Targeted Temperature Management (TTM) After Cardiac Arrest

If your you grind your teeth when you have resuscitated a patient post cardiac arrest in fear of having to initiate a cumbersome protocol with hypothermia, the TTM trial may be just what you were looking for. Up to this point only 2 randomized trials have been performed comparing “usual care” to hypothermia, totaling about 350 patients. These 2 studies have changed the way we approach post-cardiac arrest resuscitation, but many questions were left unanswered.  

Why is this topic important?

All emergency physicians will face caring for patients after cardiac arrest, and few interventions have been shown to improve neurologic survival. Therapeutic hypothermia has demonstrated in two RCT to improve neurologically intact survival with a number needed to treat of six. However, despite the dramatic effects seen with treatment many unanswered questions remained. How cold, how fast, how long and how to rewarm these patients? The TTM attempted to answer one small piece of this puzzle.

What does this study attempt to show?

The study hypothesis was that targeting “relative” normothermia at 36 degrees and avoiding febrile episodes would be non-inferior to hypothermia at 33 degrees Celsius. The authors believed most of the benefit from trials comparing hypothermia to control was derived from avoiding hyperthermia and not necessarily from the neuroprotective effects of hypothermia.

Patients aged 18 years and older who had a GCS < 8, with out of hospital cardiac arrest (OOHCA) irrespective of initial rhythm and had maintained pulses > 20 consecutive minutes were eligible.

The primary outcome of the study was all-cause mortality at the end of the trial, with a predefined secondary outcome of poor neurologic function or death defined as a CPC >2 (basically unable to function independently). I think this is a great primary end-point mostly because it is binary; as compared with CPC scores which we know from the stroke studies that the mRS can be highly subjective.

What are the essential findings?

Between January 2010 and January 2013 950 patients were enrolled, with 476 assigned to the 33 degrees Celsius and 473 to the 36 degrees Celsius.  The groups had similar pre-randomization characteristics, although some skeptics have argued that fewer patients in the normothermia group had AMI and ischemic heart disease, although there were not more interventions completed for this previously.

Of the patients randomized to T33C 253/473 (50%) had died by the end of the trial as compared to 255/466 (48%) in the T36C cohort (OR 1.06 95% CI  0.98-1.28, p = 0.51).  Minimal neurologic deficit (CPC 1 and 2) occurred in 47% in both arms and mRS </= 2 occurred in 45 and 44% in the 33 degree and 36 degree groups respectively.

There was shorter duration of mechanical ventilation in the T36C group: T33C = 0.83 versus T33C = 0.76 median days receiving mechanical ventilation/days in ICU (P=0.006)

How is patient care impacted?

Everyone will likely have a different opinion on this. The fact of the matter is survival after cardiac arrest has improved since the original publication of the HACA and Bernard hypothermia trials. New interventions like hands only CPR, early defibrillation, and cardiac catheterization likely have a part in some of the improvements in mortality seen, but certainly a proportion of this improvement must be attributed to the hypothermia protocol.

That being said, in the largest trial performed to date on optimal temperature management there was no difference in the primary outcome of mortality. The HACA and Bernard papers were flawed in that they only included patients with VF/VT arrest and had NO regulation of temperature in the control arm, which resulted in many patients becoming febrile.

Hypothermia induces diuresis, electrolyte disturbances, shivering, and often requires heavy sedation and sometimes paralytics. These nuances make targeted temperature control a more attractive option, with the best available evidence suggesting at least equivalent outcomes.

As a clinician in both the emergency department and ICU I am always looking for the simplest answer for a complex problem. Thus in my view TTM to 36 degrees seems, at least for the time being, to be a reasonable alternative. The MAJOR drawback of TTM is for clinicians to get relaxed about temperature management and patients may develop fever which is has been demonstrated, albeit in different patient populations, to result in worse neurologic outcome. THEREFORE, if you adopt a 36-degree protocol you should think of the temperature like you would blood pressure, and aggressively treat fluctuations.  

 Major Limitations of the Study

The study does not reflect the subset of patients seen in most urban county hospitals, with prolonged downtime and most initial rhythms in this study being shockable. That being said, the Bernard and HACA trials excluded all patients with non-shockable rhythyms and these studies still dramatically changed our practice.

Also the study was powered to detect an 11% changed in mortality, which is rather large. Excluding a smaller improvement in mortality is not possible, however there was no trend or even suggestion based on this study that this would be the case.

Lastly the improved survival in all of these studies could reflect increase attentiveness to critically ill patients may result in improved outcomes regardless of the actual intervention employed.   

TAKE HOME POINTS:

-No difference in mortality between T36C and T33C by the end of the study.

-T36C is less cumbersome and associated with less physiologic perturbations and is simpler.

-Ignoring temperature management all together SHOULD BE DISCOURAGED, and temperature management should be considered a critical component of resuscitation until proven otherwise.

-Dave

Rapid Blood Pressure Lowering in Patients with Acute Intracerebral Hemorrhage (INTERACT-2)

When a patient rolls in unresponsive and hypertensive intracranial hemorrhage is at the top of our differential. When the CT scan shows a large hemorrhage, we are quick to reverse coagulopathy if present, intubate if indicated, discuss the case with neurosurgery and pray. However, the management of blood pressure tends to vary based on the attending physician and their underlying training and experience. The dogma of avoiding blood pressure control because of concern over neurologic deterioration in acute intracerebral hemorrhage has been debated intensely.

Preliminary data had suggested that it reduced hematoma growth, a marker for poor outcomes in patients with ICH, but patient-oriented outcomes were lacking. A recent Study based on the original pilot study INTERACT1; INTERACT2 has just been published on May 29^th in the NEJM.

1.  Why is this topic important?

The current blood pressure management of patients with ICH is unknown. Guideline recommendations suggest maintaining a systolic blood pressure of <180 mmHg. However, many physicians still practice on old dogma that permissive hypertension be allowed to a systolic of < 180 and to avoid relative hypotension in order to maintain perfusion to the ischemic penumbra surrounding the hemorrhage.

2.  What does this study attempt to show?

This study attempts to demonstrate that in patients with spontaneous intracranial hemorrhage with:

1.   Hypertension, systolic BP > 180 mmHg

2.   Not early surgical candidates (who these people are no one knows)

3.   Had an admission GCS >5

4.    Did not have a large hematoma with a poor prognosis based on attending physician discretion

Were randomized to intensive blood pressure lowering to a systolic BP <140 within one hour of randomization and continuing with a goal blood pressure of <140 for the next 7 days or guideline therapy maintaining a systolic blood pressure below/near 180 mmHg.  The type of anti-hypertensive agent was not specified, and 7 main anti-hypertensive agents were used.

  The study attempts to demonstrate that in patients who receive early aggressive anti-hypertensive treatment, maintained for 7 days, there is improvement in death and disability, defined as a mRS >2.

3.  What are the essential findings?

A total of 2,839 participants were enrolled in the study, with > 60% of participants in each arm coming from China. 1,403 patients enrolled in the early intensive treatment arm, and 1,436 assigned to receive guideline-recommended treatment.

  Baseline characteristics were similar (NIHSS was slightly lower in the intensive treatment arm 10 vs. 11) Table 1.

