observation that some uncomplicated myocardial infarction patients have arterial hypoxemia due to fluid retention in the lungs and a ventilation-perfusion mismatch

In a Cochrane review by Cabello et al (2013), reviewing four randomized controlled trials (n = 430 participants) of patients with suspected or proven AMI (STEMI or NSTEMI) less than 24 hours after onset, in which the intervention was inhaled oxygen (at normal pressure) compared to air and regardless of cotherapies provided, the pooled RR of death was 2.05 (95% CI 0.75 to 5.58) in an intention-to-treat analysis and 2.11 (95% CI 0.78 to 5.68) in participants with confirmed AMI. While suggestive of harm, the small number of deaths recorded means that this could be a chance occurrence.

Cabello JB, Burls A, Emparanza JI, Bayliss S, Quinn T. Oxygen therapy for acute myocardial infarction. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD007160. DOI: 10.1002/14651858.CD007160.pub3. URL: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007160.pub3/abstract)
According to the guideline, oxygen therapy is appropriate for patients who are hypoxemic SaO2 less than but it may paradoxically cause coronary vasoconstriction and increased coronary vascular resistance.

Why is that so? In an excellent review article by Moradkhan and Sinoway in the Journal of the American College of Cardiology titled "Revisiting the Role of Oxygen Therapy in Cardiac Patients" (click here to access full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941910/#!po=18.7500), the authors listed a few possible mechanisms of hyperoxia coronary vasoconstriction:

1. Hyperoxia leads to the generation of reactive oxygen species

Hyperoxia leads to the generation of reactive oxygen species. This in turn decreases the bioavailability of nitric oxide and results in vasoconstriction.

2. The role of K+ATP channels in hyperoxia induced vasoconstriction

During hypoxia and ischemia, a fall in the intracellular ATP concentrations mediates the opening of ATP-sensitive potassium channels, which in turn causes hyperpolarization of the vascular smooth muscle cells and vasodilation. However, in hyperoxic situations, the closure of these K+ATP channels, mediate coronary vasoconstriction.

3. Hyperoxia can induce vasoconstriction by acting directly on L-type Ca2+ channels

Animal studies demonstrate that oxygen sensitive L-Type calcium channels are present on vascular smooth muscle cells that control the local circulatory flow during hypoxia and hyperoxia.

4. Hyperoxia may affect the release of angiotensin II with subsequent changes in endothelin-1 levels

Isolated cardiac myocyte studies demonstrate that angiotensin I is produced with hyperoxia and is subsequently converted to angiotensin II possibly on the surface of endothelial cells. Angiotensin II promotes endothelin-1 release and thereby causes vasoconstriction.

5. Hyperoxia increases the production of potent vasoconstrictor 20-HETE

Hyperoxia induces the production of 20-HETE, an arachidonic acid metabolite and a potent vasoconstrictor in myogenic regulation.

The newer antiplatelet agents

Two newer P2Y12 inhibitors are discussed besides clopidogrel, viz., prasugrel and ticagrelor (* P2Y12 has been shown to be the chemoreceptor for ADP, thus P2Y12 inhibitors inhibit ADP).

Clopidogrel has been used for a long time but the antiplatelet acivitiy of clopidogrel may vary due to reasons such as different patient phenotypes (obesity, diabetes mellitus) as well as hepatic CYP450 enzyme system polymorphisms that may interfere with clopidogrel biotransformation.

Prasugrel has been shown to achieve a greater antiplatelet aggregation than clopidogrel. In the TRITON-TIMI 38 trial, prasugrel has been shown to result in a lower 30-day rate of the composite primary outcomes of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke as compared to clopidogrel in patients with ACS for whom an invasive strategy was planned. The benefits of prasugrel relative to clopidogrel in STEMI must be weighed against the increase in the risk of bleeding with prasugrel.

Ticagrelor is a reversible, nonthienopyridine P2Y12 inhibitor that does not require metabolic conversion to active drug. Ticagrelor has been gaining quite a bit of publicity due to its landmark study, the PLATO trial. The PLATO trial shows that  treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding.

However, a rather interesting finding in a subgroup analysis in the PLATO trial showed a significant interaction between treatment effect and geographic region, with an apparently smaller ticagrelor effect in North America than in other areas. This phenomenon of geographical variation is not exactly known - it could be due to chance alone, or it could be due to higher aspirin doses commonly used in the United States.

Although 1 year of dual antiplatelet therapy (DAPT) is recommended after stent implantation during primary PCI for STEMI, earlier discontinuation of a P2Y12 inhibitor may be necessary if the risk of morbidity from bleeding outweighs the anticipated benefit of DAPT.

Fondaparinux has been widely used in our setting. The guideline however, states that Fondaparinux has been associated with catheter thrombosis. Therefore, Fondaparinux should not be given as the sole anticoagulant to patients referred for PCI. Additional intravenous boluses of UFH (or bivalirudin) should be administered. Fondaparinux is also contraindicated for patients with a creatinine clearance less than 30 ml per min.

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