Research Proposal
Title of project: Does anemia contribute to end-organ dysfunction in ICU patients?
Investigators:
Hemauer Duhs, Sarah
Kingeter, Adam
Pandharipande, Pratik
Weavind, Lisa
Specific Aim(s) and Hypotheses
We aim to study the relationship between severity of anemia and markers of end-organ dysfunction
(acute kidney injury, myocardial ischemia, and cerebral dysfunction) in ICU patients.
We hypothesize that tight transfusion triggers are associated with lower hemoglobin in ICU patients,
ultimately contributing to tissue ischemia, end organ dysfunction, and worsened outcomes.
Background and Significance
The balance between oxygen supply and demand is a daily challenge in the care of ICU patients.
Oxygen demand of tissues is often increased in critical illness, however many patients are unable to
increase oxygen supply to match demand [Ruokonen, 1993]. When oxygen delivery is insufficient, there
may be tissue ischemia leading to end-organ dysfunction. As oxygen-carrying capacity of blood depends
on hemoglobin concentration, patients with anemia have higher risk of inadequate delivery of oxygen to
tissue.
Anemia is common in the ICU patient population. 63% of ICU patients present with hemoglobin
concentrations of less than 12g/dL on admission, with up to 95% of ICU patients developing anemia by
hospital day 8 [Vincent, 2002]. The pathogenesis of anemia of critical illness involves both increased loss
of RBC (due to hemolysis, phlebotomy losses, oozing at injury sites, invasive procedures, gastrointestinal
bleeding, prophylactic or therapeutic anticoagulation [Vincent, 2002; Corwin ,1995; Barie, 2004;
Hadfield , 1995]) and decreased RBC production (nutritional deficiencies, iron metabolism, EPO
production, [Rodriguez , 2001; Weiss, 2005]).
The physiological consequences of anemia can be seen in both healthy and diseased individuals.
Acute isovolemic reduction in hemoglobin concentration in resting healthy humans leads to progressive
increases in heart rate, stroke volume, oxygen extraction, and cardiac index [Weiskopf, 1998]. There has
also been report of reversible cognitive dysfunction found during severe acute anemia in healthy
subjects [Weiskopf, 2000]. Anemia correlated with increased risk of mortality and hospitalization,
independent of age, sex, diabetes, and chronic disease score in a study of over 12000 adults [Culleton,
2006]. Studies in patients with COPD [Martinez, 2006; Chambellan, 2005], congestive heart failure [Go,
2006], acute myocardial infarction [Salisbury, 2010], and chronic kidney disease [Mehdi, 2009] have
found anemia to be associated with adverse outcomes or mortality. In ICU patients, anemia is a risk
factor for failure of liberation from mechanical ventilation [Khamiees, 2001], myocardial infarction
[Thygesen, 2007], and increased risk of death [Rasmussen, 2010; Carson, 2002]. Hemoglobin less than
10 g/dl was associated with a 5 fold increase in need for reintubation after successful spontaneous
breathing trial and extubation [Khamiees, 2001] in a cohort of 91 patients. In 300 surgical patients who
declined blood transfusion for religious reasons, odds of death within 30 days of surgery increased with
each gram decrease in hemoglobin below 8 g/dl [Carson, 2002].
Despite the risks associated with anemia, treatment of anemia (most commonly RBC transfusion)
is also not without risk. Thus, optimal management of the anemia of critical illness is an area of much
controversy and ongoing research. The CRIT study found that 44% of patients received one or more RBC
units while in the ICU [Corwin, 2004]. However, the use of RBC transfusion is expensive (in 2008, the
mean payment for one unit of leukocyte-reduced red blood cells in the United States was $ 223 per the
2009 national blood collection and utilization survey report), resource intensive and of unclear clinical
benefit. Apart from complications such as allergic reactions, volume overload etc., the CRIT study also
found that the number of RBC units transfused was an independent predictor of worse clinical
outcomes. Other studies have shown that blood transfusions are associated with immunosuppressive
complications, especially in the critically ill.