  Also the hematoma volume (<15ml) and superficial location of the hematoma favored the treatment arm, (both known to be better prognostic markers) Figure 1.

   At 90 days 719 participants (52%) in the intensive-treatment group, as compared with 785 (55.6%) in the standard-treatment group, had a poor outcome defined as a mRS >2 (OR 0.87; 95% CI, 0.75-1.01; p = 0.06). Table 3.

   On ORDINAL analysis (different prespecified vantage point) there was a shift in the distribution of scores on the mRS favoring the intensive blood pressure-lowering treatment (OR 0.87; 95% CI, 0.77 to 1.00; P =0.04). Table 3.

   There was no difference in the pre-specified safety outcomes of ACS, hypotension, and neurologic deterioration in the first 24 hours, Table 3.

   An interesting finding was that there was no statistically significant decrease in size in hematoma expansion in the intensive lowering of blood pressure group at 24 hours, the presumed mechanism by which blood pressure management was thought to be protective.

4.  How is patient care impacted?

Given that there were few adverse events and that there is a small signal of potential benefit I can see the guidelines changing to recommend a more strict control of blood pressure after ICH. See below.

5.  Is this an area of controversy?

Acute management of blood pressure has been a critical question in all neurologic emergencies; stroke, subarachnoid hemorrhage and ICH. It is believed that auto-regulation of blood pressure by the cerebral vasculature is lost during neurologic insults such as ICH. The authors of the INTERACT2 trial believed the mechanism of benefit to be a reduced hematoma size, based on their pilot study INTERACT1. The trial failed to demonstrate this, but it must be mentioned that finding statistical significance among means may not be appropriate. There is potential that some patients had marked reduction in their hematoma size and they accounted for most of the benefit, but were washed out by the overwhelming number of patients who did not see such a reduction.

   Also it is possible that small reductions in hematoma volume (on the order of 2mL could have profound impact on neurologic sequelae, but this question remains unanswered.)

   It is also interesting that they picked a primary outcome of a mRS >2, because had they of picked a mRS of >1, as is typical in most acute stroke trials, the evidence of benefit would have been statistically significant with a lower end point (OR 0.83; 95% CI 0.70 to 0.98; p =0.03).

   This study although suggestive is certainly not definitive, and will be aided by the ATATCH2 study to be published in 2016. Proponents of blood-pressure control will argue that there is no downside to aggressive blood pressure control, and potential a benefit in an otherwise group of patients with a high morbidity and mortality rate. Others will argue that the baseline characteristics of the treatment arm were heavily favored, based on NIHSS, location of hemorrhage, and % of patients with initial hematoma volume < 15mL.

6.  Major Limitations of the study?

The study has several strengths. First it is a large multi-center randomized controlled trial. Their outcomes are patient-centric and they pre-specified their secondary outcomes and sub-group analysis.

   However, multiple flaws in the study design are present. First, the choice of anti-hypertensive agents was markedly different than is used primarily in the United States. Urapidil, a potent alpha antagonist was used in a third of patients in the intensive blood pressure control arm, and nicardipine and labetalol only accounted for another third. Other less titratable medications such as nitroprusside, furosemide, hydralazine and nitroglycerine accounted for the other third. This was almost certainly because 2/3’s of patients recruited in the study were from China. Whether or not this limits the generalizability of the results is questionable.

   In addition it is important to note that the results of ATATCH II (antihypertensive treatment of acute cerebral hemorrhage) is almost completed with recruitment, and the results of the study will be much anticipated in 2016. The study design is in North America, with similar inclusion criteria to the INTERACT2 study, except that nicardipine was used as the sole agent, and patients had to receive intensive blood pressure control in < 4 hours, whereas in the INTERACT2 trial 50% of patients were randomized after 4 hours.

Despite the limitations several an important concept was addressed:

 Intensive blood pressure control may have a neurologic benefit in patients with intracranial hemorrhage and at worst does not seem to result in any increased morbidity. The mechanism by which this occurs is not entirely clear.

Until next time!

-Dave

Anderson et al. Rapid Blood-Pressure Lowering in patients with Acute Intracerebral Hemorrhage. NEJM. 2013; 1-11. 

Pre-Hospital Intubation after Cardiac Arrest

Prehospital Advanced Airway Management with Neurologic Outcome and Survival in Patients with Out-Of-Hospital Cardiac Arrest

Out of Hospital Cardiac Arrest occurs in approximately 375-390K individuals yearly in the United States. Few interventions have ever been demonstrated to improve neurologically intact survival, and airway has always remained a priority in the initial resuscitation of the patients with cardiac arrest.

 Despite this, advanced airway management in patients with cardiac arrest has never been shown to improve mortality. In fact, several studies have challenged the commonly held belief that advanced airway management in the pre-hospital setting improves mortality in trauma patients and pediatric patients.

 In January JAMA published a prospective population based study completed in Japan looking at neurologically intact survival in patients who had pre-hospital advanced airway management (endotracheal intubation, or supraglottic airways) in a large cohort of patients.

 1.                Why is this topic important?

 Pre-hospital advanced airway management has long been a part of many EMS protocols, despite the lack of evidence for improved neurologic survival. This study evaluates a large cohort of patients with pre-hospital cardiac arrest and attempts to evaluate the effect on mortality and neurologic function at one month using a modified rankin scale (mRS) in patients who have advanced airway management vs. bag-valve mask ventilation.

 2.             What does this study attempt to show?

 The authors of the study believed that pre-hospital advanced airway management had no affect on neurologically intact survival.  They defined their outcomes as return of spontaneous circulation (ROSC), one-month survival and neurologically intact survival at one month (mRS >/= 2). The authors chose a set of potential confounders a priori based on biological plausibility and a priori knowledge. Age, sex, cause of cardiac arrest, first documented rhythm, witnessed arrest, type of bystander CPR, use of public AED, epinephrine administration, and time interval from call to CPR by EMS and from receipt of call to hospital arrival were all chosen.

 The authors recognized that a randomized controlled trial large enough to demonstrate clinical and statistical significance would be difficult due to the dismal outcome of cardiac arrest in general, and the large number of patients needed to show a meaningful difference. Instead they chose a population based study, completed prospectively acknowledging that potential confounders could have a significant impact on outcome.

 3.             What are the essential findings?

 A total of 649,359 patients were ultimately included (658,829 eligible), 367,837 (56.7%) underwent bag valve mask ventilation, and 281,522 underwent advanced airway management (43.5%).

 Of the patients who underwent advanced airway management a total of 41,972 (6.5%) received endotracheal intubation, and 239,550 received supraglottic airways (36.9%).

 Table 1 shows the demographics of patients with out of hospital cardiac arrest.

 Table 2 summarizes the survival outcomes, first unadjusted, adjusted for selected variables, and adjusted for all covariates.

 An overview is provided for ease here:

 Rates of ROSC:                                 

Unadjusted:

-BVM 25, 904 (7%)

-Endotracheal Intubation 3,514 (8.4%)

-Supraglottic Airway 12,785 (5.3%).

