The Adventure of the Second Stain Continues

Meningitis_-_Lumbar_puncture

The CT-LP (lumbar puncture) diagnostic pathway has been a permanent fixture in the arsenal of the Emergency Physician for what seems like an eternity. Steadfast in its dependability, for many generations, the LP was a necessity for Emergency Physicians to safely exclude the diagnosis of subarachnoid hemorrhage (SAH). And yet, rarely a moment has passed over the past few years when Dr. Jeffrey Perry has not politely demonstrated how little we truly know about this disease process and the diagnostic tools associated with it. His 2011 paper questioning the necessity of an LP following a negative head CT under 6-hours from symptom onset, shook the once solid ground that the LP firmly stood upon (1). As if this attack on our reliable comrade was not enough, his most recent publication examining the diagnostic capabilities of the lumbar puncture itself has left our confidence in this once dependable testing strategy in turmoil.

In this paper, published in February of 2015 in The BMJ, Perry et al utilized a subset of patients from two cohorts originally enrolled to derive and validate his Ottawa SAH rule (3,4). Authors examined 1739 of these patients who received a lumbar puncture as part of their workup for SAH (2). They then sought to assess the diagnostic accuracy of this tool. Similar to common practice, they prospectively defined a positive tap as greater than 1 RBC on fluid aspirate. When this impossibly low threshold was upheld, LP’s performance was less than stellar. Of the 1739 patients who received an LP, 641 (36.9%) had positive findings, only 15 of which were actually from subarachnoid blood. Most of these false positive results were trivial, as 476 (74.3%) had counts of ≤100×106/L and 94 (14.8%) had counts of 101-1000×106/L. Only 10.4% of these patients were found to have clinically concerning levels of RBCs in their CSF (counts of >1000×106/L). Despite the predominance of low RBC counts, a great majority of the patients in whom the LP was positive (419) received invasive angiographic imaging.

When the LP was found to be negative (No RBCs in the CSF), it boasted a sensitivity of 100%. In an attempt to compensate for the unacceptably high number of false positives the authors retrospectively determined the ideal RBC cutoff to be 2000×106/L. At this threshold the LP had a sensitivity of 93.3% (95% confidence interval 66.0% to 99.7%) and specificity of 92.8% (90.5% to 94.6%) for aneurysmal subarachnoid hemorrhage.  If visual xanthochromia was added to this RBC cutoff, the sensitivity for ruling out SAH became 100% (95% confidence interval 74.7% to 100.0%).

These numbers are of course fraught with methodological pitfalls. The threshold of 2000×106/L was retrospectively derived to best fit this specific cohort. Only 15 of the 1739 patients examined actually had the disease in question making these calculations incredibly unstable (the confidence intervals surrounding their 100% sensitivity dropped as low as 74.7%). The threshold of 2000×106/L is hardly robust enough for clinical use and will inevitably fail when applied in prospective fashion to a novel cohort.

Though this data is not definitive and further studies validating these findings are required, a number of valuable conclusions can be inferred. Surprisingly the most important of these has little to do with the diagnostic utility of the lumbar puncture.

In 2011 Perry et al published their game changing article in The BMJ examining the accuracy of a non-contrast head CT performed under 6-hours from symptom onset for the diagnosis of SAH (1). This paper was a secondary analysis of the original cohort used to derive the Ottawa SAH Rules (4). Using this preexisting cohort they assessed the accuracy of head CT for the diagnosis of SAH before and after a 6-hour threshold. The authors claim a sensitivity of 100% when CT was performed within 6-hours of symptom onset. However when the CT was performed after this 6-hour threshold, the sensitivity fell to 85.7%. Suggesting that when performed within 6-hours, a non-contrast CT is sufficient to rule out SAH, allowing practitioners to forego a subsequent lumbar puncture. Though many have viewed this as practice changing, others argue a number of flaws in the study’s design prevent us from interpreting these conclusions with such conviction.

The most obvious and often discussed weakness of this study is the use of a surrogate endpoint in place of a true gold standard. Not all patients who had a negative head CT underwent a confirmatory lumbar puncture. In its place, the authors used a 6-month proxy outcome to demonstrate the safety of CT alone. Patients underwent a structured phone interview at the 6-month mark to ascertain their wellbeing. When attempts to reach patients over the phone failed, authors endeavored to determine their status by searching medical records from regional neurosurgical centers as well as coroner’s death records. Patients were considered to be free of SAH if on 6-month follow-up they were alive and well. In the case of patients who were discovered to have passed away during the follow-up period, if the cause of death was determined to be due to something other than SAH, their deaths were not counted as a missed diagnosis. Of the 1931 patients examined, 421 were lost to follow-up. Authors found 8 of these patients had passed away since their initial workup for subarachnoid hemorrhage. Although none of these patients were determined to have died because of SAH, the reliability of post mortem cause of death is questionable at best (5).

A far less discussed aspect to this study was how the authors’ definition of a positive CT influenced the validity of their results. The standard that Perry et al used to calculate the sensitivity of head CT was based upon the Neuroradiologist’s official report. In most facilities (as was the case at the centers participating in this study) what guides Emergency Physicians’ clinical decision-making is the initial wet read usually done by Radiology house staff or even the ED physicians themselves. The sensitivity we are concerned with is that of the wet read. The Neuroradiologists in this study were not blinded to the patients’ lab findings. As such we are unable ascertain how many CTs done within 6 hours were initially read as negative, and only later after a positive LP was performed was the final report recorded as positive. If this had occurred with any frequency it would obviously harm the internal validity of the results. We are able to get a sense of how frequently this occurred by examining how many of the patients who were diagnosed with SAH had both a positive CT and LP. At least in theory, if the CT was positive then there would be no reason to perform the subsequent LP.

Of the 15 patients with SAHs that were diagnosed using a positive LP, 10 underwent head CTs and LPs that were both positive. The vast majority of these subarachnoid bleeds (n=8) were found in patients who received their CTs beyond the 6-hour threshold. There were however two patients that were identified as having received their CTs within 6-hours of symptom onset. In both these patients their initial CT was read as negative and only after a positive lumbar puncture was the final report changed to positive. If these two patients are taken into account, the adjusted sensitivity of CT under 6-hours from symptom onset is only 98.3% (with the confidence interval dropping as low as 93.6%).

These findings of course do nothing accept muddy the already cloudy waters. Head CT though fairly sensitive, will on occasion miss a subarachnoid bleed. The addition of CSF aspirate will very often offer a further degree of ambiguity. Furthermore the utilization of LP, at least in its current strategy, leads to an unacceptable number of false positives, exposing a large number of patients to needless downstream testing. If a more liberal view towards RBCs in the CSF is taken, the LP’s utility may be justifiable. Even with the retrospective best fit diagnostic capabilities calculated by Perry et al, the prevalence of SAH following a negative CT in under 6-hours is so low that further testing will likely lead to identifying far more false positive results than true subarachnoid bleeds. Cleary the conviction and certainty we once held for this testing strategy has suffered. Perhaps it is time for a shared decision making model. After all it is our patients’ value systems rather than our own biases that should guide these investigative journeys. Dr. Perry has demonstrated that the CT-LP pathway is far from straightforward. Perhaps it is time we confess these imperfections to the world at large and begin a far more honest conversation.

Sources Cited:

  1. Perry JJ, Stiell IG, Sivilotti ML, et al. Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study. BMJ. 2011;343:d4277.
  2. Perry JJ, Alyahya B, Sivilotti ML, et al. Differentiation between traumatic tap and aneurysmal subarachnoid hemorrhage: prospective cohort study. BMJ. 2015;350:h568.
  3. Perry JJ, Stiell IG, Sivilotti ML, et al. Clinical decision rules to rule out subarachnoid hemorrhage for acute headache. JAMA. 2013;310:(12)1248-55.
  4. Perry  JJ, Stiell  IG, Sivilotti  ML,  et al.  High-risk clinical characteristics for subarachnoid haemorrhage in patients with acute headache: prospective cohort study. BMJ. 2010;341:c5204.
  5. Wexelman, BA et al. Survey of New York City Resident Physicians On Cause-Of-Death Reporting. 2010. Prev Chronic 2013 10:E76

The Adventure of the Cardboard Box Continues

sigmund-abeles_portrait-of-parasomniac

For those whose beliefs are already firmly in favor of endovascular therapy for acute ischemic stroke, the publication of the MR CLEAN trial earlier this year and more recently the EXTEND-IA and ESCAPE trials only serve as a big fat, “I TOLD YOU SO!” For the perpetual disbelievers, each of these trials possesses enough flaws to discredit their findings. For the appropriately skeptical among us, though these trials initially appear to discredit our well meaning rants, on closer examination they are far more validating.

Earlier this year the publication of a large, well done, RCT examining the use of endovascular treatment for acute ischemic stroke threatened to drastically change the acute management of CVA as we know it. And though this trial was given a most unfortunate name (MR CLEAN), it marked the first time endovascular therapy has demonstrated any clinically relevant benefit (1). We have discussed this trial in depth in two previous posts. While MR CLEAN’s results were promising, there are many reasons why they should be viewed with a healthy dose of skepticism. Before we commit to a resource heavy intervention like that of endovascular therapy, more studies validating these findings are required. Since the publication of MR CLEAN, two active trials were stopped early for benefit, seeming to be the very validation for which we asked. The results of both of these studies, EXTEND-IA and ESCAPE, were recently published in the NEJM (2,3).

The first trial, Extending the Time for Thrombolysis in Emergency Neurological Deficits — Intra-Arterial (EXTEND-IA) trial, by Campbell et al, is a multi-center RCT that examined the efficacy of endovascular treatment in patients with CVA whose symptoms began within 4.5 hours of randomization. Like MR CLEAN this trial was a stunning success. In fact its results far outpaced the, by comparison, paltry benefits found in MR CLEAN. EXTEND-IA was stopped early after enrolling 70 patients for overwhelming benefit. The rate of significant improvement after 3 days (reduction in NIHSS > 8) was 80% vs 37% in the endovascular group and control group respectively. Likewise the rate of favorable outcome at 90-days (mRS of 0-2) was 71% vs 40% respectively, boasting an absolute difference of 31% (2).

The second and far more statistically robust trial is the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial, published by Goyal et al. In this trial, authors examined patients up to 12-hours after symptom onset, (though the large majority of the patients enrolled were evaluated within 3-hours of symptom onset). Like EXTEND-IA, the ESCAPE trial was an overwhelming success. Authors randomized 316 patients to either standard care or standard care plus endovascular therapy. Like EXTEND-IA, the authors found overwhelming benefits of the endovascular therapy. The rate of functional independence at 90-days (mRS of 0-2) was 53.0% vs 29.3% in favor of the endovascular arm. With authors noting a 33.7% absolute increase in positive outcomes in patients who received endovascular therapy. For the first time in the history of reperfusion therapies for acute ischemic stroke, a clinically significant mortality benefit was demonstrated. 90-day mortality was 10.4% in the endovascular group compared to 19.0% in the control group. Not to mention the surprisingly low rate of intracranial hemorrhage, (3.6% vs 2.7%) (3).

Neither trial is definitive in its own right. The EXTEND-IA cohort only examined the efficacy of endovascular therapy in 70 patients. Originally intending to enroll 100 patients, this trial was stopped prematurely after an interim analysis demonstrated such impressive results. This premature investigation of the sealed data was not performed because of a pre-planned interim analysis, but rather because of the publication of MR CLEAN (2). Though the remaining 30 patients would have most likely not have altered the results, we cannot view this poorly powered trial as anything more than hypothesis building. In isolation, EXTEND-IA can only offer a guideline for the future of endovascular management in acute ischemic stroke. Even the authors themselves conceded this point in the statistical analysis plan they published in January 2014, in which they clearly defined EXTEND-IA as a phase II trial (4). A definition that is conveniently left out of the formal publication in the NEJM, an oversight possibly induced by the unexpected magnitude of their success causing well deserved delusions of grandeur.

ESCAPE, though far more statistically hardy than EXTEND-IA, is still a rather small cohort suffering from the same unfortunate biases. Originally intending to enroll 500 patients, the authors called for an early stoppage, prior to their planned interim analysis, again because of the results of MR CLEAN. Although the sample size of 316 patients lends a stronger validity than the 70 patients examined in EXTEND-IA, the early stoppage prevents us from confidently assessing the true effect size this treatment may provide. Interestingly when implementing this unplanned analysis, the authors utilized a dichotomous outcome comparing the mRS scale of patients alive and independent (mRS of 0-2) at 90-days rather than the ordinal analysis they had originally chosen and utilized as their primary outcome when performing the power calculation. The ordinal scale has recently gained favor as an outcome measure in stroke trials because of its ability to augment the p-value and turn otherwise negative trials into statistical successes. Conversely it is almost impossible to determine the clinical relevance of the odds ratio it produces. Given the impressive benefits of both trials, the small statistical augmentations offered by ordinal analysis are irrelevant. As such the authors of both trials favored the more traditional dichotomous outcome. The 33.7% absolute difference measured by the dichotomous scale in the ESCAPE trial, appears far more impressive than an odds ratio of 2.6 offered by ordinal analysis (3).

With the overwhelming success of both EXTEND-IA and ESCAPE, the MR CLEAN data appears almost lacking. In the MR CLEAN cohort, patients randomized to receive endovascular therapy had a 14% absolute benefit over those in the controls. It is safe to say neither group did all that well, with the amount of patients alive and independent at 90-days reported as 33% and 19% respectively(1). The EXTEND-IA and ESCAPE cohorts however did exponentially better (71% vs 41% and 53.0% vs 29.3% respectively) (2,3). Are we truly looking at the same patients as were examined in MR CLEAN, or do the EXTEND-IA and ESCAPE cohorts represent a completely different population?

It should come as no surprise that both the EXTEND-IA and ESCAPE cohorts included vastly different patients than those enrolled in MR CLEAN. In MR CLEAN, to be eligible for inclusion patients were required to have an occlusion of distal intracranial carotid artery or middle cerebral artery (M1, M2) or anterior cerebral artery (A1) as identified by CT angiography (CTA), magnetic resonance angiography (MRA) or digital subtraction angiography (DSA)(1). Both EXTEND-IA and ESCAPE had far stricter inclusion restrictions. Patients who were enrolled in the EXTEND-IA cohort needed to demonstrate an ischemic penumbra on perfusion imaging with a small infarcted core(2). Though slightly different criteria were utilized, like EXTEND-IA, the ESCAPE cohort used CT angiographic imaging to identify patients with small infarcted cores and large areas of salvageable tissue (3). These inclusion criteria significantly narrowed the subset of stroke patients examined. These differences in patient selection are not only responsible for the almost unbelievable efficacy demonstrated in both of the EXTEND-IA and ESCAPE trials, they mark the first time that imaging criteria was successfully used to identify a cohort of stoke patients who may benefit from reperfusion therapy.

There has been a long history of failure in the use of perfusion imaging for the management of acute ischemic stroke. Early studies investigating the use of diffusion weighted MRI to identify potentially salvageable ischemic brain failed to show benefit (5,6,7,8,9). These failures may be due in part to the industry bias of only enrolling patients presenting > 3 hours after onset, in the hopes of extending FDA approved treatment windows and more importantly their profit margins. Though these trials showed promising rates of reperfusion, the consistently high incidence of intracranial hemorrhage overshadowed the minimal benefits. The MR RESCUE trial, published in NEJM in February 2013 was the first to utilize this technology to identify potential candidates for endovascular therapy (10). Again this trial failed to demonstrate that patients with ischemic penumbrae benefitted from revascularization. However this may have been due more to the trial’s flawed design than the technology’s deficiencies. The authors of MR RESCUE only enrolled patients after initial IV tPA failure. In contrast to these historical failures both the EXTEND-IA and ESCAPE cohorts, unencumbered by fears of disproving tPAs early successes, aggressively pursued reperfusion therapy after salvageable tissue was identified on CT imaging. In doing so, these trials have, for the first time, identified the population that will most likely benefit from reperfusion therapy.

At the risk of sounding optimistic, both EXTEND-IA and ESCAPE are impressively positive trials. Although small and methodologically flawed, with likely exaggerated effect sizes, when viewed in concert with MR CLEAN, these trials present endovascular therapy in a promising light. For some time now legitimate cries for more data regarding tPA’s safety and efficacy in acute ischemic stroke management have been disregarded and marginalized. This almost fanatical acceptance based around the success of the NINDS trial, a single poorly powered study which treated patients with IV tPA within 3-hours of symptoms onset. Despite the many methodogical flaws of NINDS, its results were never duplicated because of the pharmaceutical industry’s fear of losing the tenuous ground they had gained. Although there are significant harms associated with the administration of tPA, the literature has consistently suggested that there is a subset of patients who will benefit from its administration. Rather than working to identify this narrow population, we have witnessed an industry driven effort to expand the indications for reperfusion therapy. EXTEND-IA and ESCAPE have identified potential cohorts of patients who will likely benefit from reperfusion therapy. If these results can be confirmed, no longer will we be forced to use the blunt tool of perceived time from symptom onset to determine which patients are eligible for treatment. These trials should inspire us to not only explore the successful utilization of endovascular therapy, but also reexamine the harmful practice of thrombolytic therapy we currently employ.

Sources Cited:

  1. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:(1)11-20.
  2. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection. N Engl J Med. 2015.
  3. Goyal M, Demchuk AM, Menon BK, et al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. N Engl J Med. 2015.
  4. Campbell BC, Mitchell PJ, Yan B, et al. A multicenter, randomized, controlled study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy (EXTEND-IA). Int J Stroke 2014;9:126-132
  5. Davis SM, Donnan GA, Parsons MW, et al. Effects of alteplase beyond 3 h after stroke in the echoplanar imaging thrombolytic evaluation trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008;7:299–309.
  6. Albers GW, Thijs VN, Wechsler L, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol. 2006;60:508–517
  7. Hacke W, Albers G, Al-Rawi Y, et al. The desmoteplase in acute ischemic stroke trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36:66–73.
  8. Furlan AJ, Eyding D, Albers GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. 2006;37:1227–1231.
  9. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009;8:(2)141-50.
  10. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J 2013;368:(10)914-23.

The Adventure of the Blanched Soldier

fallen-bugler

 

So often in the management of the critically ill we are forced to choose between the lesser of two evils. The transfusion of blood products in the face of hemorrhagic shock is in some ways the best compromise of less than ideal choices. Every drop of resuscitative fluid given that does not mimic the blood a patient has recently lost further dilutes their already diminished coagulative capabilities. And yet an overtly zealous administration of blood products has the potential to cause a multitude of adverse events downstream, further complicating the patient’s potentially arduous recovery. That being said, the endeavor to replenish as close a surrogate to whole blood as logistically possible is an extremely feasible concept to accept as beneficial. Yet despite this strong biological plausibility, the balanced administration of packed red blood cells (PRBCs), plasma and platelets has never been demonstrated to be efficacious beyond this physiologic reasoning. A number of retrospective trials examining this concept have claimed benefit(1,2,3,4), but their results are so confounded by survivor bias, it is difficult to interpret their true meaning (8). Even the PROMMTT trial, the largest trial to examine this question in a prospective fashion, failed to include a prospectively randomized control group and as such, its results were equally limited. With the publication of the PROPPR trial, the first large RCT to evaluate the efficacy of a balanced transfusion strategy, we finally have some strong data to guide us (6). On first glance this well-done RCT seems to have vindicated those in support of the 1:1:1 transfusion strategy, but I fear, in reality it may have left us with more questions than answers.

The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial by Holcomb et al, published in JAMA on February 3, 2015, sought to identify the preferential ratio of plasma, platelets, and blood cells when resuscitating the critically ill trauma patient. The authors randomized 680 patients to either a 1:1:1 or 1:1:2 ratio of plasma, to platelets, to PRBCs. Inclusion criteria included; patients identified as having severe bleeding or being at risk of severe bleeding (defined as having at least 1 U of any blood component transfused prior to hospital arrival or within one hour of admission and prediction by an Assessment of Blood Consumption score of 2 or greater or by physician judgment of the need for a massive transfusion). Although authors specified the order and ratio that blood components should be transfused, the decision to administer products was left to the discretion of the treating physician. Using this pragmatic trial design authors hoped to examine the effects of each transfusion strategy on the primary endpoints, 24-hour and 30-day mortality. Holcomb et al also examined a number of secondary endpoints of importance including, time to hemostasis and the number and type of blood products administered until hemostasis was achieved.

On first glance the difference in transfusion strategies did not seem to make a difference, as the authors failed to find statistical significance in either of their two primary endpoints. A closer look reveals that this was more likely due to the authors overestimation of the true effect size of the 1:1:1 ratio rather than a lack of efficacy for this balanced transfusion strategy. Specifically the 24-hour mortality was 12.7% and 17.0% in the 1:1:1 and 1:1:2 groups respectively. Though not statistically significant this 4.3% absolute difference in favor of the more aggressive transfusion strategy clearly trends towards clinical relevance. Especially given that the rate of death due to exsanguination (9.2% vs 14.6%) and the percentage of patients who achieved hemostasis (86.1% vs 78.1%) were noticeably improved. Likewise though the 30-day mortality failed to reach statistical significance, it did maintain a robust absolute difference of 3.7% in favor of the 1:1:1 group.

As far as the transfusion related adverse events, the 1:1:1 strategy appears to be safe when compared to a less aggressive protocol. None of the 23 adverse events prospectively recorded seemed to occur with a greater regularity in patients randomized to the more aggressive strategy. There was a slight non-significant surge in the rate of systemic inflammatory response syndrome (SIRS) (5.2% absolute increase) in patients randomized to the 1:1:1, but it is hard to make much of this as the rates of both sepsis and acute respiratory distress syndrome seem equivalent.

It is important to note, despite the authors best intentions, this trial did not truly compare 1:1:1 vs 1:1:2 resuscitative strategies. Rather Holcomb et al examined a protocol intending to give 1:1:1 vs 1:1:2.  In reality neither group truly reached their proportional expectations. The 1:1:1 group in actuality was given products closer to a 2:1:2 ratio, while the 1:1:2 group only received products in a 2:1:4 ratio. It is difficult to know how these shortcomings affected outcomes.

By all intents and purposes it seems the rate of adverse reactions was not significantly increased when a more aggressive use of plasma and platelets was administered, though these results may too have been biased by the less than stringent implementation of each groups assigned blood product ratio. Throughout the intervention period the 1:1:1 group received a significantly higher ratio of PRBCs to plasma and PRBCs to platelets than the 1:1:2 group. However this ratio was reversed when the post-intervention period was examined. During the post-intervention period the treating physicians were able to select blood products in any ratio they deemed clinically relevant, and as such they attempted to replenish all the plasma and platelets they were restricted from giving during the intervention period. Though the total quantity was far less than what was given in the intervention period, the PRBCs to plasma to platelets ratio was higher in the 1:1:2 group during the post-intervention period. This in and of itself may have led to an increase in the rates of adverse events observed in the 1:1:2 group without providing the coagulative benefits the early administration of these products provided in the 1:1:1 group.

Despite some minor inconsistencies, the results appear to be a validation of the balanced transfusion strategy. And yet one has to ask, “what did these authors truly demonstrate?” Holcomb et al compared a 1:1:1 strategy to the slightly more conservative 1:1:2 strategy. Ideally the only difference in these two groups should have been that the 1:1:1 group received marginally more platelets and plasma during the initial resuscitation. Are these two transfusion strategies really dissimilar enough to demonstrate a clinically relevant difference? Should they have compared a balanced transfusion strategy to a reaction method where platelets and plasma are only administered when patients develop a coagulopathy? More importantly is any empirically chosen ratio the ideal strategy in today’s age of point of care testing? In 2013 CMAJ published a trial by Bartolomeu et al that compared a fixed ratio similar to that used by Holcomb et al (1:1:1) to a laboratory-guided transfusion strategy (7). In this laboratory-guided strategy, blood product administration was guided by INR, PTT, Hb and platelet values. Although the trial was far too small to be definitive (n=67), the results were interesting nonetheless.  The mortality in the laboratory-guided group was far less at 14.3% when compared to the 32.5% observed in the 1:1:1 strategy. Although a lab value guided resuscitation strategy is clearly impractical in the acute resuscitation period, a point-of-care based system like TEG may provide us with the instantaneous feedback we require to tailor our resuscitation strategies to the specific needs of the patient rather than the empiric strategy currently advised.

I doubt these results will lead to a significant change in practice. It seems the 1:1:1 massive transfusion strategy has become firmly entrenched in trauma resuscitation dogma. At least the PROPPR trial offers support to the notion that if one is going to use an empirically based transfusion strategy, striving for a equal ratio of cells, plasma and platelets appears to be of some benefit.

Sources Cited:

1. Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008; 248: 447–458.

2. Borgman, M.A., Spinella, P.C., Perkins, J.G. et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007; 63: 805–813.

3. Holcomb, J.B., Wade, C.E., Michalek, J.E. et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008; 248: 447–458.

4. Maegele, M., Lefering, R., Paffrath, T. et al. Red-blood-cell to plasma ratios transfused during massive transfusion are associated with mortality in severe multiple injury: a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie. Vox San. 2008; 95: 112–119.

5. Holcomb, J.B., del Junco, D.J., Fox, E.E. et al. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study. JAMA Surg 2013; 148: 127–136.

6. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 2015;313:(5)471-82.

7. Bartolomeu et al. “Effect of a Fixed-Ratio (1:1:1) Transfusion Protocol Versus Laboratory-Results–guided Transfusion in Patients with Severe Trauma: a Randomized Feasibility Trial.” CMAJ : Canadian Medical Association Journal 185.12 (2013): E583–E589. PMC. Web. 6 Feb. 2015.

8. Ho AM, Zamora JE, Holcomb JB, Ng CS, Karmakar MK, Dion PW. The Many Faces of Survivor Bias in Observational Studies on Trauma Resuscitation Requiring Massive Transfusion. Ann Emerg Med 2015.

The Case of the Balanced Solution

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Saline-based resuscitation strategies were first proposed as far back as 1831 during the Cholera Epidemic. In an article published in the Lancet in 1831, Dr. O’Shaughnessy suggests the use of injected salts into the venous system as a means of combating the dramatic dehydration seen in patients afflicted with this bacterial infection(1). Saline’s potential harms were first observed in post-surgical patients who after receiving large volumes of saline based resuscitation fluids during surgery were found to have a hyperchloremic acidosis (2). Though these changes appear transient and clinically trivial, it is theorized that when applied to the critically ill, the deleterious effects on renal blood flow may increase the rate of permanent renal impairment and even death. Unfortunately, no large prospective trials have demonstrated this hypothesis to be anything more than physiological reasoning. Small prospective trials have exhibited trivial trends in decreased renal blood flow, kidney function, and increased acidosis, though these perturbations were fleeting and of questionable clinical relevance (3, 4, 5, 6, 7). A larger retrospective study, bringing all the biases such trials are known to carry, demonstrated small improvements in mortality of ICU patients treated with a balanced fluid strategy, though it failed to demonstrate improvements in renal function (the theoretical model used to support balanced fluid administration) (8). In 2012 Yonus et al were the first to attempt to prospectively answer this question in an ICU population. Published in JAMA, on first glance the results seemed to vindicate those in support of the use of balanced fluids (9). Yet despite its superficial success, a closer look reveals this trial does little to demonstrate the deleterious effects of chloride-rich resuscitative strategies. In a recent publication in Intensive Care Medicine, Yonus et al re-examine this question in the hopes of once again demonstrating the benefits of balanced fluid strategies for the resuscitation of the critically ill (10).

In the original publication Yonus et al, using a prospective open-label before and after cohort design, hoped to demonstrate that use of balanced fluids in ICU patients would lead to improved renal function and decreased administration of renal replacement therapy (RRT). For the initial 6-month period fluid administration was left entirely to the whims of the treating intensivist. This was followed by a 6-month span during which ICU staff were trained and educated on the evils of chloride-rich solutions and the benefits of a more balanced approach to fluid selection. Following this smear campaign on normal saline and its high-chloride co-conspirators, authors spent the next 6-months recording fluid administration and subsequent patient outcomes. The authors’ co-primary outcomes were the increase in creatinine levels above baseline during ICU stay and the incidence of acute kidney injury (AKI) as defined by the RIFLE(Risk, Injury, Failure, Loss, End-stage) criteria. Secondary outcomes listed by the authors included the need for RRT, ICU length of stay, and mortality (9).

As far as convincing ICU staff that balanced solutions were beneficial, the authors’ experiment was an overwhelming success. 1,533 patients were examined, 760 patients during the 6-month control period and 773 patients during the subsequent 6-month intervention period. The total amount of normal saline used over the two periods was 2,411L and 52L respectively. Likewise the total chloride administration decreased by a total of 144,504 mmol, or by 198 mmol/patient (9).

On face value the study appears to have been a success, demonstrating statistically significant benefits for both primary outcomes. During the intervention period patients experienced a statistically lower rise in creatinine levels, 14.8 μmol/L (95% CI, 9.8-19.9 μmol/L) than during the control period 22.6 μmol/L (95% CI, 17.5-27.7 μmol/L). Authors also found a 5.6% absolute decrease in the rate of RIFLE defined kidney injury and kidney failure in patients during the intervention period when compared to those in the control period (9).

These seemingly positive results should be tempered by the fact that while statistically significant, the differences are, for the most part, clinically irrelevant. A 7.8 μmol/L increase in creatinine translates to an approximately 0.09 mg/dl difference between the control and intervention periods, which is hardly clinically pertinent. The 5.6% difference in rate of AKI was primarily powered by the 3.3% difference in rate of the less severe RIFLE class, kidney injury. When kidney failure was examined alone, unaccompanied by this statistical augmentation, the difference was found to be statistically insignificant (9).

Even the 3.7% absolute decrease in RRT in the intervention period (10.0% vs 6.3%) is hard to conclusively attribute to the balanced fluid strategy, given the open nature of the trial design and the fact that these benefits did not translate into either a decrease in the rate of long term dialysis requirements or mortality. Furthermore the annual rates of RRT during the control and intervention periods are almost identical (7.4% vs 7.9%). In fact, the rates of RRT in the years bookmarking this study are highly variable, which speaks to the potential for unmeasured bias and the cyclic nature of random chance causing the observed differences in these groups, rather than the intervention in question. It is important to remember that though RRT appears to be a finite objective endpoint, it is largely dependent on the treating physician’s subjective judgement. In an open label design such as this, in which the authors are clearly in favor of one intervention over another, the potential for bias affecting this outcome is evident (9).

In a secondary analysis of their data set, Yunos et al hoped to address some of these uncertainties. In this manuscript, published in Intensive Care Medicine in 2014, the authors added an additional 6 months of patient data to both the control and intervention periods, with the intention to demonstrate that the positive findings of their initial publication were due to the favorable influences of balanced fluids. The control period was expanded to include patient data (n=716) from the 6-month period prior to the study’s original start date. The authors then incorporated an additional 6 months of data to the intervention group (n=745) after its original stop date. Overall the two augmented periods ran from February 2007 to February 2008 and August 2008 to August 2009. The authors again found success. And though their primary endpoints remained of questionable clinical significance, the magnitude of their triumph was certainly more impressive (10).

With the addition of this 12-month period of data, the authors boast a 4.8% absolute decrease in the rate of moderate or severe kidney injury as compared to the control. Though the absolute difference in the rate of RRT decreased from 3.6% to 3.0%, when the additional patients were added to the analysis, the difference still remained statistically significant (10). Interestingly, despite both the added control and intervention groups regressing to the mean, the overall magnitude of benefit reported by the authors seemed to increase. This slight of hand was achieved not by some complex form of statistical wizardry, but rather simply lowering the bar for what the authors defined as success.

In their original manuscript, Yunos et al used the RIFLE criteria to define the varying degrees of AKI. Conversely in the more recent publication, AKI was evaluated using the Kidney Disease: Improving Global Outcomes (KDIGO) scale. Despite its grandiose title, in reality this scale is essentially the amalgamation of the previous two scales traditionally used to define AKI (the RIFLE and AKIN criteria). Creators of the KDIGO criteria hoped to identify a greater proportion of patients who would benefit from RRT, and thus created a novel tool by incorporating both definitions of AKI (11). Of course, as is typical with any diagnostic tool, augmenting its sensitivity is achieved by sacrificing its specificity.

Such is the case for the KDIGO score. Not surprisingly, when examined, the KDIGO score identified significantly more patients in renal failure than either the RIFLE or AKIN criteria. In a trial published by Critical Care in 2014, Luo et al compared RIFLE, AKIN and KDIGO’s abilities to identify clinically important AKI (12). They found that the use of the KDIGO criteria identified more overall patients as having AKI (51% compared to 46.9% and 38.4% respectively) as well as classified an larger subset of patients as being in failure (16% compared to 13.8% and 12.8% respectively). Despite the increased yield, no difference was seen in each respective criterion’s abilities to predict death (AOC were 0.738, 0.746, 0.757 respectively). It is still unclear whether the additional patients identified using the KDIGO criteria benefit from early aggressive management of their subtle renal impairment or are harmed from the invasive interventions performed in hopes of treating pathology that would likely resolve without interference. What is clear is that changing from the more conservative RIFLE criteria to the more liberal KDIGO, makes interpreting the clinical relevance of Yunos et al’s results difficult.

In the 2014 publication by Yunos et al, the absolute difference in AKI is similar to that described in the 2012 publication (4.8% vs 5.6%), but unlike their original population there is a shift to a more severe spectrum of renal impairment. Using the KDIGO criteria authors found significantly more stage 3 AKI than in their original publication. In the original manuscript the difference in RIFLE failure (class 3) AKI failed to reach clinical significance. In their updated cohort the authors now cite a statistically significant decrease in the rate of KDIGO class 3 AKI (the equivalent of RIFLE failure). The original trial states an absolute difference in the rate of RIFLE class 3 AKI of 2.1%. In their more recent document Yunos et al now cite a 4% (14% vs 10%) absolute decrease in KDIGO stage 3 AKI. Likewise the original manuscript states an absolute difference of 3.3% in the rate of RIFLE class 2 AKI. In the more recent document this same difference is now stated to be only 2%. Clearly the use of the KDIGO criteria has shifted the severity of the cohort in an alarming fashion. This increase in class 3 AKI may be a more accurate interpretation of reality, but given that these differences did not translate into a decrease in either long-term dialysis or mortality, its clinical relevance is unlikely.

Even these clinically questionable differences cannot be directly attributed to the more balanced fluid strategy utilized during the intervention period. It is equally likely the multiple biases introduced by a before and after study design were responsible. Using a multivariant regression model, Yunos et al hoped to account for many of these biases. On initial presentation authors seem to be vindicated in their assertions that these differences in renal function were due to the change in fluid administration. When the addition of the extended control and intervention periods were included in the multivariable analysis, the rate of KDIGO stage 2 and 3 AKI and RRT remained statistically significant. This benefit was powered completely by the initial cohort, the addition of the extended cohorts served only to regress these benefits towards the mean. The odds ratio in the original cohort for preventing AKI was 1.68 (1.28-2.21). When the extended groups were incorporated the odds ratio falls to 1.32 (1.11-1.58).  In fact a thorough examination comparing the four time periods uncovers the initial results are hardly as robust as they originally appear.  When the extended time period is examined alone (control vs intervention), there was no difference between in the incidence of AKI or RRT. Additionally when the extended control is compared to the original intervention period, the decrease in difference in AKI remains significant but the rate of RRT is no longer statistically significant. There is even a statistically significant increase in the rate of AKI when the original intervention period is compared to the extended intervention period. In fact this is the very same difference in both AKI and RRT that is observed when comparing the original control group to the extended intervention group (10) . Essentially, though it was the authors intent to validate the findings of their initial study, the inconsistent benefits demonstrated in the extended cohort do just the opposite.  These differences seem to be due more to random chance than any beneficial effects of a balanced fluid strategy.

The interpretation of medical literature very rarely is as straightforward as we would like to imagine. Much like searching for truth in a magic mirror, so often it serves only to confirm our own beliefs and supports our incredulities. And yet if we are to claim to be authentic curators of truth in medicine, it is important we apply just as much academic rigor when examining topics which we support as we do with those we distrust. A balanced approach to fluid administration has a strong physiological base to support its use. But physiologic reasoning has led us down many blind paths and dark alleys. It is only when we shine the light of critical research we reveal which are dead ends and which lead us and our patients to a better place. Currently we are uncertain as to whether the success of a balanced fluid strategy is due to its chloride-sparring effects or due to the uncontrollable bias introduced by a non-randomized, unblinded trial design, with serious potential for the Hawthorne effect. It may very well be that any fluid in excess is harmfull and “balanced” fluids high in acetate and lactate have their very own unintended consequences when administered in high volumes. The SPLIT trial (scheduled to be published in 2015) may validate our beliefs in the superiority of a balanced fluid strategy, but until then it is important we resist the urge to become quite so dogmatic with our cries of indignation towards chloride-rich solutions.

 A brief disclosure: I am, in fact, overwhelmingly and irredeemably in favor of the Stewart approach to acid-base disorders. although there is no convincing evidence directly demonstrating its superiority over the more traditional Henderson-Hasselbalch model, its elegance and intuitive nature make it perfect for the swirling chaos and uncertainty of the Emergency Department. As such it is not hard to imagine that the more judicious administration of fluid, specifically those high in chloride content, would benefit our patients by reducing hyperchloremic acidosis and the concomitant renal failure. I am however, less enthused by the evidence supporting this premise.

-A special thanks to Anand Swaminathan (@EMSwami) for his thoughts and guidance during the writing of this post.

-As always a special thanks to my ever patient wife, Rebecca Talmud(@DinosaurPT), for her editorial wizardry without which this blog would be the unstructured ramblings of a madman.

Sources Cited:

  1. O’Shaugnessy, WB (1831). “Proposal for a new method of treating the blue epidemic cholera by the injection of highly-oxygenated salts into the venous system”. Lancet 17 (432): 366–71
  2. Scheingraber S, Rehm M, Sehmisch C, Finsterer U. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynaecologic surgery. Anesthesiology. 1999;90:1265–1270
  3. Quilley CP, Lin Y-S, McGiff JC. Chloride anion concentration as a determinant of renal vascular responsiveness to vasoconstrictor agents. Br J Pharmacol. 1993;108:106–110
  4. Hansen PB, Jensen BL, Skott O. Chloride regulates afferent arteriolar contraction in response to depolarization. Hypertension. 1998;32:1066–1070.
  5. O’Malley CM, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, Bennett-Guerrero E. A randomized, double-blind comparison of lactated Ringer’s solution and 0.9% NaCl during renal transplantation. Anesth Analg. 2005;100:1518–1524
  6. Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer’s solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 2001;93:817–822.
  7. Hatherill M, Salie S, Waggie Z, Lawrenson J, Hewitson J, Reynolds L, Argent A. Hyperchloraemic metabolic acidosis following open cardiac surgery. Arch Dis Child. 2005;90:1288–1292
  8. Raghunathan K, Shaw A, Nathanson B, Stu ̈ rmer T, Brookhart A, Stefan MS, Setoguchi S, Beadles C, Lindenauer PK (2014) Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Crit Care Med 42:1585–1591
  9. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M (2012) Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 308:1566–1572
  10. Yunos NM, Bellomo R, Glassford N, Sutcliffe H, Lam Q, Bailey M. Chloride-liberal vs. chloride-restrictive intravenous fluid administration and acute kidney injury: an extended analysis. Intensive Care Med. 2014.
  11. http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf
  12. Luo X, Jiang L, Du B, et al. A comparison of different diagnostic criteria of acute kidney injury in critically ill patients. Crit Care. 2014;18:(4)R144.

 

 

A Secondary Examination of The Adventure of the Cardboard Box-Addendum

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Published in the NEJM on December 17th 2014, ushered in with the inflated fanfare only the medical industry capable of, MR CLEAN marks the first successful trial of interventional therapy for acute ischemic stroke. In direct contrast to IMS-3, SYNTHESIS and MR RESCUE, MR CLEAN is a significantly positive trial.  The authors demonstrated success in their primary outcome, “improved neurological outcomes at 90 days” with an adjusted odds ratio of 1.67  (95% confidence interval [CI], 1.21 – 2.30). (1). Why MR CLEAN was positive when the three trials that came before were negative is still unclear. As discussed in my previous post (as well as far more elegant posts on emlitofnote.com and stemlynsblog.org) it may be due to better equipment, faster symptom onset to recanulization times, and the incorporation of CT angiography to identify a cohort of patients who would truly benefit from these invasive interventional strategies. Conversely it may simply be due to the traditional therapy group performing so poorly.

A closer look at the results from MR CLEAN reveal that though the interventional group outperformed the placebo group by a significant amount (an absolute increase of the number of patients alive and independent by 13.5%) compared to its peers, its performance was far from exceptional. In the IMS-3 trial, 40.2% patients in the control arm (tPA alone) were alive and independent at 90 days compared to only 32.6% of the patients in the intervention arm of the MR CLEAN trial (1,2). Even the placebo groups in NINDS and ECASS-3 who received no reperfusion therapies had better outcomes than the patients receiving interventional therapies in the MR CLEAN trial. 26% and 45.5% of the control patients in the NINDS and ECASS-3 trials respectively had a mRS of 0 or 1 at 90 days (3,4). Compared to only 11.6% of the patients in the interventional arm of MR CLEAN.

Though it is difficult and not completely appropriate to compare groups from different trials, it does call into question the reasons for MR CLEAN’s staggering success. It may very well have been the patients in the MR CLEAN cohort were far sicker than the earlier stroke trials, (though both their presenting NIHSS and 90 day mortality rates seem quite similar). It may be that the utilization of CT angiography to select patients for recruitment excluded the majority of the stroke mimics who were included in these earlier trials, and will universally have good outcomes (this seems to be the answer given by the authors when queried by Dr. Ryan Radecki). The subgroup analysis, which indicated only the patients with a NIHSS of greater than 20 demonstrated a statistically significant benefit from endovascular therapy, seems to support this supposition (1). The authors point to a meta-analysis of the six trials examining endovascular therapy for acute ischemic stroke as additional proof (5). In this analysis by Fargen et al, published in the J NeuroIntervent Surg, the authors examine the subgroup of patients with radiographically confirmed large vessel occlusion (LVO). Similar to MR CLEAN, patients receiving endovascular therapy had better outcomes at 90 days (a mRS of 0-2 38.3% vs 25.8% respectively ). Even in this combined cohort with radiographically confirmed LVO, outcomes were not as dire as those observed in the MR CLEAN trial.

MR CLEAN’s success may be attributed to the advancements in both procedural proficiency and technological prowess. But it is equally likely that the whimsy of random chance was responsible for these impressive results. On a final note it is important to remember that all of the trials examining endovascular therapy in acute ischemic stroke were compared to a control group that included the administration of IV tPA, an intervention whose own efficacy is very much in doubt. Although the rate of adverse events in the intervention arm of MR CLEAN did not differ significantly from those given IV tPA, this is only because alteplase comes with its own terrifying set of unpleasantries. When compared to a true placebo group, I am certain the rate of symptomatic intracranial hemorrhage and new ischemic stroke (7.7% and 5.6% respectively) would appear far more concerning.

Given the universal failure of the previous three trials examining the very same question, surely more confirmatory evidence is required before investing the unimaginable resources required to support the vast infrastructure needed to make interventional therapy a reality. Since MR CLEAN’s success was announced at the 9th annual World Stroke Conference in Istanbul held in October 2014, two trials examining endovascular therapy in acute ischemic stroke, ESCAPE and EXTEND IA, have halted enrollment early for benefit. It will be interesting to see if these premature stoppages were because of preplanned interim analyses or if MR CLEAN’s success influenced their early termination. I hope we invest the time and resources required to answer these questions with the methodological rigor they deserve. It would be frustratingly tragic to once again be forced to practice with continual doubt because we halted all further investigations out of the fear of discovering that reality is not as promising as the false-truth gained from interpreting only the data that pleases us.

Sources Cited:

  1. The MR CLEAN Investigators. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. N Engl J Med, December 17, 2014.
  2. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893-903.
  3. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581-7.
  4. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-29.
  5. Fargen KM,
Neal D, Fiorella DJ, et al. J NeuroIntervent Surg Published Online First: [please include Day Month Year] doi:10.1136/ neurintsurg-2014-011543.

A Case of Identity Part Two

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Our standards for acceptable benefit of antiplatelet agents in the management of ACS have become deplorably low. When ISIS-2 was first published we defined success only by aspirin’s ability to affect mortality. The number commonly cited, 2.4%, only describes aspirin’s absolute benefit to decrease death (1). In the one trial that examined its properties to prevent further infarction, published in the NEJM in 1988, aspirin demonstrated additional capabilities to decrease myocardial infarction as well as save lives (2). If in ISIS-2, aspirin had performed as poorly as clopidogrel did in its efficacy defining study, the CURE trial, it may have never gained the stature it currently holds in the management of ACS (3). To date aspirin has been the only antiplatelet agent that has demonstrated a consistent and clinically relevant mortality benefit. Despite the obvious benefits, it was not long before we turned towards other agents in an attempt to supplement aspirin’s antiplatelet properties. The concept of dual antiplatelet therapy so appealing, its theoretical basis so believable, it soon became a perfunctory part of our management strategy for patients presenting to the Emergency Department with ACS.

Our current concept of dual antiplatelet therapy was first defined in 1996 with the publication of the CAPRIE trial. Published in The Lancet in November of 1996, this trial was the first of many to indicate clopidogrel’s efficacy in finding clinically irrelevant reductions of methodologically deceitful composite endpoints (4). So began the era of dual antiplatelet therapy in which, based off weak endpoints and statistical chicanery, clopidogrel and its post-patent clones have bullied and fibbed their way to success.

Throughout the literature examining clopidogrel in a multitude of ACS cohorts of varying degrees of severity, its vaulted dual anti-platelet capabilities have never demonstrated a clinically relevant mortality benefit. Its success has been powered by the reduction of non-fatal MIs, the majority of which are peri-procedural troponin leaks of questionable clinical significance. The only clinically relevant endpoint clopidogrel has consistently demonstrated is a 1% absolute increase in serious bleeding. Despite these mediocre capabilities, Bristol-Meyer, through sheer force of will and marketing prowess, catapulted their drug to the forefront of pharmaceutical sales for over a decade. The true level of clopidogrel’s mundanity has been discussed in a previous post. The more important question for Emergency Physicians is, does the upstream administration of P2Y12 inhibitors provide added benefit over only administering these medications after confirming appropriate coronary anatomy during catherization?