Restricted transfusion thresholds and outcomes. In a randomized controlled trial of critically ill
patients [Hebert, 1999] a strategy of transfusing only when Hb dropped below 7g/dl compared to if it
dropped below 10 g/dl showed a reduction in transfusions in the restrictive group with no worse
outcomes. Subgroup analysis of younger patients and those less severely ill showed worse outcomes in
the liberally transfused group. Furthermore, a 2012 Cochrane review analyzed 19 studies of 6264
patients to examine the relationship between red cell transfusion thresholds and change in clinical
outcomes [Carson, 2012]. Patients assigned to a restrictive transfusion strategy (Hgb 7-9 g/dL) had
received on average 1.19 fewer units of RBC and had hemoglobin concentration on average 1.5% lower
than patients assigned to a liberal transfusion strategy. Hospital mortality was 23% lower in patients
assigned to a restrictive transfusion strategy as compared to those assigned to a liberal transfusion
strategy.
Restricted transfusion practices are now incorporated into routine care. Many hospitals have
created institutional guidelines in an attempt to reduce blood product use, with a subsequent reduction
in mean Hgb concentrations. For example, Vanderbilt has developed strict transfusion guidelines
implemented at the point of order entry. All orders entered at Vanderbilt must be placed through a
computerized order system (Wiz). Specific order sets have been designed for the ordering of RBC’s, FFP
and Cryoprecipitate, and platelets. To order red blood cells, the ordering physician must list reason for
transfusion, number of units to be reserved and/or transfused, whether or not irradiated blood is
required, and method of delivery of blood products. Utilizing this existing digital framework, Wiz order
sets for the transfusion of RBC’s were modified. Transfusions for the reason of symptomatic anemia
were limited to 1u pRBC, and all transfusions required listing of attending physician approving the
transfusion.
Although the CRIT study found transfusion to be independently associated with increased
mortality, nadir Hb was also independently associated with worsened outcome [Corwin, 2004]. We
hypothesize that restrictive transfusion strategies result in lower daily Hb and an increase in ischemic
related complications, end organ dysfunction, morbidity, and health care associated costs, even when
the risks of transfusion are accounted for.
Research Design and Methods
Methods: The proposed study will be a post-hoc analysis of prospectively collected data from the
BRAIN-ICU observational cohort study of medical and surgical ICU patients admitted with respiratory
failure or shock
Study Population: Vanderbilt BRAIN-ICU cohort
ANALYSIS 1: Daily lowest Hb and predicted outcome the next day (while in ICU)
Independent Variable
-Daily lowest hemoglobin
Dependent Variables (next day):
- Daily delirium (positive CAM-ICU)
- Daily troponin (>0.1) as an index of cardiac dysfunction AND as a continuous variable
- Daily renal SOFA score (≥2) as an index of acute kidney injury AND as a continuous variable (creatinine)
- Daily resp SOFA score (≥2) as an index of acute respiratory dysfunction
- On ventilator Y/N (as a measure of success of extubation)
Confounders:
Baseline
- Age
- Weight
- Medical vs. surgical ICU status
- APACHE score
- Charleston comorbidity index
- Framingham stroke risk profile
Daily risk factors
- Lowest daily mean arterial pressure
- ICU day
- ICU day * lowest daily Hb
- daily severe sepsis yes/no
- transfusion (nos of units)
Statistical Analysis: Linear (troponin, creatinine) and logistic (delirium, SOFA, ventilator) mixed effects
regression will be used to assess the effect of daily lowest hemoglobin level on each dependent variable,
adjusting for the fixed effects of confounders listed above. Random effects will be used to account for
the correlation among repeated measurements on individual patients. The adjusted effect (linear or
odds ratio) of lowest daily Hb will be summarized using 95% confidence intervals.
ANALYSIS 2: Hb during ICU stay and predicted outcomes
Independent Variable
-Lowest hemoglobin during ICU (prior to outcome)
-mean Hb during ICU stay (running average prior to outcome)
Dependent Variables:
A. ICU mortality
B. Time to event analysis
1. Death
2. Cardiac dysfunction (Troponin I > 0.1)
3. Renal dysfunction (renal SOFA >2),
4. Time to dialysis
5. Time to resolution of delirium (CAM negative for 48 hours)
6. Time to successful extubation (off ventilator for 48 hours)
Confounders:
Baseline
- Age
- Weight
- Medical vs. surgical ICU status
- APACHE score
- Charleston comorbidity index
- Framingham stroke risk profile
Time varying
- mean SOFA score (running average prior to outcome)
- duration of severe sepsis (prior to outcome)
- number of units transfused (running average prior to outcome)
Statistical Analysis: Logistic regression and or Cox proportional hazards regression with time-varying
covariates will be used to assess the effects of lowest and mean hemoglobin on the dependent variables
listed above, adjusting for each confounder. The adjusted effects (odds or hazard ratios) will be
summarized using 95% confidence intervals.
