tPA in ischemic stroke, “answers”


Check out our own Dr. Anand Swaminathan discussing this topic and more on ischemic stroke on ER Cast here and here!

1. How do you control blood pressure (BP) in patients who will be or/are receiving tPA?

For patients not receiving tPA for acute ischemic stroke, allowing autoregulation of blood pressure has long been the norm. tPA has muddied the waters, somewhat, for management of blood pressure for acute ischemic stroke. In the pilot NINDS study (Haley, 1993) of tPA in acute stroke, and in previous tPA and myocardial infarction studies, there was a higher association with intracranial hemorrhage (ICH) in patients with a blood pressure greater than 185 mm Hg systolic, 110 mm Hg diastolic, or who underwent aggressive treatment to reach these levels. Thus, in the randomized NINDS tPA Stroke Study (NINDS, 1995), patients were excluded if their blood pressure did not reach these goals. In the NINDS study, the term “aggressive treatment,” was not defined prospectively in the protocol. However, it has been thought to mean by expert consensus: intravenous nitroprusside, repeated doses of IV labetalol, enalaprilat, or nifedipine.

EML tPA answers

Specifically, if patients have a diastolic blood pressure >140 on two readings, they should be started on a continuous IV infusion of an antihypertensive agent, and they are not candidates for tPA therapy (Broderick, 1996). Patients who require more than two doses of labetalol or other antihypertensive agents to decrease blood pressure to <185 systolic or 110 diastolic are typically not appropriate for thrombolytic therapy (Broderick, 1996). This is a relative contraindication to thrombolytic therapy. Some stroke physicians, however, will still treat an acute ischemic stroke with tPA after two labetolol doses have been used, and a nicardipine drip has been started despite the lack of significant evidence for this practice.

Agents used to treat blood pressure in ischemic stroke should be easily titratable, have a quick onset of action, and limited risk of excessive or sudden onset of action.

In patients who require blood pressure treatment to be at an appropriate range for thrombolytic therapy, IV labetalol is a popular first line agent. Labetalol is easily titratable and is commonly started at 10 mg IV over 1-2 minutes. This can be repeated or doubled every 10 to 20 minutes. Another choice for blood pressure control is enalaprilat, which can be given in 1.25 mg increments. Nicardipine is commonly used as a titratable continuous infusion. Agents such as nitroglycerin or sublingual nifedipine may have effects that are more unpredictable like rapid drops in pressure with reflex tachycardia, so are considered second line, and are rarely used. Any patient who receives antihypertensives for ischemic stroke requires serial neurologic exams to look for signs of deterioration (Broderick, 1996).

2. Do you treat patients with tPA up to 4.5 hours after onset of symptoms. If so, which ones?

In February 2013, the American College of Emergency Physicians (ACEP) released a clinical policy statement on acute ischemic stroke, stating that they were giving treatment between 3 and 4.5 hours a Class B recommendation (ACEP, 2013). However, at this time, the use of tPA for stroke patients between 3 and 4.5 hours is not yet FDA approved, and remains widely and passionately debated.

Evidence for thrombolytics between 3 and 4.5 hours largely comes from the ECASS III trial. The benefit of tPA between 3 and 4.5 hours was directly tested in the ECASS III randomized controlled trial (Hacke, 2008). This trial used the same dosing as well as the same inclusion/exclusion criteria as the NINDS trial. This trial also excluded patients greater than age 80, those with a baseline NIH stroke scale (NIHSS) of 25 or greater, any oral anticoagulant use, and those with the combination of a previous stroke and diabetes mellitus. The number needed to treat in ECASS III was 14 patients, a more modest number than that found in NINDS, where the NNT was 8. Although the ICH rate in ECASS III was 27% in treated patients compared to 17% in untreated patients, there was no significant difference in overall mortality at 90 days. The incidence of symptomatic intracranial hemorrhage was 2.4% in treated patients compared to 0.2% in untreated patients.  Furthermore, the rate of symptomatic ICH was not higher in ECASS III compared to that in the NINDS trial (Hacke, 2008).  These trials defined a symptomatic ICH as one in which a new ICH was found on head CT in a patient with clinical deterioration following an acute ischemic stroke (NINDS, 1995).

In 2009, a metanalysis was published to specifically look at the efficacy and safety of tPA in the 3 to 4.5 hour time frame (Landsberg, 2009). They evaluated pooled data from patients in this time frame from four fairly homogenous studies: ECASS-I (n = 234), ECASS-II (n = 265), ECASS-III (n = 821) and The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) (n = 302). These authors concluded that patients treated in this time window have an increased rate of favorable outcome without adversely affecting mortality (Landsberg, 2009).

One of the concerns physicians expressed behind allowing tPA administration up to 4.5 hours is that patients and treating physicians might feel as though they had more time to treat acute ischemic strokes, which could lead to a decreased benefit of the drug. Another controversy behind administering tPA up to 4.5 hours out in acute ischemic stroke was that the ECASS III study used a slightly different definition of symptomatic ICH (sICH) than the NINDS trial did. However, even once the more conservative NINDS definition of sICH was applied in the ECASS III trial, the percent of sICH remained the same in both of the studies.

Based on these studies, tPA may be safe when administered 3 to 4.5 hours after symptom onset, as long as the specific safety criteria from the ECASS III and NINDS trials are met. However, patients still have the best outcome when tPA is administered as early as possible. The final line in the ECASS III trial states: “Having more time does not mean we should be allowed to take more time.”

3. How do you determine if an acute ischemic stroke is improving enough to not give tPA to a patient?

One of the most common reasons to withhold tPA in ischemic stroke is with mild or rapidly improving stroke symptoms (Nedeltchev, 2007).  For example, the American Heart Association stroke guidelines state that eligibility for tPA requires that “neurological signs should not be minor and isolated” (Adams, 2007). The reason behind this is that patients with rapidly improving symptoms are likely having a TIA, rather than a CVA .

The NINDS recombinant tPA Stroke Trial (NINDS, 1995) included RISS (rapidly improving stroke symptoms) as an exclusion criterion to avoid treatment of transient ischemic attacks which would have recovered completely without treatment. The NINDS trial included a very small number of RISS patients, which they defined as an NIHSS of 5 or less (58 patients with RISS were included, but 2971 were excluded due to mild symptoms). Thus, conclusions about this subgroup of stroke patients cannot be drawn from the NINDS study (Khatri, 2010).

When the FDA approved tPA in 1996, all eligibility criteria from the NINDS recombinant tPA Stroke Study were adopted (NINDS, 1995). The package insert gave contraindications and warnings directly from the study protocol, including excluding those with RISS.  The TREAT task force attempted to clarify this exclusion criteria (TREAT, 2013). They held an in-person “RISS Summit” to obtain a better understanding of this phenomenon.

The results of the TREAT task force were that, in the absence of other contraindications, patients who experience improvement of any degree, but have a persisting neurologic deficit that is potentially disabling, should be treated with IV tPA (TREAT, 2013). Improvement should be monitored for the time needed to prepare and administer the IV tPA. There was also consensus in the TREAT task force that all neurologic deficits present at the time of the treatment decision should be considered in the patient’s individual risk and benefit, as well as the patient’s baseline functional status (TREAT, 2013).

Many studies, however, have suggested that the outcome of patients with MRIS (mild and rapidly improving symptoms) who do not receive tPA is not always benign. A large study from Canada found that 32% of patients considered “too good to treat” were dependent at hospital discharge or had died (Barber, 2001). A separate study from Massachusetts General Hospital reported that patients with a high initial NIHSS, but with RISS, had a four times greater chance of neurologic worsening than patients presenting with initial mild symptoms (Adams, 2007). A third study, from UCLA, demonstrated that 10% of patients who were excluded from thrombolysis only because of their RISS status showed early neurological deterioration. Twenty percent showed a poor outcome at discharge as defined by a modified Rankin score of 3 or greater (Rajajee, 2006).

Nedelchev, et al., also found that patients with persisting proximal vessel occlusions and RISS were 7 times (95% CI: 1.1 to 45.5; P0.038) more likely to have an unfavorable outcome at three months (2007). They defined proximal occlusions as those of the internal carotid artery, M1 and M2 segments of the middle cerebral artery, A1 segment of the anterior cerebral artery, V4 segment of the vertebral artery, basilar artery, and P1 segment of the posterior cerebral artery. They also found that rapidly improving but still severe symptoms (NIHSS greater than or equal to 10 points on admission) increased the odds of unfavorable outcome 17-fold (95% – CI: 1.8 – 159.5; P = 0.013). These findings suggest that patients with persistent large-vessel occlusions and those with a NIHSS score greater than or equal to 10 points at onset of symptoms might benefit from thrombolysis despite resultant mild symptoms or rapidly improving symptoms at presentation (Nedeltchev, 2007). This study demonstrated that 75% of patients with mild or rapidly improving symptoms who were not treated had a favorable outcome at 3 months, defined by a modified Rankin score of 0 or 1, without treatment.

4. Do you use a specific age cutoff when determining whether or not a patient should or should not receive tPA?

Elderly patients with acute ischemic stroke have historically been challenging for neurologists and other stroke physicians to treat. Physicians have typically feared a higher incidence of symptomatic ICH in this group of patients. They are often excluded from trials on tPA and ischemic stroke for this reason. Thus, little data exists on the safety and efficacy of treating elderly patients with tPA for acute ischemic stroke.  This is an important topic to study, since 30% of strokes occur in patients over the age of 80 (Mishra, 2010).

In all the ECASS studies, the age restriction was set at 80. In the NINDS trial, only 44 patients older than 80 were randomized.  There had been an initial age limit of 80 years or older, but this was removed, so that some patients 80 and older were ultimately included. Their outcomes at three months were not significantly improved compared to those who did not receive tPA (NINDS, 1995). In a later subgroup analysis of this patient population, it was found that 25 of the 44 patients older than 80 had been given tPA. This group of patients were 2.87 times more likely than their younger counterparts in the study to experience a symptomatic ICH (Longstreth, 2009).

However, other studies have demonstrated more positive results of treating elderly patients with tPA. In fact, a meta-analysis of the SITS-ISTR and VISTA data (n = 29,228) revealed that increasing age is associated with a poorer outcome in general in acute ischemic stroke, but that this association was found regardless of whether or not patients were treated with tPA (Mishra, 2010). This study compared outcomes at 90 days in patients who received tPA and controls. Specifically, they examined the association of thrombolysis treatment with outcome between various age groups, with 3,439 patients aged over 80. The number needed to treat for a favorable outcome (score of 0-2 on a modified Rankin scale) was 8.2 patients. They stated that poorer outcomes are more likely to occur in the elderly due to other comorbidities rather than an increase in symptomatic ICH (Mishra, 2010). Furthermore, the tPA stroke survey experience, published in Stroke, concluded that there was no evidence to withhold tPA in patients greater than 80, as long as they were appropriately selected (Tanne, 2000). A third study, looking at stroke patients in three German stroke centers, found similar results in 228 patients, 38 of whom were 80 years or older. This study found a higher mortality in older patients (21.1% versus 5.3% at 90 days), but no difference in the rate of ICH between younger and older patients, with the authors also concluding that there is no evidence to exclude ischemic stroke patients from thrombolysis based on a predefined age threshold (Berrouschot, 2005).

At EM Lyceum we love debate, and know this is an area of particular controversy for EPs. Although our aim this month is not to rehash the controversies, we hope to add some more data to your thinking about this topic.  Even amongst our group of writers and editors we differ greatly in how we approach these questions.  We would love to hear your thoughts.

Thanks to Dr. William Knight of the University of Cincinnati for his expert thoughts on this topic.



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tPA in ischemic stroke, Questions

1. How do you control blood pressure in patients who will be/are receiving tPA?EML tPA questions

2. Do you treat patients with tPA up to 4.5 hours from onset of symptoms, and if so which ones?

3. How do you determine if an acute ischemic stroke is improving enough to not give tPA to a patient?

4. Do you use a specific age cutoff when determining whether or not a patient should or should not receive tPA?

EML Ischemic Stroke and tPA Questions Poster

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Fluid Responsiveness, “Answers”

1. How do you assess fluid responsiveness in the ED? Do you use IVC collapsibility in spontaneously breathing patients?

Although fluid resuscitation is paramount in the treatment of sepsis, volume overloading critically ill patients has been shown to worsen outcomes including length of intensive care unit (ICU) stay, days on a ventilator, and mortality (Rosenberg, 2009). Methods of assessing volume status (preload) and hemodynamic response to fluid challenges (volume responsiveness) are thus very important when managing these patients. Until recently, central venous pressure (CVP) monitoring dominated clinician guidance of fluid management and was used regularly by over 90% of intensivists (McIntyre, 2007). CVP represents the right atrial pressure and has erroneously been extrapolated to estimate left ventricular preload and thus fluid responsiveness. A recent meta-analysis found no relationship between CVP and circulating blood volume, left or right ventricular preload, or fluid responsiveness (also known as the “seven mares” article, Marik, 2008). Alternative methods of determining volume status and fluid responsiveness have subsequently been sought with greater fervor.

EML fluid responsiveness answers

Pulmonary artery occlusion pressure (PAOP) measured via a pulmonary artery catheter, like CVP, fails to reflect preload or volume responsiveness (Marik, 2010). Other static indices including left ventricular end-diastolic area (LVEDA) measured by transesophageal echocardiography and global end-diastolic volume measured through a cardiac output monitor (PiCCO), although predictive of preload, also fail to accurately predict fluid responsiveness (Marik, 2010).

Dynamic measurements perform better in predicting fluid responsiveness but generally require mechanical ventilation to control for substantial variation in respiratory cycle volumes and intrathoracic pressures characteristic of spontaneous breathing patterns. Pulse pressure variation (PPV) measured by arterial waveform and stroke volume variation (SVV) measured by arterial or pulse oximeter plethysmographic waveform, have been show to correlate very well with volume responsiveness. The sensitivity and specificity of PPV has been documented at 89% and 88% respectively, and that of SVV has been documented at 82% and 86% (Marik, 2010). Accurate measurements do require tidal volumes of 8-10L/kg and specialized analysis devices. Inferior vena cava diameter distensibility (dIVC) with respiration, although criticized by some as having limitations similar to CVP (Marik, 2010), has been studied repeatedly in mechanically ventilated patients and appears to be a valid option for predicting volume responsiveness. Barbier showed that dIVC >18% predicts volume responsiveness with a sensitivity and specificity of 90% (Barbier, 2004). Other studies, though small and observational, show a similar correlation (Machare-Delgado, 2011; Moretti, 2010).

Unfortunately, all the aforementioned techniques possess limitations that will often preclude their application in the Emergency Department. In the ED, the ideal method for measuring fluid responsiveness must be technically easy, fast, non-invasive and, importantly, reliable in spontaneously breathing patients. SVV measured by arterial waveform has been shown to be predictive of volume responsiveness in spontaneously breathing patients at a threshold of 17% (PPV 100%, NPV 82%, p=0.03) in at least one study (Lanspa, 2013). This technology, however, requires placement of an arterial line and specialized equipment not available in most EDs. Similarly, straight leg raise predicts fluid responsiveness reliably but requires invasive monitoring like an a-line or specialized equipment (Benomar, 2010). IVC collapsibility on the other hand is technically easy, non-invasive and recent studies suggest it may have a role in spontaneously breathing patients. In spontaneously breathing patients, the IVC collapses on inspiration and distends on expiration.  Upon intubation, the patient’s physiology reverses from negative pressure to positive pressure.  As a result, the IVC distends on inspiration and collapses on expiration. The best available IVC data consists of two observational studies, which ultimately offer cautious support for use of IVC collapsibility in breathing patients. The first found IVC inspiratory variation greater than 40% to predict fluid responders with a sensitivity of 70% and specificity of 80%. Values of below 40%, however, could not be used to exclude fluid responders (Muller, 2012). The second study found variations in inferior vena cava index less than 15% to have 100% negative predictive value (p=0.03) for fluid responsiveness whereas over 50% variation had a positive predictive value of 75% (p=0.09) (Lanspa, 2013). Both studies used subcostal windows to assess inferior vena cava diameter variation as it entered the right atrium. Though promising, this data should be interpreted carefully given the small size of the studies, the lack of statistical significance for some values, and the wide range of clinically indeterminate values of IVC collapsibility.

It is important to remember that all of the cited studies apply to initial resuscitation in the ICU, often after aggressive fluid resuscitation in the ED. The need for a more cautious approach to fluid resuscitation during the initial management of critically ill, particularly septic, patients in the ED is less established.

2. Which crystalloid fluid do you use to resuscitate critically ill patients?

Normal saline (NS) is traditionally the first-line fluid for resuscitation of critically ill patients in the ED. NS first came into widespread use in the 1830’s during the European cholera epidemic, saving countless lives. The actual electrolyte content of NS during its early days was likely more “normal” than it is today, with estimated levels of sodium and chloride at 134 and 118 mmol/L respectively (Yunos, 2010). Today, NS is neither normal nor physiologic, containing 154 mmol/L of both sodium and chloride. Every liter of NS administered thus delivers supra-physiologic levels of these electrolytes, which play key roles in the acid-base physiology. Alternate crystalloid solutions including Hartmann’s Lactated Ringers (LR) and balanced electrolyte solutions (BES) such as Plasma-Lyte offer more physiologic concentrations of electrolytes and may have unique advantages for resuscitation in critical care. Small variation in electrolyte content can make clinically important differences when resuscitating with large volumes or when caring for patients over extended periods in the ICU. In the current era of hospital overcrowding and extended ED stays, this concern becomes particularly relevant to all ED physicians.  See table below for details of electrolyte content of commonly used fluids (Table 1).

Table 1: Electrolyte Content of Common Crystalloid Solutions (mmol/L)

Plasma Normal Saline Hartmann’s LR Plasma-Lyte
Sodium 140 154 131 140
Potassium 5 0 5 5
Chloride 100 154 111 98
Bicarbonate 24 0 0 0
Calcium 2.2 0 2 0
Magnesium 1 0 1 1.5
Lactate 1 0 29 0
Acetate 0 0 0 27
Gluconate 0 0 0 23

Specifically, high chloride content has been targeted as a potential source of harm in large volume crystalloid resuscitation. New understanding of complex acid-base physiology, namely the Stewart physiocochemical approach, is the driving force behind recent attention given to chloride. Briefly, under this approach, chloride is the predominant negative strong ion in plasma and a key component of the strong ion difference (SID), which directly influences hydrogen ion concentration and thus acid base status (Yunos 2010). NS resuscitation has been clearly linked to hyperchloremic metabolic acidosis (HMA), but debate exists regarding its clinical significance (Yunos, 2010; Heijden, 2012). Preclinical and healthy human volunteer data provide increasing evidence for chloride-associated hypotension, reductions in renal cortical perfusion, decreased glomerular filtration rate (GRF) and pro-inflammatory states (Chowdhury, 2012; Yunos, 2010; Wilcox, 1983; Kellum, 2004; Kellum, 2006). Recently, a prospective, open-label study looked at chloride liberal vs. chloride restrictive fluid resuscitation of critically ill patients and its effect on acute kidney injury (AKI). Importantly, in this study of over 1500 patients, resuscitation with chloride restrictive fluids was associated with statistically significant lower rise in serum creatinine levels and less incidence of AKI. Though a secondary outcome, patients receiving chloride restrictive fluids also received less renal replacement therapy (Yunos, 2012). The combined existing evidence, now bolstered by a well-designed clinical trial, calls into question the routine use of potentially harmful chloride-rich fluids when alternative, equally effective options are available.

Choice of crystalloid fluid may be particularly important in conditions with disarray of electrolytes and acid-base status such as diabetic ketoacidosis (DKA). Patients in DKA are profoundly volume depleted and require large volumes of NS for resuscitation. As a result, HMA commonly occurs during treatment and complicates the management of DKA (Morgan, 2002). A blinded, randomized controlled trial compared a balanced electrolyte solution (BES), Plasma-Lyte, to NS for prevention of HMA during resuscitation of patients with DKA. Patients receiving BES were found to have significantly lower levels of chloride and higher levels of bicarbonate, consistent with prevention of HMA (Mahler, 2010). A smaller, non-randomized study found similar results (Chua, 2012). Less evidence is available for LR and DKA. A randomized controlled trial compared NS to LR for resolution of acidosis. This study was small and terminated early due to poor enrollment; there was a non-significant decrease in time to resolution of acidosis in the group receiving LR (Van Zyl, 2011) As mentioned previously, the clinical significance of HMA is still debated, but mounting evidence suggests avoidance of HMA may be beneficial to the patient.

3. Do you ever use hypertonic saline in patients with septic shock?

Through multiple inflammatory mechanisms, sepsis creates a pathophysiologic state of vasodilation and increased endothelial permeability with resultant maldistribution of blood flow. Rapid and high-volume fluid resuscitation is a key element to counter this effect and to adequately deliver oxygen to tissues in patients with septic shock. Hypertonic fluids may offer unique benefits over other crystalloids. Hypertonic saline osmotically pulls fluid from intracellular spaces into the vasculature, resulting in rapid plasma expansion that supersedes the actual volume infused. This effect permits use of smaller fluid volumes, decreasing risk of edema, further improving oxygenation of tissues. Preclinical data supports the use of hypertonics in sepsis, with cardiovascular benefits ranging from improved volume expansion to increased cardiac contractility and better splanchnic perfusion (Garrido, 2006; Ing, 1994; Oi, 2000). Additionally, enhanced immunomodulatory effects including reduced bacterial colony counts and enhanced bacterial killing have been demonstrated with hypertonics (Shields, 2003).

Good clinical data on hypertonics and sepsis, however, is limited and further studies are needed. Two small, randomized controlled trials evaluated an initial bolus of hypertonic saline with colloid compared to colloid or NS alone and found improved cardiac function with hypertonics (Oliveira, 2002; van Haren, 2012). In Oliveira’s study, the group receiving 7.5% saline/dextran was found to have significant increases in cardiac index, pulmonary artery occlusion pressure and stroke volume index without significant side effects (Oliveira, 2002). Van Haren found the 7.2% hypertonic/hydroxyethyl starch (HES) group to have increased cardiac contractility and a decreased need for further fluid resuscitation in the following 24 hours. Although these studies were randomized, both were extremely small thus preventing the evaluation of clinically important measures including mortality and potential risks including hypernatremia and acid-base effects.


4. What is your threshold for giving blood transfusions? Does this change in patients with cardiac disease or GI bleeds?

In states of high metabolic demand accompanying critical illness, oxygen requirements can outpace supply, creating an oxygen debt at the tissue level. Allogeneic red blood cell (RBC) transfusions have long been a cornerstone in critical care management to counter this imbalance and augment delivery of oxygen to tissues. Prior to the TRICC trial in 1999, a hemoglobin (Hgb) transfusion threshold of 10 g/dL was standard practice. Growing concern over the complications of RBC transfusions, including immunosuppression, inflammation, infection and transfusion reactions, particularly in the critically ill, prompted the landmark TRICC trial. This was a randomized controlled trial comparing a restrictive versus liberal (7.0 g/dL vs.10.0 g/dL) Hgb transfusion threshold. Actively bleeding patients and those with acute coronary syndrome (ACS) were excluded; patients with cardiac disease were included. The TRICC trial showed no difference in 30-day mortality for a restrictive compared to liberal transfusion threshold (18.7% vs. 23.3%, p=0.11). Additionally, fewer cardiac adverse events and smaller changes in multi-organ system dysfunction scores were seen in the restrictive group (Hebert, 1999). This trial firmly established a threshold of 7.0 g/dL as an acceptable Hgb transfusion strategy in the critically ill. Supporting this conclusion, a 2012 Cochrane review found restrictive strategies to result in a 39% reduction in blood transfused, an overall reduction in in-hospital mortality, and no difference in mortality at 30 days (Carson, 2012).

In a subgroup analysis of the TRICC trial, the restrictive arm showed no difference in 30 and 60-day mortality for patients with cardiovascular disease 20.5% vs. 22.9% (p=0.69). This finding differed significantly from preexisting observational data, which showed increased mortality with a restrictive strategy (Carson, 1996). Complicating the picture, when confirmed ischemic heart disease, severe peripheral vascular disease, and severe comorbid cardiac disease were isolated from all cardiac disease (i.e. group of most clinically relevant cardiac disease), a non-significant trend towards increased mortality was seen in the restrictive group (p=0.3) (Hebert, 2001).

To address this discrepancy, the FOCUS trial compared a liberal (Hgb <10 g/dL) vs. restrictive (Hgb <8 g/dL or symptomatic) transfusion threshold in patients with CAD or CAD risk factors undergoing hip surgery. Using a composite endpoint of death and inability to walk independently, the restrictive strategy was found to be no different. No difference was found in secondary outcomes of adverse cardiovascular events (Carson, 2011). This study was billed to be the definitive trial for restrictive transfusion thresholds in patients with CAD but it has received significant criticism. Utilization of a composite end point with components differing greatly on clinical significance (walking independently and death) can cloud results and lead to misleading interpretations. Although mortality was reduced in the restrictive strategy (6.6% vs. 7.6%), a much larger sample size would be required to draw significant conclusions (Meybohm, 2012). The American Association of Blood Banks’ (AABB) clinical practice guideline offers a weak recommendation for transfusion of hemodynamically stable patients with cardiovascular disease at Hgb concentrations of 8 g/dL or for symptoms (Carson, Grossman, 2012).

To date, no randomized controlled trial of transfusion strategies in patients with active ACS has been undertaken. A review of existing studies consisting primarily of observational data concluded that in patients admitted for ACS, transfusions at Hgb >11 g/dL increased mortality but at Hgb <8 g/dL, transfusions decreased mortality or did no harm. Given the observational nature of the studies, however, conclusions cannot be drawn (Garfinkle, 2013). The AABB does not make a recommendation for transfusion thresholds in patients with ACS, citing absence of quality data (Carson, Grossman, 2012).

A restrictive transfusion strategy appears to be safe in patients with CAD, but importantly, none of the above trials included actively bleeding patients. In 2013, Villanueva published a landmark paper in the New England Journal addressing transfusion thresholds in patients with acute upper GI bleeds. In this trial patients were randomized to transfusion Hgb thresholds of 7 g/dL vs. 9 g/dL. Patients in the restrictive group had significantly decreased bleeding, fewer adverse events and increased survival at 6 weeks. With this evidence, patients with active upper GI bleeds can now be considered prime candidates for restrictive transfusion thresholds, which may not only be safe, but beneficial (Villanueva, 2013).

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Fluid responsiveness, Questions

1. How do you assess fluid responsiveness in the ED? Do you use inferior vena cava (IVC) collapsibility in the spontaneously breathing?

EML Fluid response
2. Which crystalloid fluid do you use to resuscitate critically ill patients?
3. Do you ever use hypertonic saline in patients with hemorrhagic or septic shock?

4. What is your threshold for transfusing blood? Does this change in patients with cardiac disease or GI bleeds?

EML Fluid responsiveness Questions Poster

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Troponin testing, “Answers”

Troponin is a structural protein found in striated muscle and is involved in calcium processing.  Although troponin can be found in many types of muscle, cardiac troponins are structurally different from the variety found in skeletal muscle. Therefore tests can be created to selectively distinguish them.  There are three forms of cardiac troponins: I, T and C. Most troponin is structurally bound but about 3-6% exists in a “cytosolic pool.” This troponin is released immediately upon injury and is detectable within 4-6 hours of coronary occlusion, depending on assay.  Cardiac troponin remains elevated in the serum for up to 10 days (Jaffe 2005).  For the purpose of this summary, we will refer to cardiac troponins simply as “troponins.”EML Troponin testing Answers

It is important to understand that a positive troponin does not diagnose myocardial ischemia/infarction. A positive troponin risk stratifies a patient to an increased likelihood of ischemia or infarction but is not diagnostic.  Currently, a positive troponin is defined as an elevation of troponin above the 99th percentile of normal (ACC/AHA Guidelines, 2007).  However, a troponin can be elevated for a number of reasons some of which are detailed in the following table (Limkakeng, 2012).

Non-CAD Causes of Troponin Elevation
Cardiac Contusion
Aortic Valve Disease
Pulmonary Embolism
Renal Failure
Drug Toxicity

Additionally, a negative troponin does not rule out ischemia or infarction.  If a patient presents very early in their course it is possible that there has been inadequate leakage of troponin into the serum and a first troponin may be negative.  Some patients experiencing unstable angina will not produce positive troponins but are at risk of significant morbidity and mortality. Therefore, a negative troponin simply risk stratifies a person to a lower risk of ischemia or infarction.

1. Do you ever send a single troponin in patients with chest pain?  If so, when?

Acute Coronary Syndrome includes three diagnoses: ST Elevation MI (STEMI), Non-ST Elevation MI (NSTEMI) and Unstable Angina (UA).  Currently, serial EKGs and serial serum cardiac biomarkers are the workhorses of ACS evaluation.  Troponin elevations in patients with ACS symptoms have been shown to predict which patients are at risk of major adverse cardiac events.  In spite of the fact that they are cheap, noninvasive, yield rapid results, and are objective data points, a great deal of controversy surrounds their use, application, and diagnostic utility.  One of the major debates surrounds the use of a single troponin to “rule-out” ACS.

The goal of serial troponin testing is to rule out NSTEMI since STEMI is ruled in/out by presenting EKG.  ACC/AHA guidelines stress that serial troponins are necessary to rule out an acute myocardial infarction (AMI) (ACC/AHA Guidelines, 2007) and should be spaced apart by at least 6 hours (Alpert, 2000).  Serial troponin testing is the standard of care because early on in a patient’s myocardial ischemic event, it is feasible that there has not been adequate leakage of troponin into the serum to be detected by our troponin assays.  Thus, getting a second troponin spaced apart in time would catch these “early presenters.”  Although the current ACC/AHA recommendations support serial troponins at least 6 hours apart, many physicians have narrowed their time between troponin testing.  MacRae, et al., found that the window could be shortened to 3-4 hours in between troponin testing without increasing the number of missed troponin elevations (MacRae, 2006).  Additionally, this research team found that if the patient’s symptom onset was taken into account, serial troponins could be obtained 1 hour apart without missing any delayed elevations as long as at least one troponin was obtained 6 hours after symptom onset (MacRae, 2006).

Based on this logic, a more sensitive troponin assay would allow for the detection of small troponin leakage early in the clinical course and could theoretically “rule out” NSTEMI with a single test.

In September 2011, Body, et al., published an article in the Journal of the American College of Cardiology (JACC) investigating the utility of a High Sensitivity Troponin Assay (hs-cTnT) (Body, 2011).  In their study, they found that no patient with a negative first hs-cTnT assay was found to have an MI by standard serial troponin testing giving a sensitivity of 100%.  The authors concluded that a single negative hs-cTnT would rule out an acute MI.  Unfortunately, the assay had an extremely low specificity (34%) i.e., the majority of patients with a positive hs-cTnT assay were found to not have an acute event.  Raising the cutoff for hs-cTnT assay in an attempt to increase specificity predictably led to an unacceptably low sensitivity (85.4%).

What about single standard troponin assays in patients with atypical symptoms?  This is the more common question that arises in the clinical setting.  The idea of getting a single troponin to rule out an AMI (mainly NSTEMI) definitely runs counter to the traditional teaching.  However, many experts support its use in specific situations.  In patients with low risk historical features (no comorbidities, etc) and constant chest pain for greater than 4-6 hours, or with chest pain that resolved more than 4-6 hours ago, many clinicians will obtain a troponin on presentation and if negative, consider the diagnosis of AMI effectively “ruled out.”  There are no studies or clinical guidelines to support this approach but from a physiologic standpoint, it may make sense. If a patient had chest pain representative of ischemia or infarction lasting for 4-6 hours, you would expect the initial troponin assay to be elevated based on the test’s characteristics.  Similarly, if the patient had an ischemic event 4-6 hours ago (that has now subsided) we would expect the initial troponin to be elevated and reflect this.

While EKGs and troponins can be used to rule out STEMI and NSTEMI, we still haven’t addressed the third part of ACS: UA.  The current standard (as set by the AHA) for determining if a patient’s symptoms are reflective of UA is serial troponins and EKGs followed by evocative testing (i.e. stress test) within 72 hours.  Thus, no number of negative troponins (whether it be 1 or 100) rules out unstable angina since, by definition, it does not cause troponin elevation.  However, there are a number of studies demonstrating that in low risk populations, a single negative standard troponin effectively risk stratifies patients to an extremely low risk of cardiac event at 30 days (0.2%) (Marsan, 2005 Walker, 2001; Lee, 1992).  The low risk population was defined by: Age < 40, Low risk chest pain according to physician judgment, EKG without ST elevations or depressions, vital signs stable, and no history of known heart disease.

So what are our actual conclusions regarding single troponins?  The high-sensitivity troponin assay may help to rule out some patients early on without serial testing.  However, it will lead to many more false positives and the extensive workup that follows a positive assay and overall, cause more harm than good.  Using a single standard troponin to “rule out” AMI has never been validated. However, in the right, low-risk population, a single negative troponin risk stratifies patients to an ultra low-risk group and may help with early discharge from the ED with outpatient follow up.

2. How do you manage patients with end-stage renal disease (ESRD) and chest pain who have equivocal troponins?

How many times have you heard from your admitting consultant, “that troponin is meaningless.  That patient has renal failure.  He always has an elevated troponin.  It doesn’t mean he’s having an ischemic event.”  This is usually followed by a comment on how troponin is renally cleared and that the patient is simply accumulating troponin that would otherwise be urinated out by a person with normal kidney function.  Unfortunately, all of this is untrue.

Troponin is not cleared by the kidneys and thus, is unaffected by dialysis.  It has been hypothesized that chronic troponin elevations in renal failure patients results from ventricular hypertrophy, chronic fluid overload, or endothelial dysfunction (Jaffe, 2005).  Quite to the contrary, renal failure patients with elevated troponins (even asymptomatic ones) have been found to have increased long-term mortality (Apple, 2002; Khan, 2005).  Additionally, multiple studies have found that renal failure patients with chest pain and elevated troponins are at a higher risk of adverse cardiac events and death at 30 days compared to patients with and without ESRD without elevated troponins (Aviles, 2002; Kontos, 2005).

This doesn’t mean that all troponin elevations in patients with renal failure are indicative of myocardial ischemia or infarction.  In fact, patients with renal failure and elevated troponins often have no identifiable coronary disease (Lamb, 2004).   Additionally, a recent study found that 100% of asymptomatic ESRD patients had a positive high-sensitivity troponin assay result (Jacobs, 2009).

Confused?  To recap: Troponins are just one part of risk stratification in patients with chest pain, regardless of renal function.  If a patient with renal failure presents with concerning symptoms and has a positive troponin assay, they should be considered to have an increased likelihood of ischemic event and treated accordingly.  In a patient with questionable symptoms and an elevated troponin level, the clinician can consider getting serial troponins to see if the troponin level is stable or increasing.  The National Academy of Clinical Biochemistry (NACB) recommends a 20% change in troponin concentration for the diagnosis of AMI in patients with ESRD but these recommendations are based on older generation assays (Lamb, 2004).

3. Do you send a troponin on patients with presumed pericarditis?

Pericarditis in and of itself should not cause an elevation in cardiac troponin.  Inflammation of the myocardium or myocarditis leads to a leakage of troponin into serum.  Thus, the presence of an elevated troponin in a patient with pericarditis suggests myocarditis, not more severe pericarditis.  This pathophysiology is markedly different than the pathophysiology of troponin elevation in myocardial ischemia/infarction.  In one study of 69 patients with acute pericarditis, 49% were found to have troponin elevations. Of those who went on to have cardiac catheterizations, none were found to have coronary artery disease (Bonnefoy 2000).  Troponin testing in this disease raises the following question: what are the prognostic and treatment implications of a positive troponin in patients with pericarditis? It has been hypothesized that an elevated troponin may indicate more severe inflammation and may be a prognostic indicator leading some clinicians to obtain troponin levels in all patients with pericarditis.

There is scant evidence to defend this approach.  Imazio, et al., found that of 118 serial cases of pericarditis, 32.2% had elevated troponin I levels.  It appeared that young patients, those with ST elevations, and those with pericardial effusions were more likely to have detectable troponin levels.   At 24-month follow up, the troponin positive group showed no differences in important outcomes (recurrent pericarditis, death) (Imazio, 2003).

While it appears that many patients with pericarditis have elevated troponin levels, it is unclear whether an elevated troponin is a prognostic indicator or should be used to guide treatment.  It does appear clear from the literature that the pathophysiologic mechanism of a troponin elevation in pericarditis does not indicate the presence of underlying coronary artery disease.  The key issue is a good history leading to an accurate diagnosis and initiation of therapy (NSAIDs, cardiology follow up, etc.).  Although there is not yet an evidence basis to guide this, we recommend obtaining a troponin in patients with persistent tachycardia (despite treatment of fever and pain if appropriate) and in patients with pericardial effusions (as these patients may have more severe pericarditis accompanied by myocarditis).

4. Do you send a troponin on patients who present with lone atrial fibrillation and no chest pain or anginal equivalent symptoms?  What about other atrial tachydysrhythmias?

As mentioned earlier, tachydysrhthmias are one of the many non-ischemic causes of elevated troponins.  It is believed that the shortened diastole period seen in tachydysrhythmias causes under-perfusion of coronary arteries leading to subendocardial ischemia (Jeremias, 2005).  There are few recommendations from professional societies on whether patients presenting with atrial tachydysrhythmias should have troponins sent (Camm, 2010; Fuster, 2006). A number of case seres over the last 10 years have shown that atrial tachydysrhythmias frequently result in elevated troponin levels in patients without coronary artery disease on stress test or catheterization (Redfearn, 2005; Zellweger, 2003; Kanjwal, 2008; Nunes, 2004; Miranda, 2006;).

In spite of this, troponins are often sent to diagnose myocardial ischemia or infarction as a possible cause or consequence of the tachydysrhythmia.  Meshkat, et al., found that 86% of patients presenting with AFib/AFlutter had at least a single troponin sent in a retrospective chart review (Meshkat, 2011).  In this study, 13.7% of patients who were tested had elevated troponin levels and 4.9% of the patients were treated for ACS.  Forty percent of the patients had serial troponins.  Overall, only 7 patients out of the group that had positive troponins (n = 53, so 13%) had a positive workup for ACS.  As a retrospective study, this study had many limitations, making it insufficient evidence against troponing testing in atrial tachydysrhytmias.  What this study does demonstrate is the varied approaches to the workup of patients with AFib/AFlutter who present to the ED and suggests the generally low overall yield of troponin testing.

Once again, we have a paucity of good research to inform practice.  In patients with atrial tachydysrhythmias who have ischemic symptoms it seems reasonable to initiate serial troponin testing. In patients with multiple comorbidities who have been tachycardic for a prolonged period of time, serial troponin testing may be useful in risk stratifying patients, although the significance of these elevations is unclear. Finally, in young, healthy patients with new-onset atrial tachydysrhythmias (particularly AFib/AFlutter) and no ischemic symptoms, serial troponin testing does not appear to be beneficial.  Again, there is limited evidence for these recommendations and this represents an area ripe for further research.

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Troponin testing, Questions

1. Do you ever send a single troponin in patients with chest pain? If so, when?

EML Troponin Questions2. How do you manage patients with end stage renal disease (ESRD) and chest pain who have equivocal troponins?

3. Do you send a troponin on patients with presumed pericarditis?

4. Do you send a troponin on patients who present with lone atrial fibrillation and no chest pain or anginal equivalent symptoms? What about other atrial tachydysrhythmias?

EML Troponin Questions Poster

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Pneumothorax, “Answers”

1. How good is CXR for detection of a pneumothorax? Ultrasound? When do you get a chest CT in someone you suspect may have a pneumothorax but has a negative CXR?

EML PTX AnswersThe sensitivity of a chest radiograph (CXR) for the detection of a pneumothorax (PTX) depends on how it is taken, with the upright posteroanterior (PA) film being a far better study than the supine x-ray.  Interestingly, there are no published studies comparing erect PA chest x-rays with CT as a gold standard. Ball, Kirkpatrick & Feliciano (2009) quote unpublished data that suggest upright PA films have a sensitivity of 92%. Other studies have shown sensitivity closer to 80-85% (Seow, 1996), including one from 1990 in which CT was compared to upright CXR as a non-inferiority trial for CT in detection of pneumothoraces (PTXs) after CT-guided thoracic biopsies (Murphy, 1990).   Not surprisingly, they found that CT was as good, and indeed a bit better (though not significantly more so) at detecting PTXs than conventional radiography which caught only about 84% of them.

Supine anteroposterior (AP) chest x-rays–the staple imaging study performed on trauma patients–are a notoriously poor imaging modality for the detection of PTXs. This is due to the tendency of air to track to the least dependent pleural recess, which in the supine patient is the anteromedial space. Though the deep sulcus and double diaphragm signs, among others, can provide clues to the presence of a PTX, they are not prevalent enough to make the supine film a reliable means of detecting a partially collapsed lung.  One review quotes sensitivities as low as 36-48% (Wilkerson, 2010), with even lower rates (24%) found when x-rays are interpreted by a trauma team (Ball, 2009) versus by radiologists.

At least one case report has suggested that oblique AP films may be used to aid in the diagnosis of a PTX in the supine trauma patient (Matsumoto, 2010). However, a modality being more rapidly accepted and adopted is ultrasound.  While there have been many retrospective studies done evaluating the sensitivity and specificity of ultrasound for this purpose, there have been fewer prospective, blinded studies done. Wilkerson et al. (2010) performed a review of related published literature in 2010 and found four RCTs that met specified criteria. The sensitivities of ultrasound reported in these studies were 86-98%, with specificities of 97-100%.  This compared with sensitivities and specificities of 28-75% and 100% respectively for supine AP chest radiographs. Similar results were found in a subsequent prospective single blinded convenience sample study, which found ultrasound to be 81% sensitive, while only 32% of PTXs were identified on the supine CXR (Nagarsheth, 2011).

There is no clean-cut answer as to when/whether to get a CT on a patient who has a negative chest x-ray. In part this is because there is much debate about the significance and management of “occult” PTXs–meaning those that are not visible on X-ray but are seen on CT. This topic will be addressed further in the next question. The British Thoracic Society’s Pleural Disease Guidelines of 2010 states that after a standard erect PA x-ray is taken, “if uncertainy exists, then CT scanning is highly desirable.” (Havelock, 2010).

Bottom line: Upright PA chest x-rays are good at detecting PTXs (~85% sensitive), supine AP films are poor (generally far less than 50% sensitive) and ultrasound is better than either (86-98% sensitive).  Whether to get a CT depends on your initial imaging modality combined with your clinical suspicion for a PTX (or other thoracic injury, as in the case of blunt trauma), as well as whether you think it would change your management of the patient.

2. How do you manage occult traumatic pneumothoraces? What if the patient requires mechanical ventilation?

An occult PTX (OPTX) is defined as one that is not suspected clinically and is not evident on plain films but is identified on CT scan.  The increased use of CT in trauma has led to a marked increase in the number of PTXs diagnosed (Plurad, 2007).  There is much debate about how to manage these. The argument for avoiding tube thoracostomies are the high complication rate (~22%) of the procedure as well as longer associated hospital and ICU stays. Aggressive treatment, on the contrary, may prevent a worsening PTX and the development of a tension PTX.

Advanced Trauma Life Support (ATLS) guidelines state “Any PTX is best treated with a chest tube . . . Observation and aspiration of an asymptomatic PTX may be appropriate, but the choice should be made by a qualified doctor; otherwise, placement of a chest tube should be performed.” An increasing number of studies (both retrospective reviews and prospective RCTs) argue against invasive interventions for OPTX, favoring observation for signs of clinical progression. These studies note a non-significant difference in the progression of OPTX, incidence of pneumonia, and mortality between those with and without thoracostomies.

Supporting this view is a review and analysis of the related RCTs which concluded that observation may be at least as safe and effective as the placement of chest tubes for the management of the occult PTX (Yadav, 2010).  Other reviews of current pertinent literature found that it appears safe to observe patients with small to moderate PTXs (Ball, 2009; Mowery, 2011). Unfortunately, most of the available studies and trials have small sample sizes and are typically only Level III evidence. Ideally, the treatment course would be dictated by the ability to predict which OPTX will remain stable and resolve and which will progress; however, no study has been prospectively validated to accomplish this.

While there seems to be increasing agreement in managing small to medium-sized PTXs with observation, there is less consensus on what to do with the occult PTX in a ventilated patient.  ALTS guidelines state that all patients with PTXs who are undergoing positive pressure ventilation (PPV) should have chest tubes placed (PPV theoretically can turn a small PTX into a tension PTX). However, the evidence is mixed.  Two out of three small randomized control trials reviewed by Yadav, et al. (2010) found no difference in outcomes for patients with OPTX who had PPV. The third (Enderson, 1993) found a higher rate of complications, including tension PTXs, in vented patients.  However, recent practice guidelines published in the Journal of Trauma concluded from the same evidence that the studies “would support the notion that the majority of patients with occult pneumothoraces will not have progression regardless of the presence of positive pressure ventilation” (Mowery, 2011). This sentiment seems to be supported by a growing body of retrospective and prospective studies (Barrios, 2008; Mahmood, 2011).

3. In patients with a primary spontaneous pneumothorax, do you automatically place a chest tube? When might you consider a pigtail catheter or even simple needle aspiration?

Historically, most PTXs, including primary spontaneous pneumothoraces (PSPs) were treated with large bore (>24F, as defined by the American College of Chest Physicians) chest tubes.  Current recommendations regarding their management are changing based on emerging evidence that more conservative measures such as small-bore catheters (<14F), needle aspiration, or even observation are reasonable and possibly even preferable. When weighing the various approaches, one must consider several factors including: patient stability, whether this is an initial or recurrent PTX, size of the PTX, efficacy of the procedure as well as associated pain/discomfort, complications, likelihood of initial success of the procedure, and likelihood of recurrence of the PTX.

For this discussion, we will take the case of a hemodynamically stable patient with a first occurrence of PTX that is large enough to require intervention.  It is generally accepted that in the stable patient with a first episode of a small PTX, observation and outpatient management (assuming no progression after observation) is appropriate (Baumann, 2001; Macduff, 2010). “Small” is defined variably by different groups. The American College of Chest Physicians defines it as less than 3cm apex-to-cupola distance (Baumann, 2001), whereas the British Thoracic Society defines it as >2cm interpleural distance at the level of the hilum (Macduff, 2010).

The American College of Chest Physicians 2001 Delphi Consensus statement on the management of spontaneous PTXs recommends either chest tube or pleural catheter for large PTXs. They state that there is no role for aspiration except possibly in the situation of a small PTX that has progressed during an observation period in an otherwise stable patient (Baumann, 2001). On the other end of the spectrum is the British Thoracic Society (BTS) whose 2003 guidelines recommended simple aspiration as the first line treatment of “all primary pneumothoraces requiring intervention” (Henry, 2003). The 2010 update of the BTS guidelines takes a slightly more nuanced approach stating that while they believe that needle aspiration remains the procedure of first choice in most cases, they also recommend taking into account operator experience and patient choice when deciding on an approach (MacDuff, 2010).

These differences are in part a result of timing of the guidelines and partly due to the paucity of relevant data. There are few retrospective studies and even fewer well-powered and methodologically-sound randomized controlled trials comparing any two–let alone all three–of the modalities being considered here. The most studied comparison is that between needle aspiration and large bore chest tube placement which boasts four RCTs: Noppen, 2002; Ayed, 2006; Harvey, 1994; Andrivet, 1995. Comparatively, there is only one small RCT comparing small bore catheters with aspiration and no RCTs comparing small-bore with large bore chest tubes (although there is an observational study (Inaba, 2012) of chest tubes in trauma that found no difference between small versus large).  Additionally, there are four systematic reviews analyzing the four aspiration versus large bore chest tubes RCTs previously mentioned (Zehtabchi, 2008; Wakai, 2007; Aguinalde, 2010; Devanand, 2004).

The available randomized controlled trials comparing aspiration with tube thoracostomy evaluated both immediate and delayed (one week – 1+ years) success rates of each modality for treatment of spontaneous PTXs of all sizes. Immediate success rates were found to be fairly similar between the two, with aspiration succeeding from 59.3%-71% of the time across the four trials, and tube placement being effective 63.6%, 68% and 93% of the time, respectively, in the three studies that reported it (Noppen, Ayed, Andrivet). The high outlier was likely due to the generous definition of success used for tube placement in Andrivet’s trial: a tube only failed if there was a persistent leak after 10 days. One year recurrence rates were not significantly different between needle aspiration and chest tubes (~ 25%) (Noppen, Ayed, Harvey). Reported complication rates for aspiration were generally equal to or lower than that of tube placement, ranging from 0-2%. Patients with aspiration had a significantly lower admission rate (Noppen, Ayed), and either a significantly shorter hospital stay or a trend towards it (Noppen, Ayed, Harvey). They also had lower analgesic requirements and pain scores (Ayed, Harvey).

All these trials suffered from low numbers, with the largest including 137 patients (Ayed). Taken together, they included just 331 randomized patients. Nonetheless, all studies came to the conclusion that simple aspiration was an acceptable, and perhaps even preferred, first line approach to primary PTXs. The systematic reviews that evaluated these studies found there to be insufficient efficacy data to be conclusive, but that the pooled data suggest that there is no significant difference between aspiration and tube thoracostomy in terms of immediate and one-week outcomes or with respect to recurrence rates at one year. They also found that there was a significantly lower admission rate and length of hospital stay among patients who had needle aspiration.  They concluded that simple aspiration was a reasonable alternative and possibly preferred strategy in the initial management of primary spontaneous PTXs requiring intervention(Zehtabchi, 2008; Wakai, 2007; Aguinalde, 2010; Devanand, 2004).

But, what of pigtail catheters? The question of whether and when to use small-bore catheters is addressed mostly by retrospective studies. Several such studies found that small-bore catheters (these included pigtail catheters, standard small bore pleural catheters, and single lumen central venous catheters) were no less effective than large bore chest tubes in the treatment of spontaneous PTXs (Vedam, 2003; Liu, 2003; Contou, 2012; Kulvatunyou, 2011). One small RCT out of Singapore that compared small-bore catheters to aspiration found a non-significant trend towards decreased admissions (from ED or from 3-day outpatient re-evaluation) with the catheters (44%) than with aspiration (61%). There was no significant difference in failure rates, complication rates, or pain scores. The study concluded that both methods allowed for safe management of PSPs. Of note, the study included only 48 patients, having failed to reach their target of 100 due to poor recruitment and lack of funding (Ho, 2001).

Bottom Line: Despite the lack of large RCTs, the data from the existing trials and retrospective studies support using either needle aspiration or small bore catheters (especially those with a Heimlich valve which allow the patient to move about or even be discharged with it in place) in lieu of large bore chest tubes in the stable patients with first-time moderate-to-large spontaneous PTXs. There is insufficient data to recommend aspiration versus a small bore tube at this time. Factors associated with failure of aspiration include: patient age > 50, initial aspiration volume > 2.5 L (this suggests a pleural leak), and possibly initial PTX size (some studies have shown higher failure rates with PTX size > 40% as measured on CXR, but this is an actively debated risk factor) (Chan, 2008).

Reflecting these guidelines is a flowchart for managing the spontaneous pneumothorax, taken from the BTS 2010 guidelines (Macduff, 2010).

4. When do you do a needle thoracostomy?  Where do you prefer to put the needle?

Needle thoracostomy is indicated when life-threatening tension PTX is suspected. Traditionally, the recommended method for decompressing such a PTX has been to place a standard 5-cm long over-the-needle catheter into the pleural space at the level of the second intercostal space in the mid-clavicular line (ATLS). However, some have expressed concern that this location may not be optimal for reasons both of safety and likelihood for success.

Safety concerns relate to the proximity of major vessels such as the internal mammary artery (IMA) and the subclavian vessels to the traditional needle thoracostomy site.  As noted above in Question #3, exceedingly few complications were found in all the RCTs that studied needle aspiration (all of which were performed at the 2nd or 3rd intercostal space (IS) at the mid-clavicular line (MCL)). However, one group reported three cases of life-threatening hemorrhage that occurred in a six-month period in patients who had had a needle thoracostomy performed in the 2nd intercostal space, mid-clavicular line (Rawlins, 2003).  Consequently, they propose that the traditional location for tube thoracostomies–the 5th intercostal space just anterior to the mid-axillary line–may be safer  for needle decompression as it is farther from large vascular structures (Rawlins, 2003).

Concerns about the efficacy of decompressing a PTX using the traditional method relate to the thickness of the chest wall at the level of the 2nd intercostal space. CT scans demonstrate a chest wall thickness between 4 and 4.5 cm thick at the 2nd intercostal space, mid-clavicular line. The corresponding expected failure rate of penetrating the pleura with a 5cm needle was found be as high as 50%. (Stevens 2009; Givens 2004; Zengerink 2008; Sanchez 2011). All of these studies conclude that a longer needle is likely necessary to increase chances of success at needle thoracostomy, while also acknowledging the associated increased risk of damaging internal structures.

So, is a lateral approach better, given these safety concerns and a potentially high failure rate of the anterior approach? A few studies have addressed this question with conflicting results.

Two imaging-based studies evaluated the chest thickness not only of the anterior wall, but also that of the lateral wall, at the 5th intercostal space along the mid-axillary line (Wax, 2007; Sanchez 2011). Both of these studies found that the chest wall thickness was thinner anteriorly (averaging 3.1cm and 4.6cm in the respective studies) than at the mid-axillary line (3.5cm and ~5.3 cm, respectively), thus making the former a better location for needle thoracostomy.  Wax, et al. (2007) also evaluated the distance from these entry sites to key internal structures such as the heart and liver, as well as the distance from the anterior approach to the internal mammary arteries. They concluded that the anterior approach was safest based on its relatively greater distance from key organs and on its sufficient distance from the IMA (>3cm). Both studies recommended using a 7cm needle for increased success rate at penetrating the pleura.

A countering opinion was rendered by Inaba, et al. (2011) based on a cadaveric study in which they performed needle thoracostomies at both the 2nd IS MCL and 5th IS MAL in both right and left chest walls of twenty un-enbalmed cadavers.  After having placed the catheters, bilateral thoracotomies were performed to assess penetration into the pleural cavity. They found that 100% of those placed laterally at the 5th intercostal space were successful, versus only 58% of those placed anteriorly at the 2nd intercostal space. They also measured the chest wall thicknesses and found the lateral wall (3.5cm +/- 0.9cm) to be significantly thinner than the anterior wall (4.5cm +/- 1.1cm) (Inaba, 2011).

The reasons for these differing measurements and results are not immediately clear. One possible explanation is that while the exact ages of the cadavers in Inaba, et al.’s study were not known, they were stated to be “higher than the average trauma cohort” and “their muscle mass may have been more atrophic.” Perhaps this changed the relative thicknesses of the various  parts of the chest. Another plausible explanation is that the wall thickness along the lateral wall may vary appreciably within relatively small distances.  Wax, et al. found that the chest wall thickness along the 5th intercostal space was 3.5 cm at the mid-axillary line but only 2.9cm at the anterior axillary line. This dramatic difference in a short distance may well account for variances in relative chest wall thickness measurements and in success rates in pleural penetration in the cadaver study.

Bottom line: There is ample data demonstrating that either approach to needle thoracostomy may fail when using a standard sized needle.  The answer to improving efficacy of needle decompression may lie in using longer needles and catheters, keeping in mind that this increased length will increase risk of damaging other internal structures. Prospective studies are clearly warranted to further study this question, until which time it may well be advisable to use the more traditional anterior approach, especially if using a longer-than-standard needle.

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Pneumothorax, Questions

1. What is your first line imaging test to diagnose pneumothorax (PTX)? When do you get a CT?

EML Pneumothorax Questions2. How do you manage traumatic pneumothoraces found incidentally on CT (i.e., not clinically apparent, not on CXR)?  What if the patient requires mechanical ventilation?

3. In patients with a primary, spontaneous PTX do you place a chest tube? When do you consider a “pigtail” catheter or needle aspiration?


4. When do you do a needle thoracostomy? Where do you put the needle?

EML Pneumothorax Questions Poster

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Pulmonary Embolism, “Answers”

1. What decision rules do you use to determine if a patient is low or very low risk for PE?

The most commonly used decision instruments for risk stratification are the Wells’ score, Geneva score, and PERC rule. Additional tools include the Kline rule and the Pisa model, but these are less utilized.

EML PE AnswersThe Wells score is a scoring system consisting of 7 criteria, to be used in conjunction with d-dimer. It assigns patients a risk of low, moderate, or high based on the total points. In low-risk patients, a negative d-dimer is sufficient to rule out PE without further testing. One of the initial validation studies found a negative predictive value of 99.5% for this group . One major weakness of Wells’ is that one of the highest weighted criteria, “an alternative diagnosis is less likely than PE,” is a very subjective measure; however, use of Wells’ has repeatedly been validated (Wolf, 2004).

The original Geneva score was a similar scoring system comprised of 8 variables that was well-validated but limited by its reliance on lab and imaging interpretation (blood gas and chest x-ray). Therefore it was revised to only include risk factors, signs, and symptoms. The Revised Geneva score (RGS) still consists of 8 variables, and like the Wells’ score, stratifies patients into low, moderate, or high risk. There is also a Simplified Revised Geneva score (sRGS) that assigns points uniformly for each variable rather than assigning different weights (Fesmire, 2011).

Both Wells’ and the sRGS can alternatively be subject to a dichotomous interpretation of PE likely or PE unlikely. Wells’ was used in this way by the Christopher Study Investigators when they demonstrated the safety of a simple algorithm involving d-dimer for patients deemed PE unlikely versus CT for patients deemed PE likely. Of those who were PE unlikely and had a negative d-dimer, 0.5% ultimately had a venous thromboembolism (VTE) at 3-months (Christopher, 2006).

Any discussion of decision rules warrants mention of clinical gestalt and how it compares to validated criteria in assessing the pretest probability of PE. The PIOPED study was the first to corroborate the use of gestalt. Since then, a number of comparative studies (Sanson, 2000; Runyon, 2005) have found that gestalt and objective criteria such as Wells’ perform equally well. This premise was also supported by a recent meta-analysis of 52 studies estimating sensitivity and specificity for gestalt and/or a decision rule. The results are summarized here:

Decision Tool Sensitivity (%) Specificity (%)
Clinical gestalt 85 51
Wells’ (traditional) 84 58
Wells’ (alternative) 60 80
Revised Geneva 91 37

Among the 52 studies included there was significant heterogeneity of results, which was related to differing prevalences of PE (Lucassen, 2011).

The Pulmonary Embolism Rule-out Criteria (PERC) can be used to exclude the diagnosis of PE in patients who are deemed low risk.  It is critically important to recognize that the clinician must first decide that the patient is low risk for PE based on clinical gestalt before applying PERC.  This criteria was derived by Kline, et al., in 2004. Using a multi-center cohort of over 3,000 patients, the investigators collected data on 21 variables related to the diagnosis of PE. Then, by logistic regression and stepwise backwards elimination, they narrowed down the criteria to 8 variables that could be used in a block rule to justify not ordering a d-dimer if all questions are answered “no.” They internally validated the rule in a low-risk group and found a sensitivity of 96%. Of the 362 patients who were PERC negative, 5 (1.4%) were later diagnosed with VTE. This miss rate fell under the predetermined test threshold of 1.8%, a point of equipoise below which there is a greater chance of harm than benefit by proceeding with further testing.

Kline, et al., performed a large validation study in 2008, in which they sought to validate the premise that being both low-risk by gestalt (estimated risk <15%)  and PERC negative renders patients very low-risk. This categorization would signify that they should have a pretest probability lower than the test threshold and therefore not benefit from further testing. Their study identified 1666 patients who were gestalt low-risk and PERC negative. In this group, 16 (1%) had VTE or death within 45 days. The sensitivity of this very low-risk classification was 97.4% (Kline, 2008).

When the authors applied PERC to the entire study population without gestalt interpretation, they found that the false negative rate would be unacceptably high if the population’s pretest probability was >6%.  As most populations have a prevalence higher than this, the authors comment that this highlights the importance of risk stratification prior to application of PERC so that the pretest probability is sufficiently low.

PERC has been repeatedly validated. A 2012 systematic review and meta-analysis by Singh, which included 12 studies and nearly 15,000 patients in 6 countries, concluded that “because of the high sensitivity and low negative likelihood ratio, PERC rule can be used confidently in clinically low probability population settings” (Singh, 2012).

2. Are there any situations in which you modify the d-dimer threshold for ruling out PE? If so, when?

D-dimer testing has become standard practice for ruling out PE in low-risk patients due to its high sensitivity. But it is also known to lack specificity and lead to a high number of false positives. The result is an obligation to pursue the diagnosis of PE with CT pulmonary angiogram (CTPA), which poses a risk of contrast-induced nephropathy (CIN) and radiation-induced malignancy. Green and Yealy claim that 1 contrast-induced renal failure will result from every 200 CTs and that 1 radiation-induced cancer will result from every 2,000 CTs. They also assert that half of both types of adverse effects will ultimately be fatal (Green, 2012).

A wide range of data has been reported regarding the incidence rates of these sequelae, but regardless of how heavily one weighs the data, it is evident that unnecessary CTs do carry the potential for adverse consequences. In order to reduce harm, some have suggested that d-dimer not be regarded as a “one size fits all” test.

A 2009 study examined the use of d-dimer at different thresholds that varied according to pretest probability. The authors proposed doubling the threshold for low-risk patients and cutting the threshold in half for high-risk patients. Overall they found that doubling the threshold in low-risk patients increased d-dimer specificity from 58% to 75%, but decreased sensitivity from 94% to 88%. They estimated that this would result in 15% fewer imaging studies but 3-4 additional missed PEs per 1000 patients (Kabrhel, 2009). Their data did not support use of d-dimer at any threshold in high-risk patients.

Kline has also suggested doubling the d-dimer threshold in certain groups of patients in an effort to increase the test’s specificity.  He and his colleagues recently published a study investigating the effect of doubling the threshold on exclusion and miss rates. This was a multicenter prospective trial. All enrolled patients had a pretest probability calculated using Wells’ or RGS, a d-dimer measured, and a confirmatory CTPA performed upon enrollment as well as at 30-day follow-up.

They found two groups in which doubling the d-dimer threshold yielded a significantly increased exclusion rate with only a slight increase in the rate of missed PE. The first group was those deemed to have a pre-test probability of “PE unlikely” as defined by Wells’ less than or equal to 4 or RGS less than or equal to 6. In these patients, the exclusion rate doubled from about 16% to 32% when the d-dimer threshold was doubled.  The PE miss rate increased from about 3.7% to 5.4%. Almost all of these missed PEs were isolated, sub-segmental PEs and none of these patients had concomitant DVT. (The implication that sub-segmental PEs are of less clinical consequence than segmental PEs is still highly controversial).

The other group of patients for which d-dimer could safely be doubled was those over 70 years of age. D-dimer is known to increase with age and this phenomenon was seen when d-dimer was plotted against age for the 552 patients in this study without PE. The slope of the curve increases most sharply around age 70. When the investigators systematically examined 8 different d-dimer thresholds for 4 different age groups, they found that doubling the threshold after age 70 resulted in an increased rule out rate without an increase in post-test probability of PE.

Looking more closely at the implications of this change in d-dimer threshold, the authors found that out of the 224 patients who had a creatinine measured before and after CTPA, 37 developed CIN. Of these 37 cases, 10 could have been prevented by using the doubled d-dimer threshold to rule out PE (Kline, 2012).

The 2012 study did not provide any results about d-dimer in pregnancy, possibly due to the protocol’s nondiscriminatory use of CT, but pregnancy is known to increase d-dimer and confound interpretation. In a small study in 2005, Kline, et al., sought to define the magnitude of increase in d-dimer during pregnancy by employing women seeking to conceive and following them through pregnancy. They found that the percent of women with a d-dimer within normal limits was 79% pre-conception, 50% in the 1st trimester, 23% during the 2nd trimester, 0% during the 3rd trimester, and 69% 4 weeks post-partum. They concluded that normal pregnancy will cause an elevated d-dimer and that the threshold should therefore be adjusted according to trimester (Kline, 2005).

3. To which patients do you give thrombolytics for PE?

Compared to indications for thrombolytics in MI or ischemic stroke, indications remain less established and more controversial in PE. Quite recently, however, ACEP, the AHA and Chest have all published updated guidelines which are relatively in agreement. At this point it is fair to say that all patients with massive PE should receive thrombolytics (unless they have a contraindication or the risks outweigh the potential benefits), and that thrombolytics should be considered on a case-by-case basis in patients with sub-massive PE.

What do the terms massive and submassive PE mean? Massive PE was previously defined by anatomical criteria: >50% obstruction of pulmonary vasculature or occlusion of 2 or more lobar arteries. It is now more commonly defined by hemodynamic instability, which is a function of both embolus size and underlying cardiopulmonary status.  As such, a sub-massive embolus in a patient with poor cardiopulmonary reserve could produce similar outcomes to a massive embolus in a patient without prior cardiopulmonary disease.  Therefore, any combination of angiographic obstruction and cardiopulmonary function that causes hemodynamic decompensation qualifies as massive PE (Wood, 2002).

The AHA’s 2011 guidelines give more concrete definitions. Massive PE requires one of the following:

  • sustained hypotension (systolic <90 for >15min or the need for inotropes)
  • pulselessness
  • profound bradycardia

Sub-massive PE is characterized by normal BP but evidence of either:

  • RV dysfunction (RV dilation, elevated BNP, suggestive EKG changes)
  • myocardial necrosis (elevated troponin)

What is the evidence for thrombolytics? What we know about thrombolytics in PE is that at 24 hours they achieve reduced pulmonary artery pressures, increased pulmonary perfusion, and decreased RV dysfunction (Jaff, 2011). How this more rapid angiographic resolution of PE translates to overall outcomes is less certain. There is a paucity of high quality studies specifically looking at thrombolytics compared to heparin alone in patients with massive PE. A 2004 meta-analysis showed a 4% vs. 7% rate of recurrent PE and a 6% vs. 13% rate of  death, respectively, for thrombolytics vs. heparin alone in massive PE (Wan, 2004). In cases of sub-massive PE, the jury is still out. No study has shown lower mortality in these patients who receive thrombolytics, but small studies, including one from the MOPETT trial, published in January 2013, have suggested that thrombolytics in some of these patients may decrease the risk of future CHF and pulmonary hypertension. Whether this is true, the effects on overall mortality, and the appropriate dose for sub-masive PE are still unclear.

However, the risks of thrombolytic therapy should not be underestimated. In the ICOPER registry, intracranial bleeding occurred in 3% of patients who received thrombolytics versus 0.3% of those who did not. The incidence of any major bleeding was 22% versus 9% in these groups (Goldhaber 1999). Absolute and relative contraindications to thrombolysis are the same as for MI. For patients in whom thrombolytics are contraindicated, or who remain hemodynamically unstable despite medical treatment, surgical or catheter embolectomy may be indicated.

Just as in MI and ischemic stroke, there is a “golden hour” in severe PE. In fatal cases of PE, two-thirds of patients die within 1 hour of presentation. Furthermore, thrombolytics are thought to be more effective in achieving reperfusion when administered early (Wood, 2002).

4. When, if ever, do you discharge a patient diagnosed with PE?

Standard treatment for PE has traditionally been inpatient-based and centered upon unfractionated or low molecular weight heparin (LMWH) bridged to a vitamin K antagonist. The down sides to this protocol include the resources and cost of hospital admission, frequent injections, multiple medications, and the need for extended lab monitoring. Therefore, there has been much research into whether outpatient treatment, and possibly even outpatient treatment with oral medication, is a viable option.

In 2010, one prospective and two retrospective studies published in the Journal of Thombosis and Haemostasis looked at outpatient treatment with LMWH for hemodynamically stable patients without significant comorbidities. All three found that outpatient treatment was safe and effective in this population (Agterof, 2010; Erkens, 2010; Kovacs, 2010).

In 2011, Aujesky, et al., conducted the first multicenter, prospective, randomized, non-inferiority trial comparing outpatient and inpatient treatment, both with LMWH. All enrolled patients were deemed to have a low risk of death (PESI class I or II; see below for more on this index). For outpatient and inpatient groups, respectively, rates of 90-day recurrent VTE were 0.6% and 0%; rates of 90-day major bleeding were 1.8% and 0%; rates of mortality were 0.6% in both groups. 14% of outpatients would have preferred to stay longer in the hospital. 29% of inpatients would have preferred early treatment at home. The conclusion made by the authors is that for select low-risk patients who prefer early discharge, outpatient treatment is a safe and effective option.

Are there any decision tools that can help determine which patients may be safe for outpatient treatment? The Aujesky study used the pulmonary embolism severity index, or PESI. The PESI is a prognostic model designed to risk stratify patients with acute PE according to estimated 30-day all cause mortality. It is the most accurate and easiest to use PE prognostic score. It consists of 11 variables that are given differing weight. The total score places patients into one of five severity categories, each with a discrete mortality risk. The more recently derived Simplified PESI (sPESI) consists of 6 variables. If all are negative, the patient is low-risk. If any are positive, the patient is high risk.

Erkens, et al., sought to determine if the original and sPESI could be used to accurately characterize which low-risk patients are appropriate for outpatient treatment. From their study they concluded that both models were accurate in identifying these patients; however, many high-risk patients were also treated as outpatients, without adverse outcomes. More research is clearly needed to further elucidate outpatient eligibility and outcomes (Erkens, 2012).

Troponin and brain natriuretic peptide (BNP) have also been investigated as markers of increased disease severity.  The latter has shown a positive correlation, but lacks specificity.  Church and Tichauer, in their review of ED management of PE, recommend using troponin, in conjunction with sPESI and focused echocardiography, to further risk stratify patients with PE (Church, 2012).

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Pulmonary Embolism, Questions

1. Which decision rule(s) do you use to determine if a patient is low or very low risk for PE?EML PE Questions

2. Are there any situations in which you modify the d-dimer threshold for ruling out PE? If so, when?

3. To which patients do you give thrombolytics for PE?

4. When, if ever, do you discharge a patient diagnosed with PE?

PE Questions Poster

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