ICU Rounds Report - The Trouble with Transfusions

When to give blood continues to perplex. In the past we've blogged about paucity of good, randomized data to help decided transfusion triggers. Now, surgeons have added yet another retrospective study showing potentially big problems with transfusion. Looking at over 10,000 patients in the American College of Surgery National Surgical Quality Program database, the authors found giving one or two units of blood was associated with greater chance of death  (odds ratio [OR], 1.29; 95% CI, 1.03–1.62) or a bad complication: pulmonary (OR, 1.76; 95% CI, 1.48–2.09), septic (OR, 1.43; 95% CI, 1.21–1.68), thromboemoblic (OR, 1.77; 95% CI, 1.32–2.38) or wound (OR, 1.87; 95% CI, 1.47–2.37).

The amount retrospective data in this area seems to grow every month. Unfortunately, there hasn't been a parallel increase in clinically useful data from RTCs. To review, here is a partial list of some big retrospective papers. Again and again, these reviews find transfusion of PRBCs is harmful in most of our common situations. Every trial makes some attempt at controlling for relevant co-morbidities, but controlling here is impossible. No one can say why the transfused group did worse - was it from the transfusion or the process that lead to it?  Remember, only the TRICC and TRACS trial have been well conducted and randomized.

In Critically Ill patients:
"For similar degrees of organ dysfunction, patients who had a transfusion had a higher mortality rate. For matched patients in the propensity analysis, the 28-day mortality was 22.7% among patients with transfusions and 17.1% among those without (P = .02); the Kaplan-Meier log-rank test confirmed this difference"
Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D: Anemia and blood transfusion in critically ill patients. JAMA 2002; 288:1499–507

"Transfusion practice has changed little during the past decade. The number of RBC units transfused is an independent predictor of worse clinical outcome."
Corwin HL, et al. The CRIT Study: Anemia and blood transfusion in the critically ill—current clinical practice in the United States. Crit Care Med 2004; 32:39–52

"Despite the inherent limitations in the analysis of cohort studies, our analysis suggests that in adult, intensive care unit, trauma, and surgical patients, RBC transfusions are associated with increased morbidity and mortality and therefore, current transfusion practices may require reevaluation."
Marik PE, et al. Efficacy of erythrocytes transfusion in the critically ill: A systematic review of the literature. Crit Care Med 2008; 36:2667–74

Perioperatively:
"Intraoperative blood transfusion is associated with a higher risk of mortality and morbidity in surgical patients with severe anemia."
Glance LG, et al. Association between Intraoperative Blood Transfusion and Mortality and Morbidity in Patients Undergoing Noncardiac Surgery. Anesthsiology 2011; 114(2):283-292

In Cardiac Surgery
"Perioperative red blood cell transfusion is the single factor most reliably associated with increased risk of postoperative morbid events after isolated coronary artery bypass grafting. Each unit of red cells transfused is associated with incrementally increased risk for adverse outcome"
Koch CG, et al. Morbidity and mortality risk associated with erythrocytes and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med 2006; 34:1608–16

"Exposure to both hemodilutional anemia and RBC transfusion during surgery are associated with increased risk of low-output heart failure (LOF), defined as placement of an intraoperative or postoperative intra-aortic balloon pump, return to CPB after initial separation, or treatment with multiple pressors."
Surgenor SD, et al. Intraoperative erythrochites transfusion during coronary artery bypass graft surgery increases the risk of postoperative low-output heart failure. Circulation 2006; 114:I43–8

"Exposure to 1 or 2 U of RBCs was associated with a 16% increased hazard of decreased survival after cardiac surgery"
Surgenor SD, et al. The association of perioperative erythrochites transfusions and decreased long-term survival after cardiac surgery. Anesth Analg 2009; 108:1741–6

"Red blood cell transfusion in patients having cardiac surgery is strongly associated with both infection and ischemic postoperative morbidity, hospital stay, increased early and late mortality, and hospital costs."
Murphy GJ, et al. Increased mortality, postoperative morbidity, and cost after erythrochites transfusion in patients having cardiac surgery. Circulation 2007; 116:2544–52

In Trauma:
"Blood transfusion is confirmed as an independent predictor of mortality, ICU admission, ICU LOS, and hospital LOS in trauma after controlling for severity of shock by admission base deficit, lactate, shock index, and anemia."
Malone DL, et al. Blood transfusion, independent of shock severity, is associated with worse outcome in trauma. J Trauma 2003; 54:898–905

"Red blood cell transfusion within the first 24 hours following admission is associated with an increase in mortality in pediatric trauma patients"
Stone, TJ, et al.  Red blood cell transfusion within the first 24 hours of admission is associated with increased mortality in the pediatric trauma population: a retrospective cohort study. J Trauma Mngmnt 2008, 2:9

During Acute Coronary Syndrome:
"Blood transfusion in the setting of acute coronary syndromes is associated with higher mortality, and this relationship persists after adjustment for other predictive factors and timing of events. We suggest caution regarding the routine use of blood transfusion to maintain arbitrary hematocrit levels in stable patients with ischemic heart disease."
Rao SV, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004; 292:1555–62

"Patients who undergo transfusion are sicker at baseline and experience a higher risk of adverse outcomes than their nontransfused counterparts."
Yang X, et al.  The implications of blood transfusions for patients with non-ST-segment elevation acute coronary syndromes: Results from the CRUSADE National Quality Improvement Initiative. J Am Coll Cardiol 2005; 46:1490–5

"Transfusion in anemic patients admitted with suspected acute coronary syndrome/non–ST-elevation MIs led to a significant increase in 30-day recurrent MI or death (odds ratio 3.05, 95% confidence interval 1.80 to 5.17, p <0.001). This relation persisted after adjusting for significant univariate predictors: hypotension on presentation, pulmonary edema, and increased troponin-I levels (odds ratio 2.57, 95% confidence interval 1.41 to 4.69, p <0.001)."
Singla I, et al. Impact of blood transfusions in patients presenting with anemia and suspected acute coronary syndrome. Am J Cardiol 2007; 99:1119–21

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Jordan Hackworth, M.D.

Fellow, Critical Care Medicine
Department of Anesthesiology
University of Virginia
PO Box 800710
Charlottesville, VA 22908-0710
T (434) 924-2283
F (434) 982-0019

ICU Rounds Report - Nicotine patches and 24-hr staffing

From Daniel:
Nicotine Patches for the Perioperative Smoker? Nicotine replacement therapy (NRT) has been used in the inpatient setting to decrease cravings and lower psychological stress, but does it work perioperatively?  David Warner and friends performed a double-blind placebo controlled trial of 121 smokers undergoing elective surgical procedures and found no benefit whatsoever.  They measured Nicotine Withdrawal Scores and the Perceived Stress Scores for patients perioperatively receiving placebo vs. nicotine patches (all P > 0.19).  This contrasts to a much smaller study in healthy non-surgical volunteers where the patch was shown to reduce cravings.

Acutely, nicotine is known to have adverse effects on wound healing, lung function, immunity and may increase cardiovascular events. No perioperative studies have been done looking at NRT and these relevant outcomes- infections, healing, MI's, pulmonary complications, etc. (Although it should be noted that NRT appears safe for outpatients with known cardiovascular disease).That said, the theoretic potential for harm is real while the available data suggest that if you're jonesing for a light after surgery, the patch probably isn't going to help anyway. Further, at least 2 additional studies have found the NRT has no meaningful effect on post-operative pain scores. So, why not then just avoid them?

Joseph et al.  The safety of the transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.  1996.  N. Engl. J. Med.; 335: 1792.
Teneggi et al.  Smokers deprived of cigarettes for 72 h: effect of nicotine patches on craving and withdrawal.  2002.  Psychopharmacology; 164(2): 177-87.
Warner et al.  Effect of nicotine replacement therapy on stress and smoking behaviour in surgical patients.  2005.  Anesthesiology; 102(6): 1138-46.

Is 24-hour staffing worth the trouble? It's been known for a long time that outcomes vary widely by ICU. Admission to a high quality ICU can lower your risk of death by 40%. So, what makes a good ICU? That's the subject of intense research and debate, but adherence to evidence-based national guidelines, wide-spread use of protocols, adequate multidisciplinary staffing and 24-hour in-house intensivist staffing are generally acknowledged as the benchmarks that make a high quality ICU.

Just up the Mason-Dixon line, the University of Maryland (UM) recently completed a large hospital renovation that included a brand new, larger MICU (from 10 to 29 beds). But in addition to the new facilities, they started 24-hour in-house attending coverage (previously a fellow and 2 residents were on overnight), added a pharmacist on rounds and changed RT staffing ratios from 1:24 to 1:10. Prior to the change, the UM MICU was considered "high quality" and in fact had been honored by the Leapfrog Group for superior outcomes.

The results were big. Relative ICU mortality dropped by 19% (18.4% to 14.9%, p<.006) meaning one in five deaths were prevented. Patients were vent free longer and received less fentanyl and versed. Is this intervention feasible? Who knows, they didn't do a cost analysis. Is it generalizable? Probably not, many of the interventions were specific to UM and all done at the same time. Does it show that thoughtful attention to ICU organization can make as big a difference in outcome as many of our equally costly clinical interventions? Absolutely.

Kahn JM, Goss CH, Heagerty PJ, et al: Hospital volume and the outcomes of mechanical ventilation. N Engl J Med 2006; 355: 41–50
Netzer G, et al. Decreased mortality resulting from a multicomponent intervention in a tertiary care medical intensive care unit Crit Care Med Feb 2011 39(2):284-293,.

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Jordan Hackworth, M.D.

Fellow, Critical Care Medicine

Department of Anesthesiology

University of Virginia

PO Box 800710

Charlottesville, VA 22908-0710

T (434) 924-2283

F (434) 982-0019

ICU Rounds Report - More evidence for early mobility

Do we need more PT? Back in October, we blogged about a cool study from the University of Pennsylvania showing the importance of early mobility and physical/occupational therapy (PT/OT). In the trial, they randomized intubated patients to nearly immediate PT versus the standard of care (wait till the tube is out). While the results were impressive (patients with early therapy were almost 3 times more like have good functional recovery, had half the delirium, spent 2.5 days less on the vent) a lot of of you (and others) raised concerns about the cost.  Certainly in our adult ICUs, PT/OT staffing is an issue.

Last week at SCCM, a large private hospital in Minnesota added some financial data to the debate. The hospital implemented a new stringent protocol where all stable ventilated patients where given aggressive PT and compared it to their historical benchmark. Prior to the protocol, 16% of intubated patients received PT rising to 45% after. Like in previous trials, benefits to patients getting early mobilization were significant (mortality dropped from 33 to 24%, delirium was halved, less sedation was used and ICU days were statistically diminished). That's not news. More importantly (to hospital administrators), mean costs per patient where reduced $6,000. In the first nine months of the protocol, the hospital saved over 2 million dollars. Is it time to add early PT/OT to the list of ICU must-haves (SBT's, sedation vacations, glycemic control, HOB elevation, etc..)?

Schweickert WD, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomized controlled trial. Lancet 2009
Society of Critical Care Medicine (SCCM) 40th Critical Care Congress: Abstract 95. Presented January 16, 2011.

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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