Sample size: Brain ICU cohort (821 patients)
Literature cited
Barie PS. Phlebotomy in the intensive care unit: strategies for blood conservation. Crit Care 2004;8:S34–
S36.
Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red
blood cell transfusion. Cochrane Database Syst Rev 2012;4:CD002042.
Carson JL, Noveck H, Berlin JA, Gould SA. Mortality and morbidity in patients with very low
postoperative Hb levels who decline blood transfusion. Transfusion 2002;42:812–818.
Chambellan A, Chailleux T, Similowski T. Prognostic value of the hematocrit in patients with severe
COPD receiving long term oxygen therapy. Chest 2005;128:1201–1208.
Corwin HL, Gettinger A, Pearl RG, 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.
Corwin HL, Parsonnet KC, Gettinger A. RBC transfusion in the ICU: is there a reason?Chest
1995;108:767–771.
Culleton BF, Manns BJ, Zhang J, Tonelli M, Klarenbach S, Hemmelgarn BR. Impact of anemia on
hospitalization and mortality in older adults. Blood 2006;107:3841–3846.
Go AS, Yang J, Ackerson LM, Lepper K, Robbins S, Massie BM, Shlipak MG. Hemoglobin level, chronic
kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the
Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study.
Circulation 2006;113:2713–2723.
Hadfield RJ, Sinclair DG, Houldsworth PE, Evans TW. Effects of enteral and parenteral nutrition on gut
mucosal permeability in the critically ill. Am J Respir Crit Care Med 1995;152:1545–1548.
Hebert PC, Wells G, Blajchman MA, Marshall J et al. A Multicenter, Randomized, Controlled Clinical Trial
of Transfusion Requirements in Critical Care. N Engl J Med 1999; 340:409-417
Khamiees M, Raju P, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Predictors of extubation
outcome in patients who have successfully completed a spontaneous breathing trial. Chest
2001;120:1262–1270.
Martinez FJ, Foster G, Curtis JL, Criner G, Weinmann G, Fishman A, DeCamp MM, Benditt J, Sciurba F,
Make B, et al. NETT Research Group. Predictors of mortality in patients with emphysema and
severe airflow obstruction. Am J Respir Crit Care Med 2006;173:1326–1334.
Mehdi U, Toto R. Anemia, diabetes, and chronic kidney disease. Diabetes Care 2009;32:1320–1326.
Rasmussen L, Christensen S, Lenler-Petersen P, Johnsen SP. Anemia and 90-day mortality in COPD
patients requiring invasive mechanical ventilation. Clin Epidemiol. 2010;3:1–5.
Rodriguez RM, Corwin HL, Gettinger A, Corwin MJ, Gubler D, Pearl RG. Nutritional deficiencies and
blunted erythropoietin response as causes of the anemia of critical illness. J Crit Care
2001;16:36–41.
Ruokonen E, Takala J, Kari A, Saxén H, Mertsola J, Hansen EJ. Regional blood flow and oxygen transport
in septic shock. Crit Care Med1993;21(9):1296-1303
Salisbury AC, Alexander KP, Reid KJ, Masoudi FA, Rathore SS, Wang TY, Bach RG, Marso SP, Spertus JA,
Kosiborod M. Incidence, correlates, and outcomes of acute, hospital-acquired anemia in patients
with acute myocardial infarction. Circ Cardiovasc Qual Outcomes 2010;3:337–346.
Semenza GL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda)
2009;24:97–106.
Thygesen K, Alpert JS, White HD. Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of
Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J 2007;28:2525–
2538.
Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D.
ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion
in critically ill patients. JAMA 2002;288:1499–1507.
Weiskopf RB, