Category: Resuscitation

All Falling Apart for Epinephrine

A staple of resuscitative care, epinephrine is enshrined in the ACLS algorithms for the pulseless patient.  And, what seems to be clear – flogging the heart with vasoactive agents produces, at least, a temporary physiologic response.  Unfortunately, such sympathomimetic abuse results in multiple adverse effects, included coronary and cerebral vasoconstriction – and the net effect, perhaps, is negative.

This is a retrospective review of 1,556 patients admitted to a “cardiac arrest center” in Paris, France, evaluating cerebral performance outcomes depending upon pre-hospital administration of epinephrine.  Of the 1,134 patients who received epinephrine, 17% ultimately had good outcome.  Of the remaining 422 patients who did not receive epinephrine, 63% ultimately had good outcome.  The authors also demonstrate worsening outcomes for epinephrine administration in a dose-dependent fashion.  Cheers.

Of course, it should follow naturally the patients receiving epinephrine probably did so because they were judged to need it – whereas, contrariwise, those not receiving epinephrine probably did not receive it because they were sufficiently stable.  And, then, failure to achieve initial return of spontaneous circulation begets additional doses of epinephrine.  Thus, you have a selection bias in which sicker patients were naturally allocated to epinephrine and less-sick patients to non-treatment – and an accounting for the dose-response relationship.  The authors perform multiple adjustments and propensity matches in an attempt to prove the outcome disparity durable to these validity challenges, but the astute reader may find them insufficient.

This study, nor any of the observational studies preceding it, definitively prove the harms of use of epinephrine pre-hospital outweighs the benefits.  I have, at least, stopped routinely using epinephrine in undifferentiated cardiac arrest, and rather try to select specific patients for whom the underlying etiology seems appropriate.

“Is Epinephrine During Cardiac Arrest Associated With Worse Outcomes in Resuscitated Patients?”

BLS is More

Coming from JAMA Internal Medicine’s “Less is More” series is this latest evaluation prehospital care for out-of-hospital cardiac arrest.

These authors compared basic life support – CPR and defibrillation – with advanced life support – as above, but with feeling (and intubation and pharmacologic flogging) – to determine, once and for all, the winner.  And the winner, by a wide margin, is BLS – 13.1% vs. 9.2% survival, and 21.8% vs. 44.8% poor neurologic functioning.  Ah, so.

Naturally, as with everything in life, the details are far muddier than this simple conclusion.  The study population established BLS or ALS level of care by utilizing a Medicare procedural coding database for ambulance services, not specific patient-level interventions.  Patients were then linked to a Medicare billing database using ICD-9 codes for cardiac arrest “present on admission”, with multiple exclusions owing to poor underlying data quality.  And, finally, their primary outcome of neurologic performance was inferred from ICD-9 codes for brain injury and vegetative state, not direct observations.  To say these authors have performed potentially specious and indirect measurements is quite the understatement.

All that considered, however, these observations very likely reflect underlying truths.  Any advantage of pre-hospital ALS over BLS for OHCA remains steadfastly unproven.  Such interventions as endotracheal intubation and sympathomimetic therapy are likely harmful, despite having been persistently assumed to be beneficial.  And, as this article points out, ALS-trained professionals are far more expensive than BLS – further salting the wound.

More, almost certainly not better.

“Outcomes After Out-of-Hospital Cardiac Arrest Treated by Basic vs Advanced Life Support”
http://www.ncbi.nlm.nih.gov/pubmed/25419698

More Futility for Mechanical CPR

A few weeks ago we reported on the use of the LUCAS-2 for crushing the thorax, resulting in significant internal injuries.  None of these injuries were judged to have contributed to any patient’s demise – but, still, concerning.  This could be more forgivable if there were other advantages, say, survival.

Unfortunately, yet again, mechanical CPR fails to demonstrate superiority.

This is the PARAMEDIC trial, from the Lancet, a cluster-randomized trial aiming to demonstrate the superiority of the LUCAS-2 device as compared to manual CPR.  Based on a deployment of 143 available LUCAS devices, these authors compared 1,652 patients randomized to attempt device deployment compared with 2,819 in a control group.  There were no important differences in the baseline characteristics of the two groups, and other measures of initial treatment were similar.  And, in the end, there was no difference between initial return of circulation, event survival, 30-day survival, 3-month survival, or 12-month survival (all dismal).

The mildly interesting aspect to this trial is that it was not directly a test of the LUCAS device – but, rather, a pragmatic trial comparing deployment with LUCAS as an option with deployment without.  Thus, 638 patients in the clusters randomized to include the LUCAS device received manual compressions.  However, on multiple causal effect analyses, no advantage was detected from cases in which the LUCAS device was used, nor was a selection bias apparent.

In the absence of efficacy data, use of mechanical devices is defended primarily on the basis of convenience – freeing up hands for other tasks.  However, this argument fails in the face of these data – as it does not appear the handsfree advantage, when available, results in improved patient outcomes.

“Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61941-3/fulltext

What Do People Remember From Cardiac Arrest?

The anecdotal experiences and reports from survivors of cardiac arrest are diverse, yet frequently describe common themes.  Detailed memories, “near death experiences” of entering another world, and sights and sounds from the arrest context are frequently reported.  And, what better place to collect cardiac arrest events than in a hospital?

As one might imagine, the population available for such interviews is rather limited – so it requires a massive undertaking, in this case, a four-year prospective evaluation across 15 hospitals in the U.S., UK, and Austria.  Essentially, the local investigator at each institution received notification of every adult, in-hospital cardiac arrest.  Survivors were identified and interviews conducted as soon as feasible, given continued comorbid illness.

Out of 2,060 cardia arrests, only 330 were eligible for study inclusion.  Investigators conducted 140 interviews – and only 55 had any memories.  Of these, 53 had detailed memories, whether unrelated or classic “crossing-over” phenomena – but nothing relating to the circumstances of their arrest event.  Only two patients had detailed memories of the circumstances of their event – one set of memories was not able to be verified, but the authors were able to fully verify the other set of memories by interview of the resuscitation staff.

So, essentially, very rarely do patients have any recollection of their arrest event.

Interestingly, one part of this study attempted to verify the veracity of the “floating above and watching” aspect of some individual’s arrest recollections.  The authors constructed shelves in areas thought most likely to have cardiac arrest, and then placed objects on the shelf that would only be visible from a perspective near the room ceiling.  Unfortunately, 70% of the cardiac arrests in this study occurred in locations where there were no shelves, including both arrests with detailed recollection.

“AWARE—AWAreness during REsuscitation—A prospective study”
http://www.ncbi.nlm.nih.gov/pubmed/25301715

CPR: Crushing It With Machines

In movies and television, CPR is a miraculous, dramatic event.  Pulses return, patients open their eyes and make a witty remark, and everyone celebrates.

The reality: CPR is a brutal, violent intervention.  And, the new mechanical CPR devices are even moreso.

This is a brief autopsy-based survey of 222 patients in whom CPR was unsuccessful, 83 of which were treated with manual CPR only, and 139 patients who received primarily mechanical CPR.  Mean age was ~67 years, about 30% female, and mean CPR time was ~35 minutes.  That is, to say the least, ample time to crush the thorax.

A brief accounting of the injuries from CPR:

  • Multiple rib fractures: 57.3% manual, 65.0% mechanical
  • Sternal fractures: 54.2% manual, 58.3% mechanical
  • Intrathoracic bleeding:  36.1% manual, 48.9% mechanical
  • Cardiac injuries: 7.2% manual, 15.2% mechanical
  • Liver injuries: 3.6% manual, 7.9% mechanical

Pathologists at autopsy, however, did not judge any of the injuries from CPR to have contributed to the cause of death.