Upstream use of P2Y12 inhibitors in ACS is commonly believed to be beneficial as it deters thrombus formation through additional inhibition of platelet adherence vs the singular capabilities of aspirin alone. Despite a dearth of evidence validating this claim and reasonable data stating otherwise, this practice has been routinely implemented since the publication of the CURE trial over a decade ago.

So is there a role for dual antiplatelet therapy in today’s Emergency Department?

Two recent publications sought to address this very question. The more methodologically ambitious of these trials was a systematic review and meta-analysis published in the BMJ in October of 2014 in which Bellemain-Appaix et al attempted to examine all the literature addressing the potential benefit of upstream use of P2Y12 inhibitors in NSTEMI patients undergoing PCI (5). Much to the chagrin of the authors, only one trial included (the recently published ACCOAST trial) specifically examines this specific inquiry. The authors, not to be dissuaded, attempted a piecemeal collection of various subgroups from a number of trials that seemed to meet their entry criteria. This resulted in a statistically and clinically heterogeneous cohort whose subsequent data should probably not have been combined into a single analysis. Nevertheless the authors plunged ahead examining the NSTEMI patients in both the CREDO and CURE trials, as well as the subset of patients in the ACUITY trial who were pre-treated with clopidogrel. Also including the entire cohort from the ACCOAST trial, the only trial included examining prasugrel. Combining these trials with the data from three observational cohorts, the authors collected information on 32,838 patients.

Contrary to most trials attempting to examine potential benefit in the use of P2Y12 inhibitors, these authors set aside the traditional composite endpoint (stroke, MI, or cardiovascular death) and looked exclusively at mortality and major bleeding. The authors found no mortality benefit in either the entire cohort, the subgroup of patients from the RCTs, or in the group that underwent PCI. Conversely, an increased risk of bleeding was observed in patients treated with upstream P2Y12 inhibitors. No difference was seen in the rate of stroke, myocardial infarction or urgent revascularization. However when a composite outcome the authors termed “adverse cardiac outcomes” was measured, they found a small reduction in risk (odds ratio 0.84, CI 0.72-098). As with all individual trials examined, this composite benefit is powered by a small increase in myocardial infarctions, that when examined alone did not reach statistical significance (odds ratio of 0.81, CI 0.64- 1.03). When the subgroup of patients who underwent PCI was isolated this decrease in “adverse cardiac events” was no longer significant (odds ratio 0.83, CI 0.99-0.1.03). This speaks more to the drastic decrease in sample size (32,383 to 17,545), decreasing the statistical power to detect clinically irrelevant differences, than a meaningful difference between those who undergo PCI compared to those who do not (5).

Unfortunately the clinical heterogeneity between the trials included in this meta-analysis is quite high. The trials included span different eras and different strategies in the overall management of patients experiencing NSTEMIs. It is questionable whether they should have been included in a formal analysis at all. Fortunately one does not require the above stated statistical manipulations to reach the same conclusions garnered by the authors. Each trial that examined the efficacy of upstream use of P2Y12 inhibitors failed to identify any clinically meaningful benefit.

The CURE trial was the earliest trial included in this analysis. This trial paved the way for clopidogrel’s use in the Emergency Department simply by utilizing composite endpoints of questionable clinical significance and a sample size large enough to bully even the smallest deviation from placebo towards statistical relevance. Published in NEJM in 2001, the authors claimed a statistically significant 2.1% absolute decrease in cardiovascular death and myocardial infarction (MI). This difference was completely powered by the 1.5% absolute difference in MIs, the majority of which were type IV MIs (peri-procedural). This small reduction is of questionable clinical consequence as the mortality rate between groups was identical at 30 days (1.0% vs 1.1%) as well as at the end of follow up (2.3% vs 2.4%)(mean of 8 months)(3).

The CREDO trial sought to answer the question of whether treatment with clopidogrel prior to angiography was beneficial, examined patients scheduled for urgent cardiac cathertization. Patients were randomized to upstream administration of clopidogrel or placebo 3-24 hours prior to cath. All patients received daily clopidogrel following PCI. Like CURE before it, the CREDO authors found no clinically important benefit to the upstream use of clopidogrel. No statistical difference was recorded in the rates of death, stroke or MI at 28 days between the placebo and upstream clopidogrel groups. The authors claim success in the statistical significance of a secondary endpoint, the per-protocol analysis of the 1-year outcomes, noting a 2% absolute reduction in the rate of death, MI, and stroke. Similar to CURE, this difference was powered by the 1.9% reduction of MIs. Interestingly, statistical significance is lost upon examining any of the three endpoints individually, or when the same composite endpoint is analyzed using the authors’ primary outcome and more statistically appropriate methodology, the intention-to-treat analysis. As is typical with all P2Y12 inhibitor trials there was a 1% increase in major bleeding events in both the CURE and CREDO trials, the vast majority of which were related to subsequent CABG procedures after coronary anatomy revealed less than ideal conditions for stent placement (6).

Neither of these trials are methodologically ideal to address the question, in the modern Emergency Department does the upstream use of P2Y12 inhibitors result in improved patient oriented benefits? In the CURE trial less than half the patients (43.8%) underwent coronary angiography and only 21.2% received PCI. In the CREDO trial only 67% of the patients were actually having an enzyme defined NSTEMI (3,6)

The final RCT included in the Bellemain-Appaix et al meta-analysis, the ACCOAST trial, is far more relevant. Using modern PCI techniques and standards, Montalescot et al specifically examined whether upstream administration of prasugrel was beneficial when compared to its administration in the cath lab after visualizing the coronary anatomy. The recent marketing disaster that was the publication of the TRILOGY trial, a completely negative study comparing prasugrel to clopidogrel in patients with ACS, was the first obstacle in prasugrel’s race to fill the post-patent void at the top of the antiplatelet hierarchy. ACCOAST was an attempt to regain the momentum lost with TRILOGY’s failure. Authors randomized 4,033 patients with NSTEMI in the Emergency Department to either 30 mg of prasugrel 2-48 hours prior to PCI or placebo. Following visualization of the anatomy during angiography and stent placement when appropriate, the prasugrel group received the remaining 30 mg of the 60 mg loading dose that is recommended by Eli Lilly. The placebo group received the full 60 mg dose of prasugrel at the time of PCI if stent placement was thought to be beneficial. The authors failed to demonstrate a benefit in upstream administration of prasugrel when compared to its administration in the cath lab, with no difference in cardiovascular death, myocardial infarct, stroke, urgent revascularization or glycoprotein IIb/IIIa bailout (10.8% vs 10.8%). As is consistent with the rest of the literature examining the use of P2Y12 inhibitors, the pretreatment group was found to have approximately 1% increase in major bleeding. Most due to an increase in bleeding during CABG (20.7% vs 13.7%)(7).

Finally, what about the added benefit of dual antiplatelet therapy in the hyperacute patient? What is the benefit of P2Y12 inhibitors in patients with a time dependent lesion? In an article published in September 2014 in the NEJM, Montalescot et al examined this very question. The authors of the “Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery (ATLANTIC)” trial randomized patients to a 180 mg loading dose of ticagrelor in either the ambulance on the way to the hospital or in the cath lab prior to angiography. The authors and their benefactors, AstraZeneca, hoped to demonstrate that upstream use of ticagrelor was an important addition to the management of these hyperacute patients. Though they included patients with ST-elevation MIs up to 6 hours after symptom onset, the majority of patients were identified within 70 minutes of symptom onset (well within the time dependent portion of STEMI pathology)(8).

A total of 1,862 patients were randomized to either pre-hospital or in-hospital treatment. The authors selected the unfortunate clinically irrelevant measures of the proportion of patients who did not have 70% or greater resolution of ST-segment elevation before PCI, and the proportion of patients who did not meet the criteria for TIMI flow grade 3 in the infarct-related artery at angiography before PCI as their co-primary endpoints. Thankfully we were saved the discussion of why neither of these metrics translated into patient oriented outcomes as the authors failed to find a difference between the pre-hospital and in-hospital groups. Nor was there a difference in the more traditional composite endpoint (rate of cardiovascular deaths, MIs, strokes, urgent revascularizations, or definitive stent thrombosis) so commonly used in P2Y12 inhibitor trials (4.5% vs 4.4%). In an altogether unsurprising twist, the authors claim this trial a success after dredging up a single secondary endpoint from the many measured that achieved a p-value of significance. Patients who received pre-hospital administration of ticagrelor experienced a smaller rate of definitive stent thrombosis when compared to patients receiving the drug in the cath lab (0.2% vs 1.2%). This difference seemed to have no clinical relevance as there was no difference in the rate of myocardial infarction or death at 30 days between the groups. In fact the mortality rate in the pre-hospital group was alarmingly higher, though the 1.3% absolute difference (3.3% vs 2.0%) in 30-mortality failed to reach statistical significance(8).

As is the case with any in depth examination of the literature supporting the use of P2Y12 inhibitors we are left entirely underwhelmed. From as far back as the CURE trial the theoretical benefits of dual antiplatelet therapy have consistently lacked evidentiary support of clinically relevant patient oriented outcomes. Even the small industry manipulated advantages seemingly evaporate when drugs are compared to their own administration downstream in the cath lab once suitable anatomy has been defined. Recently published trials examining long-term use of P2Y12 inhibitors after stent placement have been far from stellar (9,10). Both a meta-analysis and large RCT demonstrated that even in cases of anatomically confirmed disease with stent placement, these medications offer very limited benefits over aspirin therapy alone and in some cases even demonstrate a small increase in mortality (0.5% increase in all-cause mortality). This is not a case where more evidence is required. It is time we reexamine the utility of dual anti-platelet therapy in the Emergency Department. Clearly we now have convincing data that upstream use of P2Y12 inhibitors whether administered pre-hospital or in the Emergency Department do not provide any patient oriented benefits and can only lead to harm. In fact the only benefit that can be gained by maintaining this dual anti-platelet delusion is to ensure the well being of the pharmaceutical companies whose lies and manipulation have led us down this fool’s path in the first place.

Sources Cited:

  1. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988;2(8607):349-60.Heparin, Aspirin or Both NEJM
  2. Théroux P, Ouimet H, Mccans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319(17):1105-11.
  3. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
  4. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-39.
  5. Bellemain-Appaix Anne, Kerneis Mathieu, O’Connor Stephen A, Silvain Johanne, Cucherat Michel, Beygui Farzin et al. Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis BMJ 2014; 349:g6269
  6. Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-20.
  7. Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369(11):999-1010.
  8. Montalescot G, Hof AW, Lapostolle F, et al. Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction. N Engl J Med. 2014
  9. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents. N Engl J Med. 2014
  10. Sammy Elmariah MD,Laura Mauri MD,Gheorghe Doros PhD,Benjamin Z Galper MD,Kelly E O’Neill BS,Prof Philippe Gabriel Steg MD,Prof Dean J Kereiakes MD,Dr Robert W Yeh MD. Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. The Lancet – 16 November 2014

A Secondary Examination of The Adventure of the Cardboard Box

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In November of 1995 stroke care as we know it drastically and permanently changed. With the publication of NINDS-2 the NEJM ushered in the interventional era of acute ischemic stroke (1). No longer were we powerless in our management of these patients. Finally we could offer them more than an aspirin to chew on, a corner to sit in, and an appointment with a neurologist in the morning.  And yet NINDS-2 was not the first trial examining thrombolytic therapy for acute ischemic stroke. In fact three trials were published prior to NINDS-2 all of which were negative (NINDS-1, MAST-I, ECASS-1) with two finding an increase in mortality in patients given thromblytics (1,2,3). With the publication of NINDS-2 all this was forgotten. NINDS-2 was impressively positive, demonstrating a 13% absolute increase in patients who were given tPA that were alive and independent (mRS of 0 or 1) at 90 days (1). Supporters justified the 6% absolute increase in symptomatic intracranial hemorrhage by arguing that it did not increase 90-day mortality (21% vs 17%). Despite these impressive results there were still three negative trials to account for. What made NINDS-2 different than all the trials that came before it? Was it the agent? Supporters claim that tPA was the superior thrombolytic and we should ignore all trials studying other agents. Was it time? NINDS examined patients who received tPA within 180 minutes of symptom onset (half in under 90 minutes); two of the earlier trials examined patients who received thrombolytc therapy over a much broader treatment window. Was it the patient population? The authors of NINDS used very strict selection criteria to determine which patients were acceptable candidates. There was of course a fourth reason proposed by a less enthusiastic contingent, that being random chance. This more skeptical party posited that an intervention that possesses little or no efficacy, if studied enough times would eventually demonstrate positive results simply by chance alone. They reminded the more eager supporters of tPA therapy that though the findings of NINDS-2 may be true, taking these results at face value without further validation was not only bad science, but even worse medicine. Despite these warnings the FDA fast tracked the approval of tPA for acute ischemic stroke in under 3-hours and all other trials attempting to validate this benefit were abandoned. As Elliot Grosbard, Genentech scientist, said in internal communications in regards to further trials comparing streptokinase to tPA for acute coronary syndrome;

 We do not know how another trial would turn out, and if we don’t come out ahead we would have a terribly self inflicted wound… (another study) may be a good thing for America, but it wouldn’t be a good thing for us.

Four consecutive trials were published following NINDS (all examining time windows greater than 3 hours) all six were negative and four demonstrating harm (4,5,6,7,8.9). It wasn’t until the 2008 publication of ECASS-3 that another trial examining thrombolytics for ischemic stroke demonstrated benefit (10). These benefits though not as impressive as NINDS-2 were convincing enough to make us forget the seven other negative trials examining similar time windows. Unlike NINDS-2 we were unable to claim ECASS-3 was different than these other negative trials examining similar patients during similar time windows. So instead, we just ignored them. Like our nostalgia for our endless childhood summers we have chosen to selectively interpret the literature that confirms our biases. Remembering only the fireworks, campfire tales, and days spent in the crashing waves of the Atlantic Ocean, we conveniently forget the sun burnt shoulders, poison ivy scorched legs and the tattered knees so commonly acquired during childhood adventures. This tunnel-vision has (mis)guided stroke care for the last two decades. Investigators continue to role the dice, ignoring all numbers that do not suit their purposes.

19 years after the publication of NINDS changed stroke management, the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (given the unfortunate acronym MR CLEAN) once again threatens to overthrow the infrastructure of stroke care (11). The results of this multi-center trial comparing endovascular therapy to standard care were presented at the 9th annual World Stroke Conference in Istanbul held in October 2014. Though these results were not published, with the fanfare NINDS-2 experienced after its initial announcement, it difficult not to see the similarities between these two trials. Like NINDS-2, this is the first trial to show benefit of a novel therapy in acute ischemic stroke. Like NINDS, these results are in direct contrast to the 3 trials published to date examining endovascular interventions for acute ischemic stroke.

On February 7th 2013, NEJM published 3 articles all examining the efficacy of endovascular treatment for acute ischemic stroke. All 3 trials were universally negative each one failing to demonstrate benefit in their own unique manner (12,13,14). These trials were instantly discredited by endovascular apologists stating a number of reasons why they should be ignored. For one they enrolled the wrong patients. These trials primarily used only a non-contrast CT to select patients appropriate for endovascular therapies. Most experts argue this is not the optimal imaging technique for selecting patients for endovascular interventions and all patients should have undergone CT-angiography before enrollment. These trials examined endovascular therapy during the wrong time period. Proponents of these interventions argued that time-to-clot retrieval was far longer than their current standards and these delays erased any benefits endovascular therapy may have provided. Finally and most importantly these trials used the wrong equipment. The Merci retrieval device was prominently featured in all three of these initial trials. A device that most interventionists now consider antiquated and, in a number of small trials demonstrated suboptimal performance when compared to newer devices used currently by most interventionists.

In direct contrast to these results, MR CLEAN is a significantly positive trial. Although the official manuscript has yet to be published a great deal can be garnered from the poster presentation abstract, press release and previously published protocol and statistical analysis plan (11, 15, 16). MR CLEAN is a multicenter randomized clinical trial comparing endovascular treatments for acute ischemic stroke conducted in the Netherlands. Using the prospective open label, blinded endpoint (PROBE) design comparing patients randomized to receive either endovascular treatment (consisting of intra-arterial tPA or urokinase followed by clot retrieval) or standard therapy (91% of which received intravenous tPA alone). Over a 5-year period, authors enrolled 500 patients aged 18 years or older with acute ischemic stroke and a symptomatic anterior proximal artery occlusion, which could be treated within 6 hours after stroke onset.

The authors found patients randomized to endovascular treatment were more likely to have improved neurological outcomes at 90 days with an adjusted odds ratio of 1.67 (95% confidence interval [CI], 1.21 – 2.30). Though there was a significantly higher rate of adverse reactions in the endovascular group (47% vs 42%), these rates did not seem to affect either 90 day neurological outcomes or morality (21%vs 22%). If you were to use the NINDS-2 definition of good neurological outcomes (mRS of 0 or 1), endovascular treatment would have demonstrated a 14% absolute increase in patients alive and independent at 90 days, with a number needed-to-treat (NNT) of 7.

So why was MR CLEAN positive when the 3 trials which came before were negative? Was it the patients? It is true that the authors of MR CLEAN were far more selective in the patients they included. In fact authors required patients to have an occlusion of distal intracranial carotid artery or middle cerebral artery(M1, M2) or anterior cerebral artery (A1) demonstrated with CT angiography (CTA), magnetic resonance angiography (MRA) or digital subtraction angiography (DSA) before they were enrolled in the trial. Was it time? Patients received both IV tPA and endovascular treatments far faster than any of the patients in IMS-3, Synthesis or MR RESCUE. In the MR CLEAN trial patients received their IV tPA on average 85 to 87 minutes after symptom onset and underwent endovascular therapy 196 to 204 minutes after symptom onset. Was it the devices used? In contrast to the initial 3 trials, 97% of the endovascular interventions performed in the MR CLEAN cohort utilized a modern retrievable stent device. Or was it just the random fickle nature of fortune that provided us with these impressive results?

Currently we do not have the full publication of MR CLEAN, so a detailed analysis of the results proves difficult. That being said there are a number of interesting points we can take away from the published protocol and results presented during the 9th annual stroke conference. Firstly the authors claim success in their primary outcome, which they define as “the score on the mRS at 90 days” (11,15). They claim this benefit by citing an adjusted odds ratio of 1.67 (95% confidence interval [CI], 1.21 – 2.30). What are we to take from this odds ratio? What exactly were they measuring and what imbalances were they attempting to adjust that randomization would not account for? In the statistical analysis portion of their protocol the authors only slightly expand on the vague nature of this outcome. The authors used an ordinal analysis in an attempt to quantify the benefits of endovascular therapy over the entire mRS. They then decided to further adjust these outcomes using multivariable logistic regression in an attempt “adjust for chance imbalances in main prognostic variables between intervention and control group”. The specific variables they chose to adjust for were age, stroke severity (NIHSS), time since onset, previous stroke, atrial fibrillation, carotid top occlusion and diabetes mellitus (11). This is the same statistical wizardry used in IST-3 to magically transform a decidedly negative trial into a statistically positive one (17). MR CLEAN marks the first time this type of statistical analysis was used as a trial’s primary end point rather than a secondary experimental, trial saving outcome.

To be clear this trial was an overwhelming success and this analysis is in no way intended to take away from these findings. Rather to question whether an adjusted ordinal analysis is the appropriate outcome to assess efficacy. We have discussed the problems with ordinal analyses in depth in a prior post, but briefly it is an attempt to granularize the data so as to detect smaller changes in outcomes than the more tradition dichotomous cutoff (mRS 0,1, or 2 vs 3,4,5,or 6) is capable of detecting. On face value this seems like a noble pursuit, but logistically presents a number of problems when employed in a trial. Most importantly, is an ordinal analysis an appropriate measure of functional outcomes? Ordinal analysis is an attempt to examine shifts across an entire functional scale. Minute changes in outcomes that would be missed by a dichotomous measurement. To do so one has to assume flawlessness of the collection process and intrinsic reliability of the functional assessment tool. We know that the reliability of the mRS is questionable at best. In fact when two neurologists assess the same patient their results will often differ by up to 2 points (19).

The MR CLEAN 90 day mRS data was assessed using a structured phone interview conducted by a trained research nurse. This trial employed an open design where the patients were not blinded to their group assignments, using an outcome scale of questionable reliability, collected by a phone interview. Authors then utilized a secondary adjustment for variables that should have been controlled by the randomization process. (11) This data is far from flawless. To think you can granularize such data and then extract meaningful outcomes is certainly an error in judgment. Such analysis should be reserved for secondary measures only after a more robust means of appraisal has proven fruitful.

Like all the stroke literature this leaves us trying to compare the soft endpoints of functional neurological outcomes to the hard endpoints of mortality and intracranial hemorrhage (ICH). Despite its success, like NINDS before it, MR CLEAN failed to demonstrate a mortality benefit for endovascular therapies in acute ischemic stroke. The mortality at 90 days was 21% and 22% respectively (15). Add to that a 5% increase in the rate of serious adverse events (47% vs 42%) in the endovascular therapy group. Despite the claim that the newer endovascular devices were safer and caused less bleeds the rate of clinically relevant ICH was statistically equivalent to the patients who received IV tPA alone (6.0% vs 5.2%) (15). This is the same rate of ICH seen in both the IMS-3 and Synthesis trials in which the MERCI retrieval devices were the primary means of clot retrieval (12,13). Furthermore there was a concerning increase in the rate of secondary ischemic strokes in a different vascular territory (5.6% vs 0.4%) and the number of hemicraniectomies performed (6.0 vs 4.9%) in the endovascular treatment group, though given the overall functional outcomes at 90 days were markedly improved in the endovascular therapy group these strokes may not be clinically relevant (15).

So why did endovascular interventions perform so much better in MR CLEAN than in any of the 3 trials that came before it? Was it the modern devices that create superior reperfusion with fewer complications? Interestingly the rate of recanulization in the intervention group at 24 hours was approximately 80% compared to 32% in the IV tPA group alone (15). When compared to the 24 hour recanulization rates in IMS-3 the intervention group were found to have approximately 80% with similar recanulizations rates in the IV tPA group as MR CLEAN (35%) (12). Furthermore the rates of ICH and secondary ischemic infarction seem to be no less than what was observed during IMS-3 and SYNTHESIS. Seemingly these newer devices add little as far as objective effectiveness. Was it time to reperfusion? Patients in MR CLEAN received both IV tPA administration as well as endovascular therapy incredibly fast. So fast that some may question the trial’s external validity. Despite the fact that patients in MR CLEAN underwent both IV and mechanical reperfusion significantly earlier than patients in IMS-3 and Synthesis, earlier treatment with endovascular therapy did not appear to improve outcomes (15). In fact in MR CLEAN, patients who received IV tPA therapy greater than 120 minutes after their symptom onset did better when randomized to the endovascular intervention arm. Conversely when patients received IV tPA prior than 120 minutes after symptom onset, endovascular therapy demonstrated no added benefit. In both IMS-3 and SYNTHESIS no temporal benefit could be demonstrated for patients receiving endovascular therapy (12,12). Was it the patients MR CLEAN selected that made a difference? Though MR CLEAN required CT angiographic proof of a large vessel occlusion, the resulting population seems very similar to the patients in IMS-3. The median age and presenting NIHSS was fairly similar (65-66 vs 68-69 and 17-18 vs 16-17 respectively) (12,15). Even the variation in stroke location was similar with the large majority of the clots located in the M1 segment of the middle cerebral artery (MCA), followed by a third found in the carotid artery terminus and a small minority found in the M2 segment of the MCA.

A few final thoughts of interest, the authors measured change in NIHSS at 24-hour and 1-week intervals. It will be interesting if these findings are expanded upon in the published document, but as far as I can tell from the data presented at the conference, the difference in NIHSS scores between the groups was 2.3 points at 24 hours and 2.9 points at 1 week. I cannot tell if this difference reached statistical significance but seemingly it is under the threshold of a 4-point improvement on the NIHSS that was deemed clinically relevant by the authors of NINDS in their original publication(1). If this data does prove to be accurate than it means that the anecdotal stories of patients rising from the cath lab table shortly after clot removal, was just that, anecdote. Finally it is important to point out that this trial compared endovascular treatment to standard care, which for all intents and purposes was IV tPA (91% of the control group received IV tPA). It is by no means certain that IV tPA provides any added benefit over placebo alone and some skeptics, such as myself, think there is a suggestion of harm. An additional control group, comparing placebo to both IV tPA and endovascular therapy is needed. In the subgroup analysis though endovascular therapy performed better than standard care in patients who received tPA, these benefits were not seen when IV tPA was withheld.

Surely we are left with more uncertainty than when we started this line of investigation. Thankfully there are a number of studies currently underway that may provide us the clarity we require. MR CLEAN is the first trial to demonstrate the potential benefits endovascular therapy may provide, but one trial should not define the standard of care, especially when multiple trials have concluded quite the opposite. The cost and resources needed to create an infrastructure capable of delivering patients to the endovascular suite with the swiftness seen in this cohort would be extraordinary. We should require more than an ambiguous odds ratio, bolstered by further needless statistical adjustments to justify these costs.

Sources Cited:

  1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581-7.
  2. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial–Italy (MAST-I) Group. Lancet. 1995;346(8989):1509-14.
  3. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274(13):1017-25.
  4. Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial–Europe Study Group. N Engl J Med. 1996;335(3):145-50.
  5. Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA. 1996;276(12):961-6.
  6. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352(9136):1245-51.
  7. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999;282(21):2019-26.
  8. Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study: Thrombolytic Therapy in Acute Ischemic Stroke Study investigators. Stroke. 2000; 31: 811–816.
  9. Hacke W, Furlan AJ, Al-rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009;8(2):141-50.
  10. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-29.
  11. Fransen PS, Beumer D, Berkhemer OA, et al. MR CLEAN, a multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands: study protocol for a randomized controlled trial. Trials. 2014;15:343.
  12. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893-903.
  13. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368(10):904-13.
  14. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914-23.
  15. http://www.medscape.com/viewarticle/834064#vp_1
  16. Dipple et al. WSC-1158  Results of the multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in The Netherlands. The MR CLEAN Investigators. International Journal of Stroke. Volume 9, Issue S3 ,October 2014 Pages 16–40
  17. Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379(9834):2352-63.
  18. Saver JL: Novel end point analytic techniques and interpreting shifts across the entire range of outcome scales in acute stroke trials. Stroke 2007, 38:3055–3062.
  19. Banks et al. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke. 2007 Mar;38(3):1091-6. Epub 2007 Feb 1.

The Science (Fiction) of FOAM

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If you want to know how we practiced medicine 5 years ago, read a textbook. If you want to know how we practiced medicine 2 years ago, read a journal. If you want to know how we practiced medicine last year, go to a (good) conference. If you want to know how we practice medicine now and in the future, listen to the conversations in the hallway and use #FOAMed.

                                                                                                                 – Joseph Lex, MD

What if ideas in their purest form possessed mass and energy? A subatomic structure with a specific resonance that dictated each idea’s physical properties. The power and influential reach determined not by the stature of those that spoke them, or the influences of the media agent that disperses them, but by the intrinsic nature of the ideas themselves. Ideas that when set to vibrate at the perfect frequency would propagate across worlds influencing all they touched.

What if a few insightful souls recognized the power of these ideas. Realizing they possess a mass and density of their own and as such have an inherent value. In an unequaled moment of altruism these visionaries decided that rather than imprison these ideas behind walls, restricting their access to those with the monetary means to afford their worth, they would spread them freely throughout the world. Allowing the intrinsic capabilities of each idea to determine the distance travelled. Harnessing technology they propagated these ideas across the globe.

These ideas and their newly defined substance then did something that for the past 200 years was thought to be impossible. They created new ideas…

Creating matter from nothing, they defied the Law of Conservation of Mass. Ideas begot ideas and a movement was born. It wasn’t until June 2012 in a pub in Dublin, Ireland over an appropriately inspirational pint of Guinness that FOAM was officially given its name, but it has been alive long before this. Long before Osler first opened the halls of McGill University for all to learn, before Hippocrates and his students published their Corpus, before even our ancient ancestors painted on the walls of caves on the Island of Sulawesi FOAM was there.

Each year for one week a physical manifestation of the FOAM movement is held. Though the geographic location fluctuates from year to year, the concept remains unchanged. It is a rallying point for all the ideas that have been released into the world. A beacon for those who champion these ideas. The organic amalgamation of the free open market of social media and the like-minded brilliance of practitioners who understand that above all, the sharing of knowledge is key. It is a celebration of FOAM, a movement that creates students, teachers, mentors, and most importantly friends. It is SMACC 2015.

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Registration Opens November 5th/6th

The Case of the Anatomic Heart

16-3_staticOur obsession with diagnostic certainty has led us down many false paths and blind alleyways in the history of medicine. This statement has never been more true than when spoken in regards to cardiovascular health. The small successes that we have obtained when treating the highest acuity patients have been enthusiastically and incorrectly applied across the entire spectrum of coronary artery disease. Focusing too much on the anatomical definition of this disease state has limited our true understanding of the pathological process causing heart disease and in turn limiting our comprehension of how best to intervene. Despite a large body of evidence contradicting the theory, we have held fast to the “clogged pipe” model.

PCI found its initial success in the treatment of ST elevation myocardial infarctions, the most clinically obvious pathological end result of cardiovascular disease. In such cases we discovered that this invasive procedure was only slightly better than our systemic attempts to open the stenotic vessel using aspirin and thrombolytic therapy (1). In fact most data comparing PCI to thrombolytics in patients suffering from acute ST elevation MIs revealed that you had to treat close to 50 people with cardiac catheterization for one to benefit (1). Considering that thrombolytic therapy is only moderately better than aspirin alone, maybe the pedestal we have currently reserved for PCI in the management of ACS is not deserved (2).

The COURAGE trial, appropriately named for challenging the doctrine that coronary artery disease is best managed through invasive techniques, compared the efficacy of PCI vs “optimal” medical management in patients with stable coronary artery disease (3). The authors randomized patients with EKG evidence of ischemia at rest or ischemia induced by some form of provocative testing, with at least one culprit lesion of 70% occlusion or greater, to either PCI or medical management. Essentially the very patients we hope to identify through admission and provocative testing. No difference was found in the rates of death or MI during the follow up period (median 4.6 years) in the patients who received PCI vs those who underwent medical management (3).

These findings are consistent throughout the literature examining PCI vs medical management in patients with stable coronary artery disease. In a meta-analysis by Stergiopoulos et al of all 13 trials examining this question no difference could be found between medical management or aggressive interventional procedure (4). Even patients that are enzyme positive but otherwise clinically stable, no definitive benefits have been demonstrated with aggressive utilization of PCI. In fact when urgent PCI is empirically mandated, there is an increase in early mortality (5). In Emergency Department patients who have been ruled out for acute disease by EKG and enzymes, further evaluations for anatomic disease not only identify diminishingly small amounts of true positives but the interventions proposed do not result in clinically meaningful improvements in outcomes. Clearly we have overreached our meager successes and applied a crash procedure to a far different pathology than where it originally found it’s success.

This obvious lack of efficacy has not gone unnoticed. Many have suggested the need for a more refined method of identifying high risks lesions that would benefit from an invasive approach. Fractional Flow Reserve (FFR) is a technique that has been proposed as the answer to clarify which lesions would benefit from stent placement. This invasive technique is performed in concert with standard PCI and allows the interventionalist to assess the flow of blood before and after the stenotic lesion. These values are turned into a ratio in the hopes of numerically quantifying coronary flow. Anything under 0.80 is determined to be an ischemic stenosis and as such would benefit from the placement of a stent. Despite its physiologic plausibility, trials examining its efficacy have been less than stellar. The initial two studies, DEFER and FAME, comparing FFR-guided PCI to traditional PCI demonstrated a decreased rate of myocardial infarctions at 2 year follow-up (6,7). Initially these results seem to be in favor of FFR guided PCI but upon closer inspection the data reveals that the difference in the groups primarily consisted of a decrease in procedure related events. Suggesting that the only benefit FFR provides is to inhibit the ocular-stenotic reflex, quite prevalent in the modern Interventional Cardiologist (8). Neither of these studies address the important question, how does FFR-guided PCI compare to conservative medical management alone?

Introducing FAME-2. Like COURAGE before it, FAME-2 sought to answer the question whether FFR adds anything to medical management alone. The preliminary data was published in 2012 after the trials was halted prematurely (9), but the official 2-year follow-up results were recently published in the NEJM (10). Authors randomized patients with angiographic stentable lesions, with either classic anginal symptoms or positive findings on provocative testing after a negative ED workup, to either standard medical management or FFR-guided PCI. The authors utilized a composite endpoint of cardiovascular death, MI, or urgent revascularization. The trial was stopped early after enrolling only half its intended sample size, 1220 patients, due to an unacceptable number of events that occurred in the medical management group. Taken at face value this seems like an overwhelming approval of FFRs clinical utility. Long awaited proof that downstream testing after a negative ED workup results in clinically important benefits. A justification for the substantially large quantity of low-risk patients we admit to the hospital each day. Despite these seemingly positive results this trial does not justify our risk adverse strategy. Though there was a 11.4% absolute difference in the rate of primary events (8.1% vs. 19.5%) that occurred between the groups, this margin consisted entirely of an increased frequency of urgent revascularizations. There was no difference in the number of deaths or MIs that occurred between the groups. The majority of these excess revascularizations were due to persistent symptoms, demonstrating this claimed efficacy was primarily due to our biases rather than any overwhelming benefit of FFR-guided PCI.

Clearly FFR does not provide us with the clarity we seek. Even the theoretical ground FFR stands upon is thin as the ischemic threshold we currently use was derived by comparing FFR values to a gold standard of non-invasive perfusion imaging, a test with questionable clinical value (11). FFR may very well still play a role in the management of coronary artery disease, but its relevance in the management of ACS is insignificant.

How this changes the long-term management of coronary artery disease is unclear, but what is becoming increasingly apparent is an anatomic definition of coronary disease, following a negative Emergency Department work up for the diagnosis of ACS, provides no further clinical benefit. A number of trials have demonstrated that the addition of angiography or CT angiography add nothing to further risk stratify these patients (12-16). The rate of true positive disease in this cohort is diminishingly low (17). Even when the rare patient is found to truly have anatomically defined disease, direct invasive interventions add little clinical benefit over aggressive medical therapy. Anatomic investigation may very well remain an important component in the management of cardiovascular disease. Not to identify those patients that would truly benefit from cardiac catheterization, but to distinguish which patients require aggressive medical management. Surely this is not a priority in the Emergency Department evaluation of ACS.

More than ever we require a practical outlook when it comes to resource application in Emergency Medicine. Trying harder and doing more rarely lead to improved patient oriented outcomes. In the case of Emergency Department management of ACS it is imperative we admit that our current strategy has failed. We are striving to identify an exceedingly rare population in the hopes of offering an intervention which provides insignificant patient oriented benefits. Despite our technical mastery, technological advances, and intellectual mashinations, PCI remains a crash procedure that has only demonstrated proven benefit in the sickest cohorts of CAD. Outside the confines of ST- elevation MI we have yet to identify a population who consistently benefit from this invasive approach to management. Continually insisting on titling against the massive windmill that is Heart Diseae with a lance poorly equipped for this purpose, has led us too far down the path of madness. Surely its time to turn around and start the long walk back to sanity…

Sources Cited:

  1. Cucherat M, Bonnefoy E, Tremray G. Primary angioplasty ver-sus intravenous thrombolysis for acute myocardial infarction. Cochrane Database Syst Rev. 2000;2:CD001560.

 

  1. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.  Lancet. 1988;2(8607):349-60.

 

  1. Boden WE, O’rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503-16.
  2. Stergiopoulos K, Brown DL. Initial Coronary Stent Implantation With Medical Therapy vs Medical Therapy Alone for Stable Coronary Artery Disease: Meta- analysis of Randomized Controlled Trials. Archives of Internal Medicine 2012 Feb;172(4):312
  3. Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA. 2005;293(23):2908-17.
  4. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49:2105-2111
  5. Tonino PA, De bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-24.
  6. Bradley SM, Spertus JA, Kennedy KF, et al. Patient selection for diagnostic coronary angiography and hospital-level percutaneous coronary intervention appropriateness: insights from the national cardiovascular data registry. JAMA Intern Med. 2014;174(10):1630-9.
  7. De bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991-1001.
  8. De bruyne B, Fearon WF, Pijls NH, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med. 2014;371(13):1208-17.
  9. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334:1703-1708
  10. deFilippi CR, Rosanio S, Tocchi M, et al. Randomized comparison of a strategy of predischarge coronary angiography versus exercise testing in low-risk patients in a chest pain unit: in-hospital and long-term outcomes. J. Am. Coll. Cardiol. 2001;37(8):2042-2049
  11. Goldstein JA, Gallagher MJ, O’Neill WW, Ross MA, O’Neil BJ, Raff GL. A randomized controlled trial of multi-slice coronary computed tomography for evaluation of acute chest pain. J Am Coll Cardiol. 2007;49(8):863-71
  12. Goldstein JA, Chinnaiyan KM, Abidov A, et al. The CT-STAT (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment) trial. J Am Coll Cardiol. 2011;58(14):1414-22
  13. Hoffmann U, Truong QA, Schoenfeld DA, et al. Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med. 2012;367(4):299-308
  14. Litt HI, Gatsonis C, Snyder B, et al. CT angiography for safe discharge of patients with possible acute coronary syndromes. N Engl J Med. 2012;366(15):1393-403
  15. Hermann LK, Newman DH, Pleasant WA, et al. Yield of routine provocative cardiac testing among patients in an emergency department-based chest pain unit. JAMA Intern Med. 2013;173(12):1128-33.

 

“The Adventure of the Sussex Vampire”

midline picture

A brief forethought. This post we will stray from the usual whimsical rants regarding recent literature in Emergency Medicine. Instead we will focus on the far more practical topic of the insertion of  the Midline catheter. Of note, I am overwhelmingly biased in favor of these devices and have taken such a fanciful liking to them I can’t possible be an objective critic. With this in mind…

 

The dichotomy that is venous access has become far more ambiguous since the establishment of ultrasound (US) to identify vascular targets. Prior to US, admission to the circulatory system was gained via superficial peripheral veins located by direct visualization, palpation or through central veins large enough to cannulate by blindly sticking a needle in the area of their anticipated anatomic location.

Since employing US to sonographically identify a deeper set of peripheral veins, the clear-cut boundaries that once separated central and peripheral access have become blurred. Not only has US improved our success in both these traditional techniques (1,2), it has introduced a new target for our blood hungry beveled needle tips to pursue. A larger set of peripheralmidline2 veins that were once too deep for direct visualization and too small for blind exploration now, thanks to US, have become an appealing target. To our surprise and dismay these deep peripheral lines are far less durable than their size and integrity would suggest (3). In fact, the rate of line failure within the first 24-hours (46%) is unacceptably high for clinical use (3,4).

This failure is due, more likely to a deficit in our equipment rather than a deficiency in these anatomic structures. Our current line of peripheral catheters is not designed to access such deep vessels. These catheters were intended to cannulate superficial veins. When employed on deeper veins they typically do not have adequate length to sufficiently seat the catheter tip in the vessels. This creates two problems. First the catheter will often become dislodged by even the smallest movement from the patient, as the elastic recoil of the soft tissue surrounding the precariously placed catheter pulls it from its target vessel. Second the steep trajectory taken to ensure the catheter reaches these vessels often results in the needle damaging the posterior wall of the vessel. This would not be of great importance if the catheter possessed the necessary length to thread beyond the damaged endothelium. Unfortunately even our long peripheral catheters lack the required length and end up sitting right next to this damaged portion of the vessels. These deficits have led to an abnormally high failure rate.

The deep venous or Midline catheters offer a viable solution to these obstacles. A number of recent studies have demonstrated the successful use of a small wire to thread a single lumen catheter into the deep veins of the upper extremity. This technique allows for secure access to these deeper vessels, avoiding the risks associated with central line insertion. These studies, examining the insertion of such lines, have confirmed their superior durability when compared to standard catheters and far fewer line related infections than observed with central venous catheterization(7).

The most recent of these trials, by Meyer et al, examines the use of arterial catheters inserted into either the cephalic or basilic veins (5). In this study’s participating hospital it was routine for the ICU to provide “line consultations”, during which the Critical Care physician would be called to the ward to obtain venous access on particularly difficult patients. Difficult access was defined in this cohort as three failed attempts to insert a peripheral line by an experienced nurse. After which all lines were inserted by a single operator, the study’s second author, Dr. Pierrick Cronier, using either 18 or 20 gauge arterial catheters that were 8 to 11 cm in length. Catheters were placed using the Seldinger technique under full aseptic conditions.

All 29 lines were placed successfully, the majority in the basilic vein (66%) and the remainder in the cephalic vein (34%). Only three catheters were removed early. One was accidently removed by the patient up until which point it had been functioning normally. The remaining two catheters were removed due to absence of blood return and were found to be occluded. Two additional catheters were found to be colonized with coagulase.  Using ultrasound, no thrombophlebitis was visualized on any catheter prior to their removal.

The small sample size and use of a single skilled operator limit the conclusions that can be drawn from such a study and thus this trial does very little to answer the more pertinent questions Emergency Physicians have regarding the use of Midlines.

What is the optimal catheter for Midline insertion?

In the Meyer et al cohort the authors studied catheters intended for arterial use (5). In earlier cohorts both Elia et al and Mills et al employed single lumen central venous catheters of varying sizes (12 and 15 cm respectively) with equal success. While others have used catheters specifically designed for Midline insertion (3,6,7), no one study directly compares the various catheter choices, but all demonstrate similar efficacy and safety profiles in their independent cohorts. There is a Goldilocks effect in the sense that the longer the catheter inserted the greater the durability of the line, and yet if the catheter tip extends proximally enough to be seated in the subclavian vein, the rate of catheter related infections approaches numbers associated with the use of central line catheters (8). Seemingly no one catheter type appears superior to any other. It is important to remember that unlike central lines we are inserting catheters into much smaller, thin walled vessels and thus should choose a catheter insertion kit nimble enough to navigate such delicate structures.

Can vasopressors be safely administered through Midline catheters?

Most of the trials examining Midline catheters focused on the rate of successful insertion and line safety. All of these trials examining Midlines treated them as if they were peripheral lines (3,4,5,6,7), and as such there is no specific evidence evaluating the safety of administering vasopressor medication. This lack of evidence does not invalidate their use. The mostmidline3 commonly cited concern is that due to the depth of these venous structures, a delay in recognition of an infiltrative event may occur causing significant damage before the infusion could be stopped. This would be a valid concern except that unlike their more superficial cousins, Midlines very rarely infiltrate. When compared to traditionally inserted peripheral lines, Midlines fail far less often and in far different ways. Peripheral lines tend to infiltrate or become dislodged because of the short distance between insertion site and distal catheter tip in conjunction with the delicate nature of the vessels. Conversely Midlines fail later in their course, primarily due to distally located occlusions. The failure rate of Midline catheters is approximately 14% with a median time to failure of 6.19 days (3). In all the cohorts examining the insertion and use of Midlines only two infiltrative events occurred. In Mills et al, this event transpired directly after a difficult insertion performed by one of their less experienced practitioners (6). In El-Shafey et al, a single Midline catheter infiltrated shortly after its insertion (4). Both of these events occurred soon after insertion and quickly became clinically obvious. The much feared “occult” infiltration, has yet to manifest in any cohort examining the use of Midline catheters. That being said it is important to note that all Midlines are not created equal. The small tortuous vein in which one experiences great difficulty threading a catheter is a far different line than a large easily compressible vein that threads easily with adequate blood return.

Finally the generalizability of these trials is limited by the expertise of the practitioners inserting these lines. The majority of these trials called upon a few experienced practitioners to perform each catheterization. Only one trial, Elia et al, utilized a variety of practitioners (attendings, residents and nurses) with varying levels of experience (3). This variability is reflected in the lower success rate when compared to similar cohorts (86% vs 93% and 100%) (5,6). From my personal experience there is a learning curve when first beginning to insert these types of lines. The delicate act of threading the wire is far more difficult than the insertion of a central line. Because of the small size of these vessels there is a greater likelihood for the tip of the needle to become dislodged when detaching the syringe. Once this skill is perfected the placement of the lines becomes far simpler.

Our threshold for changing practice is frustratingly fickle. We have accepted that the use of US to identify deeper peripheral vessels will both improve peripheral line insertion and decrease the need for central line placement. Yet our success is limited by our use of traditional techniques and unsuitable equipment neither of which were intended to cannulate such deep vasculature. Likewise we incorrectly apply the rules that govern superficial peripheral vasculature to these deeper more durable vessels. In order to optimize our success with US guided peripheral access, it is imperative we realize these vessels are unlike their more superficial brethren and we must adapt our ideology, methods and tools accordingly.

Sources Cited:

 1. Leung J, Duffy M, Finckh A. Real-time ultrasonographically-guided internal jugular vein catheterization in the emergency department increases success rates and reduces complications: a randomized, prospective study. Ann Emerg Med. 2006;48(5):540-7.

2. Costantino TG, Parikh AK, Satz WA, Fojtik JP. Ultrasonography-guided peripheral intravenous access versus traditional approaches in patients with difficult intravenous access. Ann Emerg Med. 2005;46(5):456-61.

3. Elia F, Ferrari G, Molino P, et al. Standard-length catheters vs long catheters in ultrasound-guided peripheral vein cannulation. Am J Emerg Med. 2012;30(5):712-6.

4. Eid Mohamed El-Shafey, Tarek F. Tammam. Ultrasonography-Guided Peripheral Intravenous Access: Regular Technique Versus Seldinger Technique in Patients with Difficult Vascular. European Journal of General Medicine. 2012; Vol. 9, No. 4 .

5. Meyer P, Cronier P, Rousseau H, et al. Difficult peripheral venous access: Clinical evaluation of a catheter inserted with the Seldinger method under ultrasound guidance. J Crit Care. 2014;29(5):823-7.

6. Mills CN, Liebmann O, Stone MB, Frazee BW. Ultrasonographically guided insertion of a 15-cm catheter into the deep brachial or basilic vein in patients with difficult intravenous access. Ann Emerg Med. 2007;50(1):68-72.

7. Mermel LA, Parenteau S, Tow SM. The risk of midline catheterization in hospitalized patients. A prospective study. Ann Intern Med. 1995; 123:841-4.

8. Kearns PJ, Coleman S, Wehner JH. Complications of long arm-catheters: a randomized trial of central vs peripheral tip location. JPEN J Parenter Enteral Nutr. 1996;20(1):20-4.