ICU Rounds Report - Jan 25th 2010

ICU and Fish Oils - More than standard hype from Reader's Digest?

UPDATE 1/25/11 - The omega piece of the EDEN-Omega trial was stopped for futility. While we're still awaiting publication, it appears omega 3 are standard reader's digest hype...

Lot and lots (and lots!) of studies have been done looking at various nutritional supplements for feeding critically ill patients. Usually based on good ideas and exciting pre-clinical data, almost universally, they have disappointed. On possible except: omega-3 fatty acids in ARDS. In little mice and rabbits given ARDS, omega-3 fatty acids have antiinflammatory and vasodilatory properties that improve gas exchange, heal pathological microvascular damage and improve hemodynamics. The first humanRCT was done in 1999 on patients with severe ARDS using Opexa (a proprietary blend of omega-3s and antioxidants) versus 'standard' feeds. It looked great: better oxygenation, less time on the ventilator (11 vs. 16.3 days; p = .011), less time in the ICU  (12.8 vs. 17.5 days; p = .016) and less new organ failure (p = .015). Unfortunately, in point of fact, that trial used a non-standard formula as a control that was unusually high in potentially toxic omega-6 fatty acids, which made the results questionable and was widely dismissed.

But then two subsequent (sponsored by industry!) RCTs using proper standard feeds as controls were also positive. The results were the same, or better - better oxygenation, less ventilator time, lower length of stay and, in the more robust trial (i.e. double blinded) patients feed the Opexa have a 20% reduction in mortality (p = .037). Two larger, independent studies (i.e. the thousand patient EDEN-Omega Study) have recently been completed with publication expected this year that will hopefully settle this question, but for now I believe the preponderance of evidence argues for using Opexa in patients with ARDS.

Gadek JE,et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group.
Crit Care Med. 1999;27(8):1409-20.
Singer P, Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med. 2006;34(4):1033-8.
Pontes-Arruda A, Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med.
2006;34(9):2325-33

ICU Rounds Report - Jan 21st 2011

Subclavians, PICCs and need for Dialysis. We're often told by renal to stay the hell away from subclavian and PICC lines in patients with a current, potential or future need for hemodialysis. Why? What truly is the rate of subclavian stenosis (SCS) after subclavian lines? PICCs? What impact does SCS have on long-term AV fistula patency?  

The access goal for hemodialysis patients is always an AV fistula or graft. Among the choices, they have by far fewer complications, lower cost and significantly lower mortality rates. We know SCS rates after placement of large-diameter subclavian dialysis lines can be quite high - up to 50%, which is why you never see renal do it. Stenosis in subclavian lines is so detrimental to long term function (problems include lympaedema, graft thombosis, failure), that surgeons screen for it routinely prior to placement of AV fistulas/grafts. In one series looking for SCS in patients presenting for fistula creation, screening found occult moderate to severe stenosis in 40% of patients - in every case thought due to prior lines.

The data for the smaller catheters we commonly use are less clear, as no study has screened for SCS specifially. One meta-analysis looking at some very heterogenous papers found no difference in symptomatic stenosis rates between IJ and SC sites, although no screening was done. Remember, total subclavian stenosis is frequently asymptomatic.  So what do we know about PICC lines? Radiologists at Thomas Jefferson in Philly followed 150 patients pre and post PICC placement with venography studies and found rates of SCS from PICCs of around 7%, with a mean followup of 20 months (range 3 days - 54 months). Longer indwelling times, left side, line infections, thrombus development and malpositioned lines are all risk factors for development of SCS.

So does it matter? Yes. Graft development and maintenance in ESRD patients is a huge problem. Among patients who develop AV fistula or graft dysfunction, 25% are found to have SCS, almost universally due to prior central venous access passing through the subclavian vein. By contrast, rates of stenosis found with screening following IJ cannulation for HD lines are much lower - 0-10%.
Cimochowski GE, Worley E, Rutherford WE, et al. Superiority of the intemal jugular over the subclavian access for temporary dialysis. Nephron 1990;54: 154-160
Ruesch, SM. Complications of central venous catheters: Internal jugular versus subclavian access-A systematic review Crit Care Med 2002(30)2:454-460

Gonsalves CF, Eschelman DJ, Sullivan KL, DuBois N, Bonn J: Incidence of central vein stenosis and occlusion following upper extremity PICC and port placement. Cardiovasc Intervent Radiol 26:123–127, 2003

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ICU Rounds Report - Jan19th, 2011

Residents - workers or students? This question, which has been debated at least since the 1930's has tremendous implications from taxation to union organizing. Hospitals have claimed from the beginning that residents work primarily in an education role and therefore are not allowed to unionize, form collective bargaining agreements and are exempt from payroll taxes. Content to let the hospitals and CMS deal with this issue, the government agreed with this approach until 1990's when Social Security Administration realized it's missing out on up to 700 million dollars a years in unpaid FICA taxes. Then the court battles started.

Last week, in a unanimous decision in Mayo vs The United States, our highest court strongly rejected the argument put forward by the Mayo clinic that "the academic program of a medical resident is virtually indistinguishable from that of a third- or fourth-year medical student." Whether Mayo's attorneys were able to deliver this argument with a straight face is not known, as cameras are not allowed in the supreme court. The court instead held that residents "are clearly indispensable to the care provided at the hospitals where they are employed." They pointed to multiple instances where hospitals bemoaned the severe financial constraints created by ACGME work hours as an example. Despite hospitals rudely insisting that residents don't do any real work, Mayo's loss is a financial blow to residents straddled with six figure medical school debts.  Classification as students could have saved residents $4,000 dollars a year by avoiding FICA taxes.
Kesselheim AS. Residents: Workers or Students in the Eyes of the Law? NEJM epub Jan 12, 2011. 10.1056/NEJMp1100414

ICU Rounds Report - Jan 11, 2011

The end of therapeutic rat poisoning is coming. Coumadin is great for preventing strokes in atrial fibrillation - it reduces overall stroke risk by 70% and clearly improves overall mortality. Yet, it's vastly underutilized (in one study only half of appropriate candidates got it) and it's notoriously difficult to dose. It has a very narrow therapeutic index, requires frequent monitoring and interacts unpredictably with drugs and diet. After decades of trying, big pharma appears to have finally come through with a safer oral substitute. And it will be big. FDA approved less then 3 months ago, it is widely expected to become a first-line recommendation by the ACC/AHA for the prevention of stroke in Afib sometime this year. The relevant European and Canadian heart societies have already made such recommendations.

Dabigatran is direct acting thrombin inhibitor (similar in action to argatroban or bivalirudin) that can be taken by mouth, twice daily. In the gigantic, industry-sponsored, 18,000 patient RE-LY trial, coumadin and dabigatran (at two doses) went head to head. Higher dose dabigatran was more effective at preventing embolic strokes, caused less hemorrhagic strokes and reduced overall mortality. Major bleed rates were equal for both drugs. Main side effects were dyspepsia and more heart attacks (but not enough to affect mortality). Perhaps best of all: it requires no blood monitoring and the dose is largely fixed.

Downside: It's crazy expensive. On the other hand, with frequent lab draws so is coumadin. In one cost analysis considering the indirect cost associated with coumadin (lab draws, travel time, lost productivity) it appears dabigatran is a bit cheaper, but that study used Canadian pricing (Americans pay more for drugs because of complicated political agreements that allow drug companies to charge essentially what they want). So cost remains a question. As do the long term effects - all published followup is 2 years or less.

Here's the relevant low down for when we start seeing ICU patients on it: There is no antidote or reversal apart from time.  Recombinant factor 7 appears effective in animal studies and has been described to work with other direct thrombin inhibitors. Prothrombin complex concentrates and FFP may have a role but nothing has been described or studied. Mechanistically no one expects vitamin K, protamine, amicar or desmopressin (and the like) to aid in reversal. It is easily dialysable.

Dabigatran is metabolized in the liver and excreted partially in the urine. It should be held for renal failure and dosages reduced for renal insufficiency. Mild liver impairment shouldn't effect dosing. Half time is 12 hours, which rises to >18 with kidney failure. Although no monitoring is needed, it usually affects the PTT (2.5x normal is considered an overdose). It has no effect on the INR and the thrombin time (TT) is the most sensitive test of its effect. Unlike heparin, it binds and inactivates thrombin already present in clot. For elective surgery, it should be held 24 hours prior for low risk procedures and 2-4 days for high risk.

N.B. It also appears to be as effective as enoxaparin for prevention and treatment of VTE but it is not approved for this use in the States. It's also fine for use (non-inferior) with Afib cardioversions.
Connolly, SJ, Ezekowitz, MD, Yusuf, S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139.
Schwartz NE. Dabigatran challenges warfarin's superiority for stroke prevention in atrial fibrillation. Stroke. 2010 Jun;41(6):1307-9.

Ryn S. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anti-coagulant activity. Thromb Haemost 2010; 103: 1116–1127

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ICU Rounds Report - Dec 16th, 2010

Auto-Anticoagulation of Cirrhosis? Patients with liver failure commonly present with elevated INRs and low platelet counts. Liver dysfunction alters synthesis and production of both the pro- and anti-coagulants produced by the liver. In addition, numerous other effects alter normal coagulation in the cirrhotic patient: low platelets, platelet dysfunction, altered endothelial function (including elevated levels of prothrombotic vWF and tFVIII), elevated levels of nitric oxide, etc. Further confusing things: liver failure can dramatically increase rates of fibrinolysis. What does it all mean?

In other words: Does a liver failure patient with an INR of 2.3 needs DVT prophylaxis?

It depends on who you ask. The recent medical literature suggests that cirrhosis offers little, or no protection.  Now, in the first study of its kind, researchers at the University of Missouri looked at the relationship between pathologic INR elevations and DVT. They retrospectively evaluated 190 hospitalized patients with varying degrees of chronic liver disease and found rates of DVT of 6.3% overall (by comparison, rates of DVT in high risk surgical inpatients without prophylaxis is between 4 - 8%).  Interestingly, higher elevations in INR were associated with greater DVT risk. Lastly, the study found that receiving DVT prophylaxis didn't protect against DVT, although the study was underpowered to detect a statistical difference and only 25% of liver failure patients received some kind of prophylaxis. Sadly, there is no data available for surgical patients.

What everyone can agree on is that current panel of test used to diagnosis coagulation abnormalities in liver failure (plt count, PT, aPTT) are worthless because the balance of pro/anticoagulant factors is not considered by these tests (which tend to measure simple deficiencies of anticoagulants). Abnormal hemostatic tests have never been shown to correlate to bleeding tendencies in liver failure. Further, it is clear from liver transplantation surgery that preemptive "correction" of the abnormal values does not reduce, and probably promotes, bleeding. With this shift in thinking, many centers are now reporting the ability to keep liver transplantation "bloodless" (no transfusions needed) greater than half the time. To accurately diagnosis whether a liver failure patient is pro- anti- or euthrombotic requires much more sensitive testing, such as TEG,  which is not widely available.

So we're left where we started, which is were every good paper ends: more research is needed! Do liver patients needs SCDs/heparin? Anyone's guess. How can we even measure coagulation in liver failure? Not really possible. Does prophylaxis even work in the setting of liver failure? No one has a clue. Is working in an ICU awesome anyway? Yes, very! 
Dabbagh, O, et al. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest 2010; 137:1145.
Lisman, T, Porte, RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116:878.
Gulley D et Al.  Deep vein thrombosis and pulmonary embolism in cirrhosis patients. Dig Dis Sci . 2008; 53( 11): 3012- 3017.
Northup PG, et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol 2006 ;101(7):1524-1528.

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ICU Rounds Report - Dec 9th, 2010

Creatinine, an oldie but a goodie? Creatinine is a breakdown product of creatine kinase in skeletal muscle. First found in blood in 1896, it was noticed that levels go way up with chronic kidney disease in the 1910's. We've been fixated on it every since as the biomarker for kidney function. It's been routinely measured on hospital inpatients for at least 60 years.  It's worth reviewing it strengths and weaknesses.

In the strength column, we can place that we have lots of experience with it. It's widely available, cheap to measure and tracks chronic disease quite nicely. Downsides? First, I've never liked saying it. It's a funny word. Second, the production of creatinine is highly variable, dependent on multiple factors including age, sex, race, muscle mass, nutritional state and others. Second, up to 40% of urinary creatinine is secreted by the tubules not filtered. In other words, it will never directly correlate with GFR as well as something that is not secreted at all, such as cysatinC (CysC). This leads to delays in the diagnosis of acute drops in GFR. Which brings us to the third major problem: It's slow. When the kidney filtering slows or stops, it takes days the serum creatinine to rise because basal production rates are so slow. Currently, we have to wait 2 days to learn the kidneys have been injured, beyond the time when interventions are thought to possibly improve outcomes. Its like trying to diagnosis an acute MI without troponins and just waiting to see how it will all settle out.

These limitations have lead to the intense development of serum and urinary biomarkers that better reflect GFR, give real time information about kidney injury and will, in all likelihood, make our old friend creatinine obsolete for ICU use with in 10 years . We've got several great candidates which work quicker, correlate better with disease severity and give more prognostic information coming down the pipeline, some of which are already being used in POC testing around the world (NGAL, KIM-1, L-FAB).
Rabinowitch IM. The prognostic value of the study of the blood creatinine in nephritis: based upon the study of fourteen cases with complete postmortem examination. Can Med Assoc J 1921; 11:320–322.
Moore, E, et al. Novel biomarkers of acute kidney injury: ready for clinical application? Current Opinion in Critical Care. Dec 2010 16(6): 523–525


Ultrasound for ICP. Occasionally, (meningitis, trauma, liver failure, strokes) we wonder what the pressure inside the head is. CTs of course, let us peek inside but only allow inferences. Sometimes, we wonder so much about ICP that we have the brain surgeons put an invasive monitor thru the skull. That's nice because it can also be therapeutic (in the case of EVDs). But is there a quicker way? Yes! Does it work? Maybe!

In 2010, when someone asks the question, 'is there a quicker way' the correct answer is either Epic or Ultrasound. Ultrasound? Sure. Recall that the optic nerve is sheathed within the dura. It appears that elevated pressures allow CSF buildup in this semi-compliant sheath and widen the diameter. (That's also the basis for blathering on about papilloedema). Multiple studies have measured the diameter of the optic sheath with ultrasound (at a standardized location, 3mm past the globe) and found a nice concordance with ICP. On study found a diameter greater than 5 (normal=3mm) was strongly predictive of an of ICP >20 mm Hg (sensitivity and specificity 94% and 76%, respectively).

Further work with MRI looking at the optic nerve sheath has shown that it is even more sensitive. With MRI, a cut-off value of 5.30 mm yields a sensitivity of 100% for diagnosis an ICP greater than 20.
Soldatos T. Optic nerve sonography: a new window for the non-invasive evaluation of intracranial pressure in brain injury. Emerg Med J  2009;26:630-634
Geeraerts T, et al. Use of T2-weighted magnetic resonance imaging of the optic nerve sheath to detect raised intracranial pressure. Crit Care 2008;12(5):R114. Epub 2008 Sep 11.

ICU Rounds Report - Dec 7th, 2010

It's so cold out there! Survival after out of hospital cardiac arrest with a good outcome is a rare event. Despite advances across other fronts in medicine, survival with an intact brain hadn't improved much in the last 50 years until someone tried post-arrest cooling. Previously, post-resuscitation efforts have been entirely supportive. Now, for comatose patients after vfib arrest, cooling the body to 34 degrees for 24 hours can nearly double the chance of recovery. Currently at UVa, we're cooling 3-4 patients a month (last month we did 7!).

But how do we cool patients? Everything has been tried. From ice bags, cold saline, irrigating bladder/stomach with cold fluids to cardiopulmonary bypass. All present technical and clinical challenges, not the least of which is that body vigorously defends its tightly regulated core temperature by increasing metabolic rate and shivering, usually requiring paralysis. Surface cooling is cumbersome and ineffective. Intravascular cooling (which we use) is expensive and risky. What if there was another way?

Researchers in toasty warm LA have published a trial using cannabanoid agonists in rats after resuscitation in vfib arrest. The results are very good news if you are a rat in a coma after vfib arrest: the drug appears to safely lower body temperature to ~34 degrees with no other major noted side effects. More importantly, the neurologic and functional outcome was significantly improved relative to controls.  The idea may represent a new therapeutic class for a common and lethal problem for thousands of Americans.

Finally, a quote from recent editorial on the new findings by Samuel Tisherman, "From the campaign 20 yrs ago (showing a frying pan representing marijuana and an egg representing your brain), to current controversies regarding legal medical uses, marijuana has a long history of capturing our interest. Wouldn't it be cool if a derivative actually improves brain function rather than frying it?"
Sun S, Tang W, Song F, et al: Pharmacologically induced hypothermia with cannabinoid receptor agonist WIN55, 212-2 after cardiopulmonary resuscitation. Crit Care Med 2010; 38:2282–2286
Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557–563