Injuries in those for whom CPR is unsuccessful are intuitively more severe than for cases in which patients survive – a result of non-survivors being generally older, more brittle, and longer CPR duration.  However, it’s an interesting window into the destructive nature of vigorous CPR – and the increased injury associated with mechanical devices.

“CPR-related injuries after manual or mechanical chest compressions with the LUCAS device: A multicentre study of victims after unsuccessful resuscitation”
http://www.ncbi.nlm.nih.gov/pubmed/25277343

Nitric Oxide Supplies No Miracles in Sepsis

An interesting context to end-organ dysfunction in sepsis stems from microcirculatory dysfunction, secondary to endothelial activation and vascular disruption as part of the inflammatory cascade.  Even though abnormal vasoconstriction in sepsis may be pharmacologically ameliorated, microcirculatory perfusion remains impaired.

This interesting trial attempted to modulate microcirculation through the use of inhaled nitric oxide.  Authors enrolled patients whose macrocirculation had been optimized, using objective targets consistent with contemporary care in septic shock, and randomized them to inhaled nitric oxide or sham.  Using a custom device for 40 ppm nitric oxide inhalation – for which authors all deny COI – an enrollment of 138 patients was planned.

However, after 49 patients, the trial was stopped due to futility.  The device was a success – as measured by circulating nitrite levels.  Unfortunately, from a microcirculation perfusion endpoint, there was no difference.  Likewise, there were no obvious differences or trends in secondary clinical outcomes.  There were, at least no obvious harms related to therapy.

Next steps in evaluation of this therapy – if any – are as of yet unclear.

“Randomized Controlled Trial of Inhaled Nitric Oxide for the Treatment of Microcirculatory Dysfunction in Patients With Sepsis”
http://www.ncbi.nlm.nih.gov/pubmed/25080051

Dueling PE Meta-Analyses

A guest post by Rory Spiegel (@EMNerd_) who blogs on nihilism and the art of doing nothing at emnerd.com.

Nothing sparks controversy quite like a discussion on the utility of thrombolytics. No sooner had the wave of debate brought on by the publication of the PEITHO trial and its finding of no overall mortality benefit died down, did JAMA stoke these flames with the publication of a meta-analysis including the entirety of the literature on thrombolytic use for pulmonary embolism. Examining 16 trials, the authors found a statistically significant absolute mortality benefit of 1.12% or an NNT of 59 patients. This benefit was offset by the increase in major bleeding events observed in those given thrombolytics (9.24% vs 3.42%) with a 1.27% absolute increase in ICH.



The cascade of incendiary events continued when one week later a second meta-analysis examining the very same question was published in Journal of Thrombosis and Haemostasis. Only these authors claimed to find the exact opposite of their JAMA counterparts. In this case the authors found no statistical improvement in mortality in the patients given thrombolytics when compared to those given a placebo. Despite these contradictory claims, a more comprehensive inspection reveals these meta-analyses are extensively saying the same thing. A comparison of the two serves as a timely reminder that conclusions reached from any meta-analysis is primarily dependent on the trials selected for inclusion.  The JAMA meta-analysis included 2115 patients in 16 trials, while the Journal of Thrombosis and Haemostasis examined only 1510 patients in 6 trials. Interestingly, the absolute risk reduction in mortality was 1.12% in the JAMA publication vs 1.4% in the Journal of Thrombosis and Haemostasis publication. Though the JAMA analysis had an overall smaller absolute risk reduction, the result reached statistical significance due to the larger sample size.



More importantly the results of these publications should not come as a surprise. Before the publication of PEITHO the data on thrombolytics for PE was sparse. Most of the trials suffered from small sample sizes and questionable methodology. It is the amalgamation of these small trials that accounts for the mortality benefit in both meta-analyses. In the JAMA publication the mortality difference consisted of 17 fewer deaths in the thrombolytic arm compared to the placebo. All of which originated from these small underpowered studies. Conversely, the two large high quality trials (PEITHO and MSPPE) consisting of 1005 and 256 patients respectively made up the majority of patients meta-analyzed, neither of which found a mortality benefit with the use of thrombolytics. Moreover the 2% absolute increase in ICH seen in the PEITHO cohort is only diluted by the inclusion of these small trials, whose sample sizes were not powered to detect such rare events. A more elegant design would be to utilize a weighted average or one of the various statistical methods that takes into account each study’s sample size and event rate, allocating a greater weight to the hardier cohorts. Though one might argue an equally elegant solution would be to not include such flawed trials in the first place.


The publication of these dueling meta-analyses highlights the flaws of such statistical endeavors. Small trials with flawed methodological designs are prone to fall victim to publication bias and the fluctuating whims of chance. Collecting this data and attaching a statistical judgment to it does not correct these imperfections, it augments them. The overall benefit of thrombolytics in PE is yet undetermined, but the answer will not be elucidated in such analysis. We require further large randomized controlled trials like the PEITHO trial. Adding small flawed cohorts to this robust dataset does nothing but muddy the already murky waters.

“Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis.”
http://www.ncbi.nlm.nih.gov/pubmed/24938564

“Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism: a meta-analysis.”
http://www.ncbi.nlm.nih.gov/pubmed/24829097

Should Paramedics Intubate Out-of-Hospital Cardiac Arrest?

Airway management of out-of-hospital cardiac arrest is a controversial topic.  Most patients transported for OHCA have receive prehospital airway management.  However, attempts at establishing an airway can interrupt compressions, over-ventilation can decrease cerebral perfusion, and delays in airway acquisition impact transport to definitive care.

This study retrospectively evaluates the CARES surveillance group, a multi-site registry from North America, comparing neurologically intact survival after prehospital endotracheal intubation, supraglottic airway, or no advanced airway.  In the unadjusted results, survival rates were 5.4% for intubated patients, 5.2% for supraglottic airway, and 18.6% for no advanced airway.  After statistical adjustments and propensity scores, the authors report the ultimate winner is not attempting an advanced airway – and then endotracheal intubation is superior to supraglottic airway.

But, really, this study tells us nothing.  Even though the authors attempt several methods of statistical adjustment, the likely presence of massive unmeasured confounders invalidates these observations.  There is an entire host of patient-level and situational factors that impact the type of airway attempted, the number of airway attempts, and the aggressiveness of care provided both pre-hospital and in-hospital.  The profound differences in unadjusted outcomes, between those not receiving an advanced airway and those requiring one, paints the most obvious picture of the likely underlying differences in unfavorable physiology at work.

This is hardly the first observational report regarding the impact of prehospital airway management.  And, frankly, we’ve seen enough – this type of retrospective cohort does not hold the answer, unless the registry was specifically designed to answer such questions.  To the authors credit, they do not overstate the level of evidence provided – but an unsophisticated reader might draw the wrong conclusions.

“Airway management and out-of-hospital cardiac arrest outcome in the CARES registry”
http://www.ncbi.nlm.nih.gov/pubmed/24561079

Colloids Will Never Die

People love colloids.  Gross fluid resuscitation with crystalloids makes folks uncomfortable; the general dilutional effects and lack of oncotic pressure associated with crystalloids portends suboptimal volume replacement.

Yet, as we see again, the theoretical advantages of colloids are just that:  theoretical.

In this multi-center study from Europe, ICU patients were randomized – following initial resuscitation – to further resuscitation with crystalloids alone or crystalloids supplemented with albumin to a serum albumin target of 30g/L.  Groups were well-matched at baseline, in medical/surgical comorbidities, organ dysfunction, physiologic parameters, and pre-randomization resuscitation.  This excerpt from the authors’ conclusions condenses the results most simply:

“… the use of albumin in addition to crystalloids to correct hypoalbuminemia, as compared with the use of crystalloids alone, in patients with severe sepsis during their stay in the ICU did not provide a survival benefit at 28 or 90 days, despite improvements in hemodynamic variables.”

The last note is important, and reveals why this study will do nothing to change the use of natural and synthetic colloids for resuscitation:  clinicians love to make numbers look good, and colloids do that better than crystalloids.  Despite increased cost and no ultimate change in the primary outcome of mortality – or any secondary outcome of note – colloids improved hemodynamics in the short term.  Even though colloids are more costly, perhaps there are yet financial advantages to this small, early hemodynamic advantage?  Regardless, we are assured further research on this topic will continue apace.

My wife’s contribution to this post:  other important colloids people love include whipped cream, gravy, ketchup, and Jello®.

“Albumin Replacement in Patients with Severe Sepsis or Septic Shock”
http://www.ncbi.nlm.nih.gov/pubmed/24635772

MAPing Pressor Therapy, a Guide to Nowhere

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

Among the many questions in sepsis management, the proper use of vasopressors is one of the most vexing. Despite sparse evidence addressing their overall benefit in the management of septic shock, the use and misuse of vasopressors have been debated ad nauseam. And yet the precise time to begin pressor therapy and the ideal mean arterial pressure (MAP) to target are still very much uncertain.

Authors of the SEPSISPAM trial, or more commonly referred to as “the other sepsis trial published alongside ProCESS“, attempt to provide us with some guidance on the ideal MAP goal in septic shock. Pierre et al randomized 776 patients in septic shock, “refractory” to initial fluid bolus (30mL/kg), initiating vasopressor therapy at a MAP goal of either 65 or 85 mm Hg. The pressor used to achieve these MAPs was left to the discretion of the treating physician (though norepinephrine was the first-line pressor in the vast majority of the participating centers).

SEPSISPAM failed to find a difference between a MAP goal of 65 or 85 mm Hg in any of the many endpoints examined, with the exception of the pre-specified subgroup of patients with a history of hypertension. In those randomized to the 65 mm Hg group, they found a small increase in the amount of patients who experienced elevated creatinine levels and underwent renal replacement therapy within the first week of enrollment. Given that there was no difference in 28-day or 90-day mortality or the number of patients who survived to 28-days without organ support, its hard to imagine this momentary ascent into statistical significance as clinically relevant.

More important than the ideal MAP goal for pressor therapy, is how many of these patients should have been started on vasopressors in the first place? Patients were enrolled after they were found to be refractory to initially fluid bolus and then immediately started on pressors. And though the protocol allowed for physician judgment on additional fluid administration after the initial 30cc/kg bolus, if you examine the daily fluid administration during the first 24-hours of resuscitation, very little extra fluid was allotted. Though these patients received approximately 10 liters over the first 5 days of their resuscitation, only 3 liters were given within the first 24 hours. When compared to the ProCESS cohort, who received approximately 5 liters (depending on group allocation) within the first 6 hours, this resuscitation effort is entirely underwhelming.

It is impossible to make definitive conclusions when comparing outcomes from different trials, but these two cohorts appear fairly similar at the time of enrollment. In fact, the ProCESS cohort may have been slightly sicker (lower MAP, higher HR, higher initial blood lactate levels). These two very similar cohorts with almost identical pre-enrollment fluid administration demonstrated two very different resuscitative strategies.  The patients in the SEPSISPAM trial were given very little additional fluid after the initial bolus and were all immediately started on pressor therapy. Conversely, the ProCESS cohort were bolused generous amounts of additional fluid and only half were started on pressors within the first 6-hours of enrollment. The 28-day mortality in the SEPSISPAM cohort was 34% and 36.6% respectively. In contrast, the the ProCESS cohort found a 60-day mortality of 21.0%, 18.2% and 18.9% in the three resuscitative strategies.  Obviously not definitive data but a strong argument against the “Fear the Fluids” campaign that is so rampant in current ED and ICU management of septic shock.

“High versus Low Blood-Pressure Target in Patients with Septic Shock” http://www.nejm.org/doi/full/10.1056/NEJMoa1312173