Category: Vasopressors

Winter Recap

Spring is here down in this nuclear-free hemisphere. This blog is still effectively in stasis – but the productivity continues elsewhere!

Don’t forget the Annals of Emergency Medicine Podcast, a lighthearted feel-good romantic comedy with Rory Spiegel, available for free on your choice of streaming platforms:

Bimonthly #FOAMed in ACEPNow:

And, lastly, everyone’s favorite part of their residency curriculum, the Annals of Emergency Medicine Journal Club – in which we update folks from the wider world of medical literature in concise summaries for emergency medicine practice:

Enjoy!

The Definitive Word on Steroids in Septic Shock

As the authors say in their introduction, glucocorticoids have been in and out of favor as adjunctive treatment of patients in septic shock for over 40 years. Various trials have found results both favoring and discounting their utility – leading, finally, to this trial to end all trials: ADRENAL.

Of course, there’s hardly ever any such definitive thing in medicine – but this is as close as it comes. This multi-center, multi-country, blinded, placebo-controlled, randomized trial evaluated the use of hydrocortisone in critically ill patients on vasopressors in septic shock. Patients were randomized to receive either 200mg of hydrocortisone daily as continuous infusion, or placebo. The primary outcome was 90-day mortality, with multiple secondary outcomes regarding length of ICU stay, hemodynamics, and others.

With 3,800 patients enrolled, this trial – if any could ever say to do so – should be essentially the final word with regard to detecting any significant difference in outcomes. And the final answer is: choose your own adventure!

For the primary outcome, there was no statistically significance difference in mortality at 90 days – 27.9% in the hydrocortisone cohort, and 28.8% with placebo. Looking at secondary outcomes, the results here tended to favor hydrocortisone – a slightly faster resolution of shock, shorter ICU stays, and, oddly, decreased transfusion requirements. The purist would say: negative trial. The Bayesian would say: this doesn’t change my prior opinion. The answer is, probably, somewhere in between.

Effectively, when a massive trial fails to find a difference, there is still the possibility of there actually being a difference – but any magnitude of effect is likely to be quite small. “Small” in this case, looks to be on the order of numbers-needed-to-treat ranging from 20 to 200, depending on the outcome. To take this into context, the much lauded WOMAN trial celebrating tranexamic acid found only a 0.4% absolute reduction in death due to bleeding. Hydrocortisone, similarly, is inexpensive, displayed few serious adverse effects, and even a small advantage with regard to an outcome such as mortality ought to be considered valuable.

Thus, the choose your own adventure. I tend to feel this is a reasonable treatment adjunct, but, as far as moving the needle on outcomes, there are many other higher-yield clinical interventions to prioritize above hydrocortisone. The critically ill are complex, and there are many aspects to high-quality intensive clinical and nursing care that have a greater impact on ultimate outcomes. To spend much time engaged in debate regarding hydrocortisone should be done only to the extent it does not distract and detract from other, more important aspects of their care.

“Adjunctive Glucocorticoid Therapy in Patients with Septic Shock”

http://www.nejm.org/doi/full/10.1056/NEJMoa1705835

Angiotensin II for Refractory Shock

If you blockade the angiotensin receptor system, you have a treatment for hypertension. If you agonize that same system, it logically follows you may have a corresponding treatment for hypotension. So, this is ATHOS-3, a phase 3 trial of synthetic human angiotensin II infusion in patients with catecholamine-resistant shock.

Roughly speaking, this is a trial evaluating the effectiveness of angiotensin for improving hemodynamic parameters in adult patients in vasodilatory shock – defined by the trialists as based on sufficient cardiac index, intravascular volume measurements, and persistent hypotension. Enrolled patients also needed to display ongoing hemodynamic derangement despite “high-dose vasopressors”. Exclusion criteria abound. The primary outcome was achievement of mean arterial pressure targets at 3 hours after initiation of angiotensin or placebo infusion.

Over the ~1.5 year study period, 404 patients were screened to ultimately initiate study protocol in 321. There’s little ambiguity with respect to the primary outcome – 69.9% of patients met MAP targets in the angiotensin cohort compared with 23.4% with placebo. Improvement in MAP led to corresponding downtitration of catchecholamine vasopressors in the intervention cohort. The intervention cohort displayed improvements in the cardiovascular SOFA, but no difference in overall SOFA at 48 hours. Mortality was quite high, regardless of group assignment, and no reliable difference was noted. Adverse events were common in each group with, again, no reliable differences detected.

This trial is mostly just interesting from a scientific awareness standpoint. The beneficial or harmful effects of angiotensin infusion are not established by these data. The enrolled population – approximately one patient every four months per site, on average – cannot be reliably generalized. As with any sponsored trial replete with conflict of interest among the authors – and particularly those with slow enrollment due to extensive exclusions – skepticism is particularly warranted. That said, this novel vasopressor clearly warrants additional study and comparative effectiveness evaluation.

“Angiotensin II for the Treatment of Vasodilatory Shock”
http://www.nejm.org/doi/full/10.1056/NEJMoa1704154

Early Goal-Directed Waste For Sepsis

First there was ProCESS.  Then there was ARISE.  Now there is ProMISe.

If the prior two trials hadn’t already been celebrated and dissected, there would be much more to write regarding this one.  This, like the others, randomized patients to Early Goal-Directed Therapy for severe sepsis versus “usual care”.  This, like the others, found the basic components of resuscitation – intravenous fluids and early antibiotics – are far more important than the specific targets and protocols enshrined by Rivers et al.

These authors screened 6,192 patients to randomize 1,260.  Half had refractory hypotension, and the mean lactate levels were 7.0 and 6.8 in the EGDT and usual care arms.  Patients were enrolled within 6 hours of presentation and randomized within 2 hours of meeting inclusion criteria, with the EGDT arm receiving catheter insertion capable of SCVO2 monitoring within ~1 hour.   EGDT protocol was adhered to for 6 hours following enrollment.

As expected, randomization produced some divergence in treatment due to the EGDT protocol.  The EGDT cohort received more frequent red cell transfusions during both the protocolized period and subsequent care.  Likewise, dobutamine use in the EGDT arm exceeded usual care.  However, some differences occurred outside of the protocol.  EGDT arm patients were more likely to be admitted to an ICU setting, more likely to receive any sort of central line, more likely to receive invasive blood pressure monitoring, and more likely to be placed on vasopressors.  The remaining treatment – crystalloid resuscitation, colloid resuscitation, and other transfusions were similar.

And, finally, 90-day mortality was similar: 29.5% EGDT vs. 29.2% usual care.

A financial analysis found EGDT was more costly, but the result did not reach statistical significance.  However, the cost analysis was performed using different financial models that may not be generalizable to the billing structure in the United States.  The difference in ICU admission and length-of-stay alone certainly has important ramification both from a cost and a resource utilization standpoint.

So, finally, we have the publication of the last of the triumvirate of EGDT trials.  If there were any lingering doubts (hopes?) regarding the necessity of the most resource-intensive interventions, they ought to be laid to rest.  However, as with each of these negative trials, it is important to acknowledge the role of Rivers’ work in aggressively seeking, recognizing, and treating severe sepsis.  Even as we discard the components of his protocol, the main thrust of his work has saved many, many lives.

“Trial of Early, Goal-Directed Resuscitation for Septic Shock”
http://www.nejm.org/doi/full/10.1056/NEJMoa1500896

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

What Santa Claus, the Tooth Fairy and Low-Dose Dopamine Have in Common

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

We have known for some time that the renal sparring effects of low-dose dopamine is a story we tell to our cardiologists to tuck them in at night. Despite a large meta-analysis published in 2005, finding no evidence of this theoretical renal benefit, the authors of the recent Renal Optimization Strategies Evaluation (ROSE) felt that this question was again worth investigating. Nesiritide, a drug made infamous for causing renal failure, was also examined for its renal sparing attributes.

A total of 360 patients with acute heart failure and renal dysfunction (GFR between 15-60 mL/min) were, in a convoluted fashion (to reduce unnecessary use of central lines), randomized to either low-dose dopamine (2mcg/kg/min), low dose nesiritide (0.005 mcg/kg/min) or placebo infusion for a 72-hour period. The two co-primary end points assessed were urine output and change in cystatin C level over a 72-hour period. There was no benefit of either low dose dopamine or low dose nesiritide when added to standard therapy of acute heart failure in any of the authors’ primary, secondary or tertiary (yes tertiary) endpoints. Though there was no statistical increase in adverse events seen in either the dopamine or nesiritide groups, this is far too small a cohort to truly assess safety.
With the publication of this trial surely it has come time to close the book on low dose dopamine. So next time a consultant requests we start a dopamine infusion for its renal sparring properties, may I suggest we sit him or her down and politely explain that like Santa Claus and the Tooth Fairy, there is no such thing as renal dose dopamine.
“Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction” http://www.ncbi.nlm.nih.gov/pubmed/24247300

What Santa Claus, the Tooth Fairy and Low-Dose Dopamine Have in Common

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

We have known for some time that the renal sparring effects of low-dose dopamine is a story we tell to our cardiologists to tuck them in at night. Despite a large meta-analysis published in 2005, finding no evidence of this theoretical renal benefit, the authors of the recent Renal Optimization Strategies Evaluation (ROSE) felt that this question was again worth investigating. Nesiritide, a drug made infamous for causing renal failure, was also examined for its renal sparing attributes.

A total of 360 patients with acute heart failure and renal dysfunction (GFR between 15-60 mL/min) were, in a convoluted fashion (to reduce unnecessary use of central lines), randomized to either low-dose dopamine (2mcg/kg/min), low dose nesiritide (0.005 mcg/kg/min) or placebo infusion for a 72-hour period. The two co-primary end points assessed were urine output and change in cystatin C level over a 72-hour period. There was no benefit of either low dose dopamine or low dose nesiritide when added to standard therapy of acute heart failure in any of the authors’ primary, secondary or tertiary (yes tertiary) endpoints. Though there was no statistical increase in adverse events seen in either the dopamine or nesiritide groups, this is far too small a cohort to truly assess safety.
With the publication of this trial surely it has come time to close the book on low dose dopamine. So next time a consultant requests we start a dopamine infusion for its renal sparring properties, may I suggest we sit him or her down and politely explain that like Santa Claus and the Tooth Fairy, there is no such thing as renal dose dopamine.
“Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction” http://www.ncbi.nlm.nih.gov/pubmed/24247300

Another Call to Retire Dopamine

The slow, gradual shift from dopamine to norepinephrine as the vasopressor of choice in septic shock has another piece of ammunition – this time a meta-analysis of the observational and randomized trials.

They perform two separate analyses – an analysis of five observational trials and an analysis of six randomized trials.  They find heterogeneity and no difference in the observational analysis – and then drop the observational trial responsible for the heterogeneity, and find an RR for mortality of 1.23 favoring norepinephrine.  Then, with the randomized trials, they find an RR for mortality of 1.10 favoring norepinephrine.  The RR for arrhythmias associated with dopamine use was 2.34 in their pooled analysis.

Of the RCTs, most of the patients came from one trial with 1044 patients and includes four trials with fewer than 50, so it’s not exactly as though this analysis adds a lot of statistical power – but it’s enough to reinforce the trends from each trial.

It is reasonable to suggest that norepinephrine is superior to dopamine – but I would also suggest the magnitude of that difference, given the data we have so far, has only been shown to be small.

“Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis”
http://www.ncbi.nlm.nih.gov/pubmed/22036860

Adrenal Insufficiency in Pediatric Shock

This falls into the “don’t use etomidate” pile of literature.  Well-demonstrated, primarily in the pediatric literature, that etomidate and its association with adrenal insufficiency results in poorer outcomes in shock.  This article doesn’t look at etomidate, but rather it describes relative or absolute adrenal insufficiency in pediatric shock, and finds it relatively pervasive.  It then finds an association between their two definitions of adrenal insufficiency and length of stay, length of ventilator days, and required doses of vasopressors.  They only 5% mortality in their study, so they can’t comment on any mortality association.

So, this is another study that helps describe why etomidate may be contributing to poorer outcomes.  The days of ketamine + rocuronium RSI are coming (we’ll save the succinylcholine vs rocuronium debate for another day).

http://www.ncbi.nlm.nih.gov/pubmed/21336126

Norepinephrine is Superior to Dopamine

Last day of Journal Club for April.

It is very interesting how generational medical practice is – currently training physicians are accustomed to using norepinephrine for virtually everything as the vasopressor of choice (except, well, when there’s a medication shortage like this past month), while previous generations have a comfort zone with dopamine.

This is a very nice study in a lot of ways and it does a good job if illustrating that dopamine and norepinephrine have very small but relevant clinical effects.  Some of their inclusion criteria are a little odd – hypoperfusion/decreased CVP after only 1000mL of crystalloid or 500mL of colloid?  And 246 of their patients suffered from hypovolemia due to acute hemorrhage – so you can really question why anyone was reaching for a pressor instead of a Cordis or the OR – and, there are a few other instances with small numbers where neither dopamine or norepinephrine is your vasopressor of choice (e.g., anaphylactoid shock, spinal shock).

But, they had good randomization and their treatment groups are very similar.  And what did they find?  No difference.

Well, not completely true – no difference in ICU mortality with a p = 0.07 in favor of norepinephrine and no difference in in-hospital mortality with a p = 0.24 favoring norepinephrine.  So, norepinephrine is favored, but statistically the results are not bulletproof.  I think the trends are reasonable, but it’s certainly worth keeping an open mind.  Alternatively, if you wanted to never use dopamine again, you can definitely argue that norepinephrine is no worse.

Secondary outcomes generally trend in favor for norepinephrine with a few reaching significance – although, when you look at 20 secondary outcomes, you’re bound to find some significant differences.  The most important difference is the incidence or arrhythmias, primarily atrial fibrillation, which occurred in 24% of the dopamine group and 12.4% of the norepinephrine group at a p = <0.001.

It’s an important paper to have around to be on the same page as the critical care colleagues.

http://www.ncbi.nlm.nih.gov/pubmed/20200382