The European Society of Intensive Care Medicine (ESICM) is conducting its international conference this week. This conference has traditionally been a hotbed for breaking results from clinical trials. In this post, I would like to briefly highlight four clinical trials whose results were presented during the President’s Session of Clinical Trials in Intensive Care yesterday. Specifically, this post will briefly summarize the HYPRESS trial (Hydrocortisone for Prevention of Septic Shock), the DESIRE trial (Dexmedetomidine for ventilated septic patients in ICU), NAVA versus Pressure Support Ventilation, and the MACMAN trial (McGrath VL versus Macintosh DL for orotracheal intubation in intensive care patients).
For those of you who have been following the blog, you might remember that I recently detailed some new studies investigating early mobility in critically ill patients (See blog post here: Is Early Mobility in the ICU at a Standstill?). This week, another new study was published, this one in The Lancet (Schaller SJ, et al. Lancet. 2016;388(10052):1377-1388). This randomized study found benefit from early mobilization in critically ill surgical patients enrolled from 5 international ICUs (3 in US, 1 in Austria, 1 in Germany). I’d like to use this opportunity to discuss the methodology and results of this study and my current thoughts on early mobility in critically ill patients. Continue reading “Update on Early Mobility: New Data. New Thoughts?”
Fight fire with fire. What does this mean? Some of you may think this is a song by Metallica (others may think it is a song by Kansas). While that is true, I am not referencing Metallica when I use it in the title for this blog post. Instead, I am referencing the definition which suggests you treat something with its likeness, or respond to something with more of that same thing. You treat aggressiveness with more aggression. In ecological terms, it might be viewed as a controlled burn – using fire to burn out areas in a controlled manner ahead of a forest fire to halt its progression.
The use of probiotics is a bit akin to this. The definition of probiotics is “living organisms that have a beneficial effect in the prevention and treatment of disease.” The purpose of probiotics is to replenish (or maintain) the natural flora of the human body, especially the gastrointestinal tract. Research has demonstrated that a significant portion of illness comes from bacteria in the intestinal tract – more than just Clostridium dificile infections, although they clearly result in disease in the intestinal tract. Bacterial translocation across the GI tract and into the bloodstream has been implicated in numerous conditions, especially in critical illness.
Modern CPR began a little over a half century ago when clinicians started performing chest compressions in patients who had in-hospital cardiac arrest. It improved survival from none to slightly more than none. Since that time, continued research in cardiopulmonary resuscitation has resulted in ACLS courses, mainstream use of defibrillators, and most importantly, slowly, but steadily improving survival rates. Unfortunately, brain injury begins within minutes of cardiac arrest, and survival with good neurological recovery remains unacceptably low. Many who survive are alive but with devastating neurological dysfunction. Continue reading “Forecast for Targeted Temperature Management: Partly Cloudy and a Bit Warmer”
It is uncommon in medicine to encounter an intervention that historically was thought of as unsafe, then some evidence suggests potential benefit, and finally the best evidence swings us back to harm. Enter the story of intensive blood pressure lowering for intracerebral hemorrhage (ICH).
We know that our critically ill patients get debilitated and weak and that it happens within days in critical illness. Because of this, we try to provide some form of physical therapy to these patients, although the ordering and administration of this physical therapy is inconsistent at best. Providing physical therapy makes sense. If patients are getting debilitated because they are lying in bed for prolonged periods of time, helping them at least move and use their muscles, and even potentially sitting up or walking may preserve some of their strength and/or attenuate some of the weakness. Furthermore, upright positioning is good for pulmonary function, increasing both tidal volume and pulmonary clearance of secretions. Unfortunately, providing physical therapy to our ICU patients is hard. Sometimes the ICU has a dedicated physical therapist. Other times they share a physical therapist with other areas of the hospital and more of the responsibility for physical therapy falls to the bedside nurse. A few institutions place a higher importance on physical therapy, and actually have mobility protocols in their ICUs, which facilitate at least sitting critically ill patients at the edge of the bed or walking them in the hallways (many of whom are mechanically ventilated). This level of physical therapy is very resource intensive, often requiring three or four nurses, a couple of physical therapists, and a respiratory therapist or two. Because of this, most hospitals did not do this for their patients. Continue reading “Is Early Mobility in the ICU at a Standstill?”
“Even though coronary, cerebrovascular, and venous thromboses are the leading killers of adults in ICUs, clinicians often have greater apprehension about bleeding than clotting.” Todd Rice and Art Wheeler wrote this first sentence in a review of coagulopathy in critically ill adults in 2009 (1). I include it to start this post for two reasons: 1. If you did not get to know Art when he was alive, this is a classic Wheeler statement that completely puts a massive critical care topic (coagulopathy) into clear perspective and 2. This is the perfect way to frame the discussion of the PATCH Trial.
The PATCH Trial (Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy: a randomized, open-label, phase 3 trial)(2) beautifully illustrates Todd and Art’s point. Antiplatelet medications, such as aspirin, have provided marked benefit in primary and secondary prevention of the most common cause of death (cardiovascular disease) with 120 more lives saved among every 10,000 patients compared to not taking aspirin; yet, there remains a focus on the 2.6% risk of hemorrhagic stroke with aspirin users compared to 1.2% in non-users (3). Additionally, if you bleed into your head while on an antiplatelet medication, there is an associated increased risk of death than if you bleed into your head and are free of antiplatelet medications. Newer antiplatelets (clopidogrel, dipyridamole) may have an associated risk of intracerebral hemorrhage as high as 4%. We critical care physicians don’t get to see the millions of healthy patients who benefit from primary and secondary prevention with these medications, so it shouldn’t surprise us, as Todd and Art wrote, that apprehension remains about the bleeding risks of these medications manifesting as a constant quest for “reversal strategies” to calm our fears.
The PATCH trial was an unblinded, randomized trial of platelet transfusion to reverse the antiplatelet effects of three potential medications: aspirin, clopidogrel, and dipyridamole. In 60 hospitals in the Netherlands, UK, and France over 6 years (2009-2015), adults presenting to the ED with supratentorial intraparenchymal hemorrhage and who had been taking one or more of the above medications for at least 7 days were included. Patients were randomized to usual care or platelet transfusion within 90 minutes of identifying the bleed on imaging. In patients randomized to platelet transfusion, patients on aspirin got one platelet concentrate versus two platelet concentrates for patients on clopidogrel. The primary outcome was the modified Rankin score at 3 months, a typical neurocritical care outcome as describing life with good or bad functional outcome is accepted as a more patient-centered outcome in brain injury than just dead or alive.
This is basically a trial of patients on aspirin, who presented looking pretty good as far as ICH goes (ICH score of 1), low volume bleeds, and median GCS on presentation of 14 (Table 1). There were some baseline imbalances between groups that may have influenced the results (more aspirin only and intraventricular extension in patients in usual care, higher ICH volume in the platelet group). In almost every analysis they performed including the primary analysis, patients randomized to platelet transfusion caused more death and poor neurologic outcomes at 3 months. Additionally, there were significantly more serious adverse events due to intracerebral hemorrhage in the transfusion group, such as ICH enlargement, edema, herniation, intraventricular extension and hydrocephalus.
Although not mentioned by the authors, there is ample evidence that this was a tough trial to conduct. They took 6 years and used 60 hospitals in 3 countries to enroll 190 patients. To put this in perspective, the original study that validated the ICH score enrolled a similar number of patients with ICH at 1 hospital over 2 years (4). The trial did not collect screening or eligible but not enrolled data, so we have no idea how representative the trial patients are of the general ICH patient population. The data presented suggests that the trial patients are very different (very low ICH severity compared to the historical ICH population, only a total of 5 patients on clopidogrel enrolled) which raises the likely possibility that there isn’t equipoise on this intervention and physicians just didn’t allow patients with more severe ICH or those on clopidogrel to be enrolled in this trial. This doesn’t affect the internal validity of the trial, but the external validity is definitely in question. Further supporting this being a difficult trial to conduct, 19% of the patients randomized should never have been enrolled in the trial as they had at least one exclusion criterion. It was reassuring that the result didn’t change when these patients were excluded from a sensitivity analysis.
In patients on antiplatelet medications (predominantly aspirin) who have a bleeding brain, why would platelet transfusion cause death and worse neurologic outcome? One potential explanation is that platelet transfusion is not harmful and the result is just a function of baseline imbalances between groups. I think this explanation is a stretch as the imbalances went for and against transfusion. The other potential, and more worrisome, explanation brings us back to Todd and Art’s point: maybe the trial transfused platelets to patients with one of the most common causes of death, thrombosis. Hemorrhagic conversion of an ischemic stroke is common in the patient population they enrolled (mean age 74 yrs) and possibly suggested by the 54 patients who had lobar ICH rather than deep ICH.
My conclusion: platelet transfusion to reverse the antiplatelet effects of aspirin in patients with relatively mild ICH cannot be recommended. I’m not saying we now have the definitive evidence to support this statement, just that we have gone from zero evidence for or against this practice to a randomized trial showing harm. I don’t think we can generalize these data to patients on non-aspirin antiplatelet medications. It may be reasonable to argue that we can’t generalize these data to more severe ICH; however if transfusions didn’t help early I’m not sure why they would then help late. Finally, I am still more worried about diseases of thrombosis than I am of bleeding.
- Rice TW, Wheeler AP. Coagulopathy in critically ill patients: part 1: platelet disorders. Chest 2009;136:1622–1630.
- Baharoglu MI, Cordonnier C, Salman RA-S, de Gans K, Koopman MM, Brand A, Majoie CB, Beenen LF, Marquering HA, Vermeulen M, Nederkoorn PJ, de Haan RJ, Roos YB, PATCH Investigators. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet 2016;0:.
- He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA 1998;280:1930–1935.
- Hemphill JC, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891–897.
With the increased understanding of the integral roles of both coagulation and inflammation (and the interaction between the two) in the pathophysiology of sepsis, attention has focused on the potential for anticoagulants as potential treatments for patients with sepsis, especially anticoagulants that also contain anti-inflammatory properties. Recombinant human activated protein C represented one such agent, but after initial promising results, subsequent data appeared less promising and it was removed from the market. Unfractionated heparin also has both anticoagulant and anti-inflammatory properties. Over the last decade, numerous articles have been written, and a few small trials have been conducted, around the potential for heparin to improve outcomes in sepsis. Unfortunately, none of the data have been overly convincing, and heparin (or other anticoagulants) has not been widely utilized specifically for the treatment of sepsis.
Until about five years ago, I never even thought of using therapeutic heparin (not venous thromboembolism prophylactic doses, but actual therapeutic doses) in the patients I was treating for sepsis. In fact, I didn’t even use heparin when my patients with sepsis also had atrial fibrillation, rationalizing that the potential harm from heparin and the risk of bleeding likely outweighed the benefit of systemic anticoagulation for a few days to a week. However, about five years ago, Walkey and colleagues published a fascinating article on the incidence of stroke and mortality in patients with sepsis and new-onset atrial fibrillation (Walkey AJ, et al. JAMA. 2011;306(20):2248). In this retrospective cohort study of almost 50,000 patients with sepsis induced organ dysfunction, they found that patients with sepsis and new-onset atrial fibrillation, defined as developing during the hospitalization in patients not previously known to have a history of atrial fibrillation, was associated with a 2.7 fold increased risk of having a stroke during that hospitalization and significantly higher in-hospital mortality. Interestingly, patients who developed sepsis with a history of chronic atrial fibrillation had similar risks of in-hospital stroke and death as those with sepsis but without atrial fibrillation. Given that this was a retrospective cohort study, the only relationship that can be drawn is an association – not evidence for new-onset atrial fibrillation causing these worse outcomes. Despite that limitation, and the possibility that these results were confounded by some of the “new onset atrial fibrillation cases being misclassified paroxysmal atrial fibrillation (which is known to have worse outcomes), the association still piqued my interest and made me wonder whether treating my septic patients with new-onset atrial fibrillation with anticoagulation (and specifically unfractionated heparin) would improve their outcomes.
This was followed last year by another cohort study that demonstrated a 37% incidence of venous thromboembolic (VTE) disease in critically ill patients with sepsis, despite those patients receiving appropriate VTE chemoprophylaxis (Kaplan D, et al. Chest. 2015;148(5):1224). And similar to the Walkey study, development of VTE was associated with worse outcomes, specifically longer lengths of stay and numerically higher mortality.
In addition, about the same time, the Canadians published a meta-analysis in Critical Care Medicine evaluating the safety and efficacy of heparin in sepsis (Zarychanski R, et al. Crit Care Med. 2015;43(3):511). While it has a number of limitations, including the fact that the dosages of heparin vary widely amongst the included studies, and that many of the included studies investigate heparin in addition to other anticoagulants, overall they found a small benefit in hospital mortality when heparin is used in patients with sepsis (RR = 0.88) with no statistically significantly increased risk of major hemorrhagic events.
Taking these three articles together, I really started wondering if I should be providing systemic anticoagulation to my critically ill patients with sepsis. Knowing that these data by no means demonstrated the cause and effect of improved outcomes, I still somewhat changed my practice – instead of not even considering it, I adopted a low threshold for starting systemic anticoagulation in my critically ill patients with sepsis, especially if they had another indication (no matter how soft the indication) like new-onset atrial fibrillation.
Well, as often happens in medicine, and especially critical care medicine, new data are available and the pendulum appears to be swinging back. This month, in JAMA Cardiology, Walkey and colleagues have published another retrospective cohort study, this one an analysis of outcomes of patients with atrial fibrillation and sepsis receiving anticoagulation (Walkey AJ, et al. JAMA Cardiol. Epub ahead of print August 3, 2016). This represents a logical follow-up to their previous study, which begged the question that if new-onset atrial fibrillation was associated with more in-hospital strokes and mortality in patients with sepsis, could we improve those outcomes with systemic anticoagulation in these patients. In this study, Walkey and colleagues investigate the use of heparin in about 40,000 patients with sepsis and atrial fibrillation. It turns out that a little more than a third of these patients received systemic anticoagulation. Now, one of the problems with retrospective cohort analyses of treatments is a specific type of bias termed indication bias. What this means is that since the choice to treat with anticoagulation is at the discretion of the treating clinician, patients who the clinician decides to anticoagulate are undoubtedly different than those in whom the decision is made to withhold anticoagulation. For example, patients with atrial fibrillation and sepsis and past history of transient ischemic attacks (TIAs) or a concurrent non-ST elevation myocardial infarction (NSTEMI) may be more likely to receive anticoagulation in their treatment course, as opposed to the patient who also has atrial fibrillation and sepsis but is actively bleeding. That patient is almost assuredly not going to receive systemic anticoagulation. This results in comparing two different populations of patients (i.e. those likely versus those unlikely to receive anticoagulation), who may have different outcomes based on differences in characteristics and not related to differences in treatment. One way of trying to deal with this indication bias (or “apples to oranges” comparison), is to adjust your analyses using a propensity score, which is what was done in this study. In order to adjust for differences in the populations, you calculate a propensity score for receiving the treatment of interest (anticoagulation in this case) and then you use this propensity score to adjust or match for the likelihood of receiving anticoagulation based on population factors.
So what did Walkey and colleagues find? As in their previous study, patients with sepsis and new-onset atrial fibrillation again had a higher rate of in-hospital ischemic stroke compared to patients with sepsis and pre-existing atrial fibrillation (nice consistency of results across studies). However, in both unadjusted and among propensity-score matched patients, the rates of in-hospital stroke did not differ between those who did and those who did not receive systemic anticoagulation (1.3% vs. 1.4%; RR 0.94). This was true for both patients with pre-existing (RR 1.12) and those with new-onset atrial fibrillation (RR 0.85). So, these data do not support anticoagulating patients with sepsis and atrial fibrillation in an effort to reduce their incidence of ischemic stroke. Furthermore, Walkey and colleagues found that clinically significant bleeding occurred more frequently in patients with sepsis and atrial fibrillation receiving parenteral anticoagulation (8.6% vs. 7.2%; RR 1.21). So they didn’t find a signal that providing anticoagulation improved outcomes but did find a signal of increased harm.
So, how will I incorporate these new (or cumulative) data into my clinical practice? Well, I think these data throw real caution to the wind around the practice of anticoagulating patients with sepsis and new-onset atrial fibrillation, especially if the intent is to prevent ischemic stroke. It seems that anticoagulation may not improve that outcome, and is likely associated with potential harm in the form of an increased risk of clinically relevant bleeding. While I still find intrigue in the potential of treating sepsis with an agent that has both anticoagulant and anti-inflammatory properties, it remains unclear to me if heparin, or other available anticoagulants, improve the outcome in patients with sepsis in general. Well designed and conducted, large, multicenter randomized trials need to be done evaluating the effect of systemic anticoagulation (starting with heparin) in patients with sepsis (with or without atrial fibrillation). Given all the data now available, I am back to not providing systemic anticoagulation to my patients with sepsis unless they have a pretty hard indication for anticoagulation (i.e. known clot, documented myocardial infarction, lupus anticoagulant, mechanical heart valve, etc).
This is a real case recently experienced in our ICU and I wanted to share it so others could also learn from it.
75 y.o. male with past medical history of atrial fibrillation (on apixaban), hypertension, obstructive sleep apnea, and gallstone pancreatitis treated with percutaneous cholecystostomy tube followed by biliary stents for stone removal presents with hematemesis and fall in his Hgb from 13 g/dL to 5 g/dL. He is tachycardic with HR 130’s and slightly hypotensive with BP 90/45 mmHg. He is given IV omeprazole, 2L of IV crystalloids and 2 units of matched PRBCs. He is admitted to the MICU for further treatment and evaluation. Despite aggressive resuscitation and administration of 4-factor prothrombin complex concentrate in an attempt to reverse his apixiban, he continues to pass melena and some hematochezia and have a marginal blood pressure. Although he is adamant about being DNR/DNI, he agrees to intubation for his EGD to evaluate his hematemesis. He states that being intubated for the procedure is fine but that he wants to be extubated after the procedure.
He is intubated at 08:30 in the morning using 20 mg of etomidate and 100 mg of rocuronium, without difficulty. Propofol infusion is used for sedation throughout the EGD, which is completed by 10:00 AM, also without difficulty. EGD found a bleeding duodenal ulcer with a visible vessel in the base which was injected with epinephrine and clipped. The patient tolerated the procedure well, and by 12:30 PM was awake and interactive. He was placed on a spontaneous breathing trial using pressure support ventilation with 5 cm H2O PEEP and 5 cm H2O pressure support. Having tolerated 60 minutes of these settings, he was extubated.
Within 5 minutes of extubation, the respiratory therapist, in a panic, grabbed us and asked us to go see the patient. Upon arrival, he clearly had respiratory distress – he was hypoxic on venti mask oxygen and had shallow breathing at a rate of 50 breaths per minute. The patient was awake and through a weak voice, asked his daughter if she could turn his head toward the other side of the bed (where we were standing) so he could see us. She turned his head. We asked him to squeeze our hands but he was unable. He also was not able to lift his head off the bed, raise his arms, or wiggle his toes. We told him that we needed to reintubate him to help him breathe but he refused, reiterating that he was only agreeable to be intubated for the procedure and would rather die than be intubated again. We placed him on non invasive ventilation (NIV), but he did not tolerate it very well.
What is his diagnosis? And what can we do to help him? Continue reading “Neuromuscular Weakness from an EGD?”
A randomized, double-blind, placebo-controlled trial in patients with out-of-hospital cardiac arrest provides some new data toward answering the headline question. However, before we get into the details of the trial, let me first start with a shout out to the Institutional Review Boards who approved this study. This was not a simple study – randomized, double-blinded, placebo-controlled trial in out of hospital cardiac arrest patients? Even though the trial was conducted under the FDA regulation of Exception from Informed Consent (EFIC), I suspect a vast majority of IRBs/ethics boards would not approve this study. How could you approve a study that tested placebo (Normal Saline in this case) in one arm in a condition (cardiac arrest) where there are all kinds of treatment protocols? ACLS calls for a strict algorithm to be followed for cardiac arrest – and placebo (or Normal Saline) is not part of it. In addition, the fact that the study was conducted under EFIC means that patients were enrolled in the study without their explicit a priori approval (consent would be attempted to be obtained after participation in the study). It took a trustworthy group of IRBs, an exceptional research team, and an indepth understanding of the significant limitations of the data that the current ACLS guidelines are based on in order for ethics boards to approve this study, even under EFIC. And a huge KUDOS to them for seeing that this was an important study which would provide extremely important data that could not be obtained easily via other study designs.
The study I am talking about was published in the New England Journal of Medicine online on April 4, 2016 and in print in the May 5, 2016 issue (http://www.nejm.org/doi/full/10.1056/NEJMoa1514204). The study is a randomized, double-blinded trial comparing parenteral amiodarone vs lidocaine vs saline placebo in over 3000 patients with out of hospital cardiac arrest. Despite its complexity, this study was exceptionally well conducted. Continue reading “Should We Continue to Use Amiodarone and/or Lidocaine in Cardiac Arrest?”