OR (95% CI) vs. Bag-Valve Mask adjusted for pre-specified variables:

-Endotracheal Intubation 0.86 (0.82-0.89)

-Supraglottic Airway 0.64 (0.62-0.65)

One-month Survival:

Unadjusted:

-BVM 19,643 (5.3%)

-Endotracheal Intubation 1,757 (4.2%)

-Supraglottic Airway 9,176 (3.8%)

OR (95% CI) vs. Bag-Valve Mask adjusted for pre-specified variables:

- Endotracheal intubation 0.72 (0.70-0.73)

- Supraglottic airway 0.71 (0.69-0.72)

Neurologically Favorable Survival (mRS >/= 2)

 Unadjusted:

- BVM 10,759 (2.9%)

- Endotracheal Intubation 432 (1%)

- Supraglottic Airway 2,724 (1.1%)

OR (95% CI) vs. Bag-Valve Mask adjusted for pre-specified variables:

- Endotracheal Intubation 0.41 (0.37-0.45)

- Supraglottic Airway 0.38 (0.36-0.40)

Plain Language summary-

 The unadjusted model demonstrated significant negative associations between ANY advanced airway management and the 3 end-point measures (P < 0.001 for all outcomes).

In the adjusted model using selected variables and all variables advanced airway management were independent negative predictors of all 3 outcomes (p < .0001).

 4. How is patient care impacted?

 This is a tough pill to swallow. I bet many people believe that this does not make much physiologic sense, how can providing oxygen to an apneic patient result in worse outcomes? Is it the additional time needed to secure the airway (if this were true why is the signal still present in patients receiving a LMA?), is it that patients who have an esophageal intubation are likely to die of asphyxiation? Is hyperoxia and reperfusion injury contributing to a significant portion of morbidity in the post-anoxic injured brain?

Or is the study really not able to account for all the variables, and a potential unidentified confounder was driving the increased morbidity and mortality rather than the advanced airway itself?

Maybe it is time to reassess the importance of advanced-airway management in patients with OOHCA, and instead focus on chest compression early recognition of ventricular fibrillation with defibrillation, and finding secondary causes of arrest (no intubation, and no epi/bicarb/atropine/pacing unless indicated). If the patient obtains ROSC then all bets are off.

5.  Is this an area of controversy?

There is really no point in stirring the pot with a mini-JC if there isn’t some type of controversy. Although some might argue that a true randomized clinical trial would be the only way to account for all differences in patients with OOHCA, I would argue that this is a large population based study. RCT’s are expensive, asses one intervention, apply only to a specific cohort of patients, and the OOHCA patients are a heterogenous group of patients. It is always difficult to account for every confounder, but in this study of almost six hundred thousand patients, there was a consistent signal of harm with pre-hospital intubation.

If this had completely gone against prior publications, it might raise a few more eyebrows, however, several studies have demonstrated that advanced airway management placed by pre-hospital providers does not improve and may worsen outcomes in patients with cardiac arrest.

6. Major Limitations of the study?

The study is non-randomized, and therefore most physicians argue that it cannot identify causation and only association. However, this is a large cohort study, the researchers identified a priori several possible confounders and attempted to adjust for these. The clinical end-point has been consistent in other smaller but more methodologically rigorous trials.

In addition they reran all the statistics favoring worse case scenarios in patients lost to follow-up and the signal of harm was still statistically and clinically significant.

Closing thoughts:

For me a 2% reduction in neurologically intact survival is important enough to have the discussion about changing pre-hospital management. Maybe one day we will learn that the drop in venous return, and subsequent hyperoxia from intubation was killing people. Whatever the truth may be the paper was worthy of a Mini-JC even if it might not change your practice tomorrow.

Till next time!

-Dave

Hasegawa et al. Association of Prehospital Advanced Airway Management With Neurologic Outcome and Survival in patients With Out-of-Hospital Cardiac Arrest. JAMA. 2013; 257-266.

Endovascular Treatment for Acute Ischemic Stroke

 How many times have you spoken with interventional radiology and heard about the latest and greatest endovascular treatment for acute ischemic stroke? If they had their way, treatment for stroke will be treated just like STEMI and patients will be taken away to angiography suites. The physiology seems to make sense, remove the clot and improve perfusion, or does it? Up until now, evidence has come mostly from a “physicians experience”, non-randomized trials, or outcomes looking at revascularization rather than hard clinical end-points like neurologic function using a modified-rankin scale. The first, to my knowledge, of a published RCT comparing intravenous tPA vs. IA thrombolysis with threombectomy has been published in the NEJM.

1.  Why is this topic important?

Several non-randomized trials and cohort studies have suggested that thrombectomy and revascularization after acute ischemic stroke improves outcomes for patients with large vessel occlusions. Up until this point no randomized controlled trials comparing the current standard of care (IV tPA) with mechanical embolectomy has been undertaken. 

2.  What does this study attempt to show?

This study attempts to identify whether there is improved survival free of disability (defined as a modified Rankin score of 0 or 1 on a scale of 0 to 6 with 0 indicating no symptoms, 1 no clinically significant disability despite symptoms and 6 indicating death) at 3 months after acute ischemic stroke.

Patients were randomized within the 4.5-hour time frame if they had symptoms of a stroke and a head CT without signs of an ICH. Patients were randomized to one of two arms:

1. Intra-arterial thrombolysis with the option for mechanical thrombectomy.

2. Intravenous thrombolysis as previously described (NINDS and ECASS).

If patients were outside the time window of 4.5 hours they were excluded. Due to operator delays patients who were randomized to IA tPA could still receive treatment up to 6 hours as long as they were randomized prior to the 4.5 hour mark.

The interventionalist could instill up to 0.9 mg/kg (or 90mg) of IA tPA (the dose given IV) and not higher. They could use a mechanical device if the operator believed it was indicated. If upon angiography there was no identifiable thrombus the operator could instill tPA into the region that was presumably affected, if clinically warranted. If the patient had no neurologic deficit, or rapidly improving symptoms then the operator did not have to proceed with angiography.

3.  What are the essential findings?

Between February 1, 2008 and April 16^th 2012, 362 patients were enrolled. 181 patients in the IA +/- thrombectomy arm, and 181 in the IV tPA (control) arm. Baseline characteristics were similar (table 1). Average NIHSS was 13.

Of the 181 patients assigned to endovascular therapy, 15 did not receive the treatment (6 because of clinical improvement, 3 because of a lack of evidence of occlusion on angiography, 3 because of dissection, 1 because of an unknown bleeding diathesis, 1 because of a groin hematoma, 1 because of delayed availability of the interventionalist.) 3 procedures were interrupted due to equipment complications.

In total 165 patients underwent endovascular treatment. 109 had IA thrombolysis, and 56 had a device deployed. The median dose of tPA was 40mg.

Primary outcome at 90 days is show in figure 1. 30.4% of patients undergoing thrombectomy survived without disability, and 34.8% of patients in the IV tPA group survived without disability, OR 0.82 (95% CI 0.53-1.27; P=0.37).

At 90 days 26 patients in the endovascular treatment group (14.4%) and 18 in the intravenous (9.9%) group had died.

On secondary analysis, stratifying for time to randomization, age, NIHSS, stroke territory did not affect odds ratio as NONE favored the endovascular treatment. Overall treatment with IV tPA was favored (figure 2).

4.  How is patient care impacted?

In patients with acute ischemic stroke, this study represents the first relatively large randomized controlled trial comparing thrombectomy to intravenous tPA. IV tPA is cheaper, less labor intensive and appears to have similar and possibly improved efficacy compared with endovascular therapy. The trial does not support the routine use of interventional procedures for acute ischemic stroke.

Previously the consensus was that endovascular therapy was superior to IV tPA alone due to increased recanalization rates seen in previous trials. This theory made clinical sense, improve flow and save the ischemic penumbra. However, several studies just released in the NEJM refute this contention.

5.  Is this an area of controversy?

As always it is. The interventionalists will argue that t IV tPA can be followed by endovascular therapies for patients who do not achieve recanalization. Also, “the latest and greatest” retrieval devices will be argued to improve outcomes as these older devices were more “rudimentary.”

This study also does not even question the utility of tPA in acute ischemic stroke as apparently that bus has left the station, despite many randomized trials demonstrating harm.  Although I don’t think it is quite dead yet, Endovascular therapy may be added to the same bin as many other interventions before it: Vioxx, Xigris, Avandia, Diehtylstilbestrol…

6.  Major Limitations of the study?

The study is a well completed randomized controlled trial. However, several limitations still exist.

First, there were inconsistencies in what types of interventions were performed. Several patients randomized to the interventional arm got both IA tPA and thrombectomy while others received IA tPA alone. Also, the dosing of IA tPA was also not standardized, and this could potential confound the results. The authors acknowledge this when they state this is a pragmatic trial as there is no standard of IA tPA or when to deploy a mechanical device, as this is mostly based on operator experience.

In addition, it is possible that patients with angiography defined acute ischemic stroke in a large vessels may have greater benefit, as that was not part of the inclusion criteria in this trial. Only 1/3 of patients had a large vessel atherosclerosis or cardiogenic embolism as the cause (the rest were small-vessel and other). Therefore whether or not more benefit would be derived from obtaining a CTA and identifying these patients first is questionable. The authors argue that the CTA adds significant time delays to an already time sensitive situation and that the probability that a CTA adds significant benefit is “unlikely”.

Lastly some interventionalists ask for systemic thrombolysis first, and then complete thrombectomy afterwards. Whether this approach is more efficacious can not be ascertained by this study.

Take home points!

1.    Intra-arterial thrombolysis in acute ischemic stroke without systemic thrombolysis does not offer improved neurologic survival compared to systemic thrombolysis for acute ischemic stroke.

OF note several trials were all presented on Feburary 8^th 2013 at the international stroke conference, ALL WERE NEGATIVE. Abstracts provided below.

MR RESCUE- Kidwell and colleagues completed a randomized controlled trial in 118 patients within 8 hours after the onset of large-vessel, anterior-circulation strokes comparing mechanical embolectomy (Merci Retriever or Penumbra System) or receive standard care. Revascularization in the embolectomy group was achieved in 67% of the patients. Ninety-day mortality was 21%, and the rate of symptomatic intracranial hemorrhage was 4%; neither rate differed across groups. Among all patients, mean scores on the modified Rankin scale did not differ between embolectomy and standard care (3.9 vs. 3.9, P=0.99). Embolectomy was not superior to standard care in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; P=0.23) or a nonpenumbral pattern (mean score, 4.0 vs. 4.4; P=0.32). In the primary analysis of scores on the 90-day modified Rankin scale, there was no interaction between the pretreatment imaging pattern and treatment assignment (P=0.14). Conclusion: A favorable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care.

IMS III trial- In patients with moderate-to-severe acute ischemic stroke who received intravenous t-PA within 3 hours after symptom onset, Broderick et al randomly assigned eligible patients to receive additional endovascular therapy or not, in a 2:1 ratio. The study was stopped early because of futility after 656 participants had undergone randomization. The proportion of participants with a modified Rankin score of 2 or less (indicating functional independence) at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA alone; absolute adjusted difference, 1.5 % points; 95% CI 6.1 to 9.1). Mortality was unchanged at 90 days ( endovascular-therapy: 19.1% versus intravenous t-PA 21.6%; P=0.52), as was the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83). Also, there were there no significant differences for the predefined subgroups of patients with an NIHSS score of >20 or <20. Conclusion: Additional endovascular therapy after intravenous t-PA was not associated with improved outcomes in acute ischaemic stroke.

Ciccone et al. Endovascular treatment for Acute Ischemic Stroke. NEJM. 2013; 1-10. 

UNTIL NEXT TIME!

-Dave

Blood Transfusions in UGI Bleeding

TRANSFUSIONS IN ACUTE UPPER GASTROINTESTINAL BLEEDING

Transfusion thresholds in medicine have been steadily falling, as more and more literature demonstrates either no improvement in outcomes or associated harms.  

Today’s mini-JC focuses on a topic extremely relevant to our practice as emergency physicians: transfusion thresholds of PRBC’s in patients with acute upper gastrointestinal bleeding (UGIB). If the patient is exsanguinating, we all know what to do, but what about in hemodynamically stable patients with an upper GI bleed?

1.  Why is this topic important?

Several non-randomized trials, and animals studies have evaluated a restrictive approach to blood transfusion in patients with bleeding from portal hypertension, as increases in effective circulating volume may lead to a rebound in portal pressure, which is associated with a risk of re-bleeding.

In addition, trauma surgery has propagated the idea of “don’t pop the clot” in patients who have penetrating trauma in order to prevent rebleeding and coagulopathy after surgery. These same mechanisms have been suggested to be beneficial in patients with arterial hemorrhage from a perforated peptic ulcer.

2.  What does this study attempt to show?

This study attempts to demonstrate that in patients with UGIB without massive exsanguination, a restrictive transfusion threshold of 7 is non-inferior to a transfusion threshold of 9. Patients were eligible if they had hematemesis, (or bloody nasogastric aspirate), melena or both as confirmed by hospital staff.

They attempted to exclude critically ill patients as well as completely stable patients as defined below:

-Patients were excluded if they had a lower GI bleed, active acute coronary syndrome (new EKG findings or positive biomarkers), massive exsanguination (hypotension, with active bleeding requiring emergent transfusion), or acute CVA.

-Patients with rockall score of 0, or a hemoglobin of 12 or greater were also excluded as these patients represented the lowest risk group.

Patients were randomized to a restrictive (transfuse if hgb <7, goal hgb 7-9) or liberal (transfuse if hgb <9, goal 9-11) transfusion groups. Randomization also was stratified for presence or absence of cirrhosis in blocks of four.

Treatment was otherwise kept the same between the two groups (protonix bolus and drip, emergency EGD within 6 hours with banding or sclerotherapy as necessary, octreotide and antibiotics if the bleed was deemed to be variceal.)

3.  What are the essential findings?

A total of 921 patients underwent randomization and 32 were withdrawn or withdrawn by investigators. 444 patients were left in the restrictive-strategy group and 445 in the liberal-transfusion group. Baseline characteristics were similar in both groups, as described in table 1.

225 (51%) of patients in the liberal group got transfusions, as compared with 61 (14%) in the restrictive group.

Mortality at 45 days was significantly lower in the restrictive-strategy group than in the liberal group 5% (23 patients) as compared with 9% (41 patients) hazard ratio 0.55 (0.33-0.92) respectively, p < 0.05.  

Death was due to unsuccessfully controlled bleeding in 3 patients in the restrictive strategy group (0.7%), and 14 patients in the liberal strategy group (3.1%).

Overall the liberal strategy group got more blood, had more rebleeding and thus required more salvage procedures especially in patients with variceal bleeding (TIPS and balloon tamponade). There were more medical associated deaths (sepsis, acute MI, acute CVA etc.) in patients who received the liberal transfusion strategies.  

4.  How is patient care impacted?

Among patients with severe acute upper gastrointestinal hemorrhage a restrictive strategy of blood transfusion improved mortality at 45 days. This survival benefit was likely conferred due to better control of factors contributing to death, such as further bleeding, rescue therapy and adverse events.  

5.  Is this an area of controversy?

Although this is an area of controversy, the evidence that blood transfusions, especially older blood in which the oxygen carrying capacity has diminished, may result in increased complications has been suggested previously. The TRICC trial, the Houston study, and several other large randomized controlled trials have all shown that patients have improved or equivalent outcomes when using a restrictive transfusion strategy.  The mechanisms for this difference in mortality are certainly different, as we know that transfusions may propagate further bleeding in patients at risk of hemorrhage. In addition, it is known that blood transfusions can result in significant immunomodulation and cytokine release resulting in acute renal failure, pulmonary edema, ARDS, and higher infectious complications in the critically ill medical patient.

This must be balanced in the situation in which acute hemorrhage is life threatening and rapid transfusion is required to restore the effective circulating blood volume.  

6.  Major Limitations of the study?

The study is a well completed randomized controlled trial. However, several limitations still exist. First, there is no direct statement as to what was defined as a life-threatening hemorrhage that excluded patients from the trial, and therefore knowing how to apply this to our patients is somewhat confusing. In addition, 32 patients were withdrawn from the study because the investigator did not believe that there was clinical equipoise. They do not further specify this in the intention to treat analysis, and how many patients from each group were removed (if all 32 patients from the restrictive strategy group were removed because the attending physicians believed that they required blood transfusions this could have a significant effect on the statistically significant mortality benefit shown in this paper.)

However, despite some limitations in the study there are several important concepts:

1.    Transfusing patients based on hemoglobin levels only may be short sighted. Looking at perfusion parameters (lactate, oxygen delivery, end organ malperfusion) may be a more appropriate approach rather than transfusing to a number (MUST KEEP KGB > 9).  

2.    Giving a blood product should be viewed as giving a potentially dangerous medication (not dissimilar to heparin, Plavix etc.) and each time you order it you should consider the risks and the benefits. It has been demonstrated time and time again that blood products have associated harms (certainly I am not arguing against transfusing the actively bleeding patient with obvious signs of malperfusion), especially in the elderly patients with multiple comorbidities or patients with cancer.

UNTIL NEXT TIME

-Dave

Villanueva et al. Transfusions Strategies for Acute Upper gastrointestinal Bleeding. NEJM. 2013; 368:11-21.

Low Risk Chest Pain- Accelerated Rule-out

Do you hate chest pain, or is it easy if you have a chest and you have pain you get admitted. Or if you are ultra-low risk (usually 0 risk) you just send them home, no testing. But what about people with a decent story? Is it safe to send someone home, or do these people need further testing as recommended by the AHA (stress within 72 hours?) 

Chest pain represents about 10% of ED visits and a diagnostic strategy to safely identify and discharge low risk patients in a rapid fashion has been debated. A quarter of all hospital admissions are secondary to chest pain, and about 85% do not leave the hospital with a diagnosis of acute coronary syndrome.

Today’s mini JC focuses on the safety of a rapid identification of the “low risk” patient who can be safely discharged from the hospital with a 2 hour-accelerated diagnostic protocol.

1.  Why is this topic important?

Rapid evaluation and discharge of low risk chest pain may substantially reduce both outpatient and inpatient LOS, cost to the patient and health care system, and reduce physician liability. A rapid diagnostic protocol that can discharge patients within two hours of being evaluated represents a superior alternative to admission for serial enzymes, and possible a stress test (which more and more seems to be of limited utility.)

2.  What does this study attempt to show?

The study attempts to demonstrate that in patients whom are low risk defined as two negative troponins, 2 hours apart, a TIMI risk score of 0 (see below) and no new EKG changes (see manuscript, but a LBBB if it was old did not preclude them from enrollment in the study) can be safely discharged home with a 30 day event rate < 1%.  Major adverse cardiac events (MACE) were identified as: death, cardiac arrest, emergent revascularization procedure, high degree AV block, and acute MI. AMI is defined as having ischemic symptoms + a rising biomarker (troponin). In this protocol no physician judgment including (patients whom the provider deemed to be low risk) was included to provide more generalizable results.  It is important to note this a prospective observational study, not an intervention study.

 3.  What are the essential findings?

1,975 patients were prospectively enrolled, and ultimately 302 patients (15.3%) developed MACE within 30 days. The accelerated diagnostic protocol (ADP) classified 392 patients (20%) as low risk. One lone patient who was ADP negative developed MACE at 30 days giving the ADP a sensitivity of 99.7%, (95% CI 98.1%-99.9%), and a specificity of 23.4% (95% CI 21.4% to 35.4%).  The lone patient that was missed by the ADP was previously healthy with no risk factors, a normal EKG, and first trop of <0.01, and 2^nd of 0.03, with the 3^rd troponin being 16.8. Angiography showed right coronary artery and circumflex artery stenosis and he had stenting in both vessels. No cardiac problems at one year follow-up.

In addition, the supplemental data from table’s 2A/B suggests that 75% of ADP negative patients underwent further diagnostic evaluation with stress testing.  7 ultimately had “non-emergent cardiac catheterization with revascularization.” Many patients were exposed to potentially dangerous anti-coagulants. 

Table 2a Use of further investigations in ADP negative patients within 30 days

	Median # of days post presentation	Inpatient	Outpatient
CT Coronary Angiogram	2.0	17	2
Stress Radionuclide	5.5	11	14
Stress Echo	11.5	5	7
Stress ECG	0.5	265	18
Angiography	2.6	26	3

Table 2b Acute treatments on ADP negative patients within 30 days

In-patient Therapy	Number
Heparin	8
LMW Heparin	20
G2b3a inhibitor	9
Heparin + G2b3a inhibitor	0
LMW Heparin + G2b3a inhibitor	27
Non-emergency Revascularization	7

ADP = Accelerated Diagnostic Protocol, LMW = Low Molecular Weight.

4.  How is patient care impacted?

Although this study is not an intervention study, it is strong food for thought. Using a TIMI risk score of 0, no new EKG changes, and 2 negative troponins, (<99%ile for your lab) 2 hours apart suggest these patients are low risk for MACE at 30 days. This study suggests that about 1/5^th of our chest pain patients, who make up approximately 10,000 patients visits a year, can be safely discharged within a few hours of their initial ED evaluation. That’s 2,000 patients annually that could avoid admission and further diagnostic testing as an inpatient.

5.  Is this an area of controversy?

Of course. The study is prospective observational, and 75% of ADP negative patients ultimately had further diagnostic testing. In order for us to believe that an accelerated diagnostic protocol is useful the protocol needs to be used on patients in a prospective fashion (patients actually getting assigned the ADP vs. traditional care), and followed for 30-day outcomes.

Others may state that although only one lone patient in the ADP negative group developed MACE at 30 days, many more ADP negative patients received further diagnostic testing (CTCA, stress echo/EKG/radio nucleotide, and angiography with 7 patients ultimately getting non-emergent revascularization.) 

What do I think about this? Well if you were to take a cohort of patients walking around who developed chest pain > 50, many may have coronary artery disease, and if cathed may have a >70% lesion. However, what we have learned from prior mini JC’s is that stable coronary artery disease can be managed medically with equivalent if not superior results to invasively. Therefore, the benefit of an invasive strategy in these patients with NO EKG changes, negative biomarkers and perhaps a positive stress test must be questioned.

6.  Major Limitations of the study?

As stated previously this is a prospective observational study, not an intervention study, although not a limitation of the study itself, it may limit the applicability to your daily practice. However, other studies have suggested similar results including 30 day outcomes in “low risk patients” when evaluating CCTA. Therefore if you have a low risk patient by history, EKG, and a delta troponin at 2 hours it is reasonable to discharge those patients home with follow-up with their primary medical doctor.

The argument against this strategy is that you are missing the “unstable angina people”.  One important factor to remember is that likely the old “unstable angina patient” who came in 20 years ago before ultrasensitive troponins likely was having some trop leak as they exerted themselves with a partially occluded coronary artery. Those patients are likely called NSTEMI nowadays. In addition, plaques that are about 70-80% lesions are much less likely to rupture than are plaques that are say 20,30,40% as these plaques are much more unstable. These type of lesions will not be picked up by a stress test, and wouldn’t get a stent if they were cathed, and maximal medical therapy would be undertaken. Therefore the utility of identifying a plaque that may rupture is inherently flawed.

I reference you to an alternative approach, used at the mayo clinic, for placing the power of decision making back into the patients hands.  

I know two articles in one mini JC, but try using it next time you have a patient with chest pain, and let me know how it works for you! Essentially it is a protocol that after initial evaluation patients are given a pamphlet with 4 options to help them decide what they ultimately want to do. See chest pain decision aid I attached for you. 

Hess E et al. The chest pain choice Decision Aid. Circ Cardiovasc Qual Outcomes. 2012;5:251-259.

Ultimately I think an ADP is useful, and that patients who meet the aforementioned ADP negative criteria can be safely discharged home, and that further diagnostic testing is not warranted from the emergency department. I would recommend having that discussion using the decision aid with your patients so that they can be part of the medical decision making process. 

Until next time!

-Dave

2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial. Than M, Cullen L, Aldous S, Parsonage WA, Reid CM, Greenslade J, Flaws D, Hammett CJ, Beam DM, Ardagh MW, Troughton R, Brown AF, George P, Florkowski CM, Kline JA, Peacock WF, Maisel AS, Lim SH, Lamanna A, Richards AM. J Am Coll Cardiol. 2012 Jun 5;59(23):2091-8

Pediatric Fever Control

Fever is often observed in patients with documented infection, and we know from personal experience that fever makes you feel like ass, so we take motrin and tylenol to feel better, but what does this mean for our patients. Our we fighting evolution here?

Egi et al performed a prospective observational study on the association of body temperature and antipyretic treatments with mortality in critically ill patients with and without sepsis, excluding patients with neurologic injury (we know fever is bad when you have a neurologic insult). 

Here is what they found:

1. Why is this topic important?

It is almost reflexive to give febrile patients tylenol or Motrin for fever control. We know that fever creates tachycardia, and is uncomfortable for patients. However, fever is a natural response and multiple studies have demonstrated an increase in heat shock proteins, and a more robust microbicidal activity in patients with fever when compared to patients with euthermia or hypothermia. However, patients who are not infected may also have fever as part of an inflammatory cascade, and this could be detrimental. In this study Egi et al examined the associated between mortality and the treatment of fever in both septic and non-septic patients who were admitted to the intensive care unit with fever. 

2. What does the study attempt to show?

The study attempts to identify associations between fever and outcomes in septic and non-septic patients who were treated with pharmocologic agents like tylenol and Motrin or cooling blankets after being admitted to the intensive care unit. 

3. What were the findings?

1,425 consectuctive adult critically ill patients WITHOUT neurologic injury requiring > 48 hours in the intensive care unit were admitted in 25 ICU's. Every 4 hours body temperature was recorded and antipyretic treatment was monitored until ICU discharge or 28 days after ICU admission, whichever occurred first. Patients were divided into septic and non-septic patients, and the maximum body temperature and use of antipyretic treatment were assessed separately to mortality. 

Treatment with non-steroidal anti-inflammatory drugs (NSAID's) or acetaminophen INDEPENDENTLY increased 28-day mortality for SEPTIC patients (OR:  NSAID's 2.61 p = 0.028 and OR Acetaminophen 2.05 p =0.01), but did not change mortality for non-septic patients (NSAIDs 0.22 P =0.15, Acetaminophen 0.58 P =0.63). Application of physical cooling methods did not associate with mortality in any group. 

4. How is patient care impacted?

Since this is an observational study only association and not causality can be inferred, but this is strong food for thought regarding the aggressive treatment of fever with antipyretics in patients with suspected sepsis. To reiterate the point that fever is a response to stimulate the body's innate immune activity through the production of heat shock proteins and inflammatory mediators that stimulate bactericidal activity of leukocytes. Although fever is associated with increased volume loss, and increased metabolic demand, intravenous fluids, antibiotics, cooling blankets may be a more suitable alternative to antipyresis in the sicker cohort of patients (septic going to the ICU, not febrile kids in the PEC). 

5. Is this an area of controversy?

Since many physicians regard fever as an evil that must be treated, and some won't ever discharge a patient home until the fever has broken I would say yes. Although there are some adverse effects to fever (as previously mentioned and febrile seizures due to rate of rise in children), there advantages to a billion years of evolution. Maybe our bodies have it right. 

6. Major limitations of the study?

The study is observational, and in the ICU patients could be treated with antipyretics at the attending physicians discretion. Maybe sicker patients got tylenol and Motrin (although multivariate analysis should have accounted for this variability). Either way a randomized placebo controlled trial would be necessary to draw practice changing conclusions. 

In summary fever is a common occurrence in septic patients, and this study demonstrated an associated with increased mortality when treating septic patients in the intensive care unit with tylenol and motrin for fever control. This suggests fever may be a host response and suppression of the febrile response might worsen outcomes in septic ICU patients. 

-Dave

To stent or not to stent?

Now onto today's mini JC topic Stents vs medical therapy ALONE for stable coronary artery disease

Stable coronary artery disease (or those without EKG signs of ischemia or positive troponin) are often admitted to the hospital, especially if they carry multiple risk factors. Most of us never followup on these or check in care connection the next day to see what happens to our stable chest pain patients. Usually we thought they probably couldn't go home OR  we had hoped that if they had some large coronary artery lesion that needed stenting we would have saved a future MI or maybe a fatality. 

A meta-analysis was recently completed comparing MAXIMAL medical therapy to percutaneous coronary intervention in patients with STABLE coronary artery disease. This study was modern that only RCT who included patients who got modern maximal medical therapy (beta blockers, ACEI, anti-plt regimens) compared to stenting (no angioplasty alone). 

Heres what was found:

1. Why is this topic important?

We admit lots of chest pain patients to the hospital with vague stories with negative troponins and non-ischemic EKG's, which increased LOS, and hospital resource utilization, the question remains where is the benefit?

2. What does the study attempt to show?

This is a meta-analysis of RCT comparing maximal medical therapy to stent placement in patients with stable coronary artery disease, in the modern medical era (ACEI, BB, new fancy anti-plt agents). Outcomes included: Death, MI, or non-planned revascularization and persistent angina

3. What were the key findings?

8 trials for a total of 7229 patients were found.

Death rate for stent implantation vs medical therapy was 8.9 vs 9.1% perspectively (OR 0.98 95% CI 0.84-1.16)

NON-fatal MI for stent 8.9% and medical therapy 8.1% (OR 1.12 95% CI 0.93-1.34)

UN-planned revascularization for stent vs medical 21.4% vs 30.7% (OR 0.78 95% 0.57-1.06)

Persistent angina 29% and 33% (OR 0.8 95% CI 0.6-1.05) 

4. How is patient care impacted?

Patients with stable coronary artery disease should be placed on maximal medical therapy and seen in their doctors office not admitted to the hospital where incentives to have invasive procedures persist. The fact that no benefit is seen in mortality or recurrent MI, AND many of these studies did not use troponin measurements (still using CK-MB's) means that the Nonfatal MI was probably higher in the stent group than actually demonstrated, this is because stenting has a periprocedural MI rate between 5-30% due to distal embolization of plaques, or distal side occlusions and was not detected on the less sensitive CK-MB assays. 

5. IS this an area of controversy?

Yes, cardiologists have a strong incentive to cath patients who likely have disease (09% stenosis, 70% stenosis etc) and place stents, they think and we think this is helping patients live longer and symptom free. But in reality its a costly intervention and we have incomplete evidence of the pathophysiology of plaque rupture. therefore what we end up with is an inability to reject the null hypothesis, PCI in patients with stable CAD does not result in a mortality reduction when compared to maximal medical therapy alone. 

6. Major limitations of the study

This is a meta-analysis of randomized controlled trials, and they tried to select out patients who got MAXIMAL medical therapy and stents + MAXIMAL medical therapy. They had almost 7500 patients, but did not show a statistical or clinically significant benefit to stents over medical therapy for stable CAD. This nebulous outcome of unplanned revascularizations tended to be less frequent in the patients who got stented previously, but I think this is more INHERENT in the fact that they already had PCI and this made a cardiologist less inclined to interrogate the patients coronaries AGAIN. 

Initial Coronary Stent Implantation With Maximal Therapy vs Medical Therapy Alone for Stable Coronary Artery Disease

Stergioplous et al

-Dave

Evaluation for PE

Hey guys,
Its been far too long for the mini JC series, but thats what happens when you are about to have a baby. This JC was stimulated by Elise, Harwood and my discussion about a cancer patient and the evaluation of pulmonary embolism. I'll set it up for you and you think about how you would evaluate the patient.

65 y/o F presents to the ED with shortness of breath. She says this started 2 days ago, and has worsened since that time. She is a breast cancer survivor and is undergoing active chemotherapy. She is not on home O2, but she has smoked and does think she has COPD as evidenced by her inhalers. 
VSS: 95, 95% on RA, 110/70, 37.1 (R), 18 (real) FSG 99
Lungs are reduced BS at bases otherwise unremarkable 
She has no signs or symptoms of DVT, she has never had a blood clot, no recent surgeries. 
What labs and imaging studies do you want?? (US machine is broken sorry!)

SO today's study is the CHristopher study looking at the evaluation of pulmonary embolism in the emergency department. 

Van Belle A et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006. 11; 295(2): 172-9.

1. Why is this topic important?

Pulmonary embolism is a commonly feared diagnosis in emergency departments in the United States. The frequency with which pulmonary embolism has been diagnosed has increased over the past ten years, with the number of massive and sub-massive pulmonary embolisms remaining relatively unchanged. This is due in large part to the over zealous testing, and the subsequent diagnosis of likely non-clinically significant pulmonary embolism. A simplified dichotomized clinical decision rule, D-dimer testing and computed tomography may reduce the number of unneeded evaluations for pulmonary embolism in the United States today.

2. What does the study attempt to show?

Consecutive patients in whom the treating physician suspected the possibility of pulmonary embolism, defined as sudden onset of dyspnea, sudden deterioration of existing dyspnea or sudden onset of pleuritic chest pain, without another apparent cause, could be potentially included in this study. The study then applied the wells score, dichotomizing patients into pulmonary embolism unlikely (score <4) and pulmonary embolism likely (score >/= 4). In all patients with a wells score of less than 4, a d-dimer test was applied, with the cutoff of >/= 500ng/mL being considered positive. If the d-dimer was negative, no further investigation was obtained, but if the d-dimer was positive, or if the wells score was >/= 4 a CT was obtained to evaluate for the diagnosis of pulmonary embolism. The study attempts to demonstrate that using this simplified dichotimzed approach to the wells score <4, and a negative d-dimer assay patients can be safely discharged home without further diagnostic evaluation.

3.  What are the key findings?

3306 study patients were eligible for inclusion, and 2206 patients (66.7%) were classified as unlikely as having a pulmonary embolism using the dichotomized wells score and underwent d-dimer testing. 1057 patients had a normal d-dimer, and 1028 (32%) were not treated with anti-coagulation.  Subsequent nonfatal venous thromboembolism (VTE) occurred in 5 patients (0.5% [95% CI 0.2%-1.1%]) no patients in this group died from a pulmonary embolism at 3-month follow-up.

In the high-risk wells group (wells score >/= 4) 674 patients (20.4%) were included. CT excluded pulmonary embolism in 1505, of which 1,436 patients were not treated with anti-coagulants; with a 3-month incidence of VTE of 1.3% (95% CI, 0.7%-2.0%). In patients in whom the initial CT scan was negative, PE was considered a possible cause of death in 7 (0.5% [95% CI, 0.2%-1.0%]). Overall 674 patients (20.3%) were diagnosed with a pulmonary embolism in patients included in this study cohort. 

4. How is patient care impacted?

This study demonstrates that in patients in whom a physician suspects the diagnosis of pulmonary embolism, the use of a dichotomized wells score < 4 and a negative d-dimer assay negate further evaluation for pulmonary embolism, with a < 1% incidence of VTE at 3-months, and no fatal pulmonary embolisms identified at follow-up.  

5. Is this an area of controversy?

The evaluation for pulmonary embolism continues to produce anxiety amongst emergency physicians. However, one of the most striking finding in this study is that the overall incidence of pulmonary embolism was 20%. Compare this to the PERC study by Dr. Kline in which the incidence was 7%, this is almost a 3-fold increase in the number of patients with pulmonary embolism. In addition, just 0.15% of patients in the Kline cohort ultimately died from pulmonary embolism, where in the Christopher Study mentioned here 0.5% died from fatal pulmonary embolism. This suggests that emergency physicians, particularly in the United States, evaluate for pulmonary embolism in a lower risk cohort than physicians in other countries. This occurs despite the fact that there is no mortality benefit, and there is a potential for harm.

6. What are the major limitations of the study?

 Several patients received anti-coagulation despite being low risk for pulmonary embolism, or having been excluded for pulmonary embolism for other pathologic causes. This could have reduced the number of VTE identified at three months in the negative, or low risk cohorts.  Also, the type of CT detector used was not standardized, and the d-dimer assay varied by site. These represent potential confounders of the study results. However, the generalizability of the study and the large number of patients included with few exclusion criteria make this an important piece of the literature for emergency medicine physicians. 

Reviewed by David Barounis

So I know this was written more research-like and I apologize, but the end result is what are you going to do about evaluation of PE in the above patient. 

I think in our patient  her wells score was between 1.5 (active cancer) and a 4 (if you said diagnosis is PE or at least as likely). If you got a trop and a BNP and they were both normal (< 0.02, and a BNP< 100) would you feel better? I think I would, and a diagnosis of PE in my mind is < 2%. However I don't think its unreasonable to get a d-dimer, and if you have a negative d-dimer, a neg trop and a neg BNP in this patient population I think the above study suggests you really do not need to CT scan these patients to look for PE. I think many people would not even get a d-dimer either. Far too often I think d-dimer is used in the ultra low risk patient or "0" risk patient, instead of the patient it was meant for, which is our wells score <4 patients. 

-Dave

ARDS

Although Lung protective ventilation has been demonstrated to significantly lower mortality in patients with ARDS, data regarding its use in patients without ARDS or  acute lung injury(ALI) has been scarce. The meta-anaylsis published in JAMA this month looked at patients receiving lung protective ventilation in patients without ALI or ARDS (6-8cc/kg IBW vs traditional ventilatory strategies with 10-12cc/kg IBW). The end points included, mortality, ventilator free days, development of acute lung injury/ARDS, pulmonary infection and atelectasis.

The most important thing to look at when reviewing this article is there is significant heterogeneity in the papers included, some randomized, others non-randomized, some in post-surgical/OR patients other medical patients and none in emergency department patients. Nonetheless, I like the results, and so I am passing the paper onto you to decide! 

1. Why is this topic important?

In patients who receive mechanical ventilation, acute lung injury and the development of ARDS are frequent complications associated with significant morbidity and mortality. The ideal ventilatory strategy is unknown, but the ARDSnetwork has demonstrated that lung protective ventilation in patients with ARDS reduces mortality, ICU length of stay, and pulmonary infections.  In the emergency department our ventilatory strategies may affect patient outcomes days down the road as lung injury has an insidious onset. Therefore the question remains whether in patients who are at risk for developing acute lung injury or acute respiratory distress syndrome benefit from the same lung protective ventilation early in the disease course i.e. beginning in the emergency department. 

2. What does the study attempt to show?

Three reviewers from the department of CCM in Brazil reviewed the available literature regarding the use of lung-protective ventilation in patients without acute respiratory distress syndrome, or acute lung injury (berlin definition of ALI and ARDS). Articles were selected if they evaluated two types of ventilation in patients without ARDS or ALI: low tidal volumes (6-8cc/kg IBW) vs. traditional tidal volumes (10-12cc/kg IBW). Studies included: prospective observational studies (before/after, cohort, cross-sectional), and RCT in a variety of settings. The study attempts to identify if lung protective ventilation is beneficial in all patients prior to the onset of ALI or ARDS.

3. What were the findings?

Twenty articles which included, with 2,822 participants analyzed.  Table 1 summarizes the characteristics of included studies, in which there was significant heterogeneity and none of the studies included began in the emergency department setting. Baseline characteristics were similar between the two groups except for several important ventilator characteristics: respiratory rate was higher in the low TV ventilation group (18 vs. 12) , while minute ventilation remained similar (8.6 vs. 8.4 L/min). The plateau pressure was lower in the low TV group although the mean Pplateau remained below 30 in both groups. PEEP was higher in the low TV group, and PaCO2 was also higher in the low TV group. See table 2 for all of the numbers. 

There was a decrease in lung injury development in the low TV ventilation group (RR 0.33 95% CI, 0.23-0.47 with a NNT 11), and a reduction in mortality in the low TV groups (RR 0.64, 95% CI 0.46-0.89; NNT 23.) The results were similar when you evaluated both randomized and nonrandomized studies.

4. How is patient care impacted?

In patients who require endotracheal intubation lower tidal volume ventilation is suggested by this meta-anyalsis to reduce both morbidity and mortality. This study included a wide-variety of patients including post-surgical, and medical patients. The intervention in this group is free, effective, and poses minimal risks to patients other than slight worsening in acidosis and increased PaCO2 which can be counter-balanced by increase respiratory rate and maintaining minute ventilation, and optimizing PEEP in order to reduce atelectasis. 

5. Is this an area of controversy?

Absolutely. Many physicians point to the fact that this is a summation of many non-randomized studies and studies in which potentially injurious lung volumes (800cc) were given to patients. In addition no prospective studies from the emergency department have EVER been completed. To complicate this issue in the emergency department the diagnosis of why a patient required endotracheal intubation is often obscured and the ability of an emergency physician to predict who may or may not develop acute lung injury is difficult if not impossible. 

Other physicians argue that low tidal volume ventilation increases atelectasis and in patients without ARDS this atelectasis may increase the risk of pulmonary infection, lower PaO2, and increase PCO2 worsening underlying acidosis, if present. 

6. Major limitations of the study?

This study is comprised of multiple prospective observational studies, non-RCT, in a heterogeneous population. Patients who are post-surgical are certainly at risk of developing ARDS, however the mechanism may be inherently different than that of a patient with septic shock. Since ARDS and ALI are clinical syndromes, and the pathophysiology for the causes is inherently different it is difficult to recommend one ventilatory strategies for all critically ill patients. 

My take on the study is that low tidal volume ventilation is potentially beneficial in all patients requiring mechanical ventilation. As long as you can manage the patients respiratory parameters with PEEP and RR while monitoring PCO2, pH, PaO2 and always keeping the plateau pressure < 30, all patients should receive lung protective ventilation. I believe this for several reasons, one of which is patients lungs who require intubation in the ED are not post-surgical they rarely are being intubated to be extubated in a few hours and we anticipate that intubation is going to be for days. Therefore, we should expect all of our patients to be at risk for ALI, and ARDS. In addition, the TV is not spread evenly throughout the lungs as the lungs often have a patchy distribution of injury, for example a LLL pneumonia means that region of the lung is filled with pus and the rest of the TV (which cannot reasonable aerate that portion of the lung) will be dispersed to the "healthy" lung possibly causing over distention and lung injury. 

Another important fact to remember is when assessing for lung protective ventilation it is based on IBW, so Jaba the hut gets ventilated based on height not weight! Rarely is a patient tall enough to require >600cc, but see the PDF in included for volume recommendations. 

The evidence is weak so read for yourself and be flexible to change as the evidence changes in the coming years, but for now I think it is reasonable to use lung protective ventilation in all emergency department patients requiring endotracheal intubation. 

-Dave

Neto AS et al.  Association Between Use of Lung-Protective Ventilation With Lower Tidal Volumes  and Clinical Outcomes Among Patients Without Acute Respiratory Distress Syndrome. JAMA 2012;308 (16): 1651-1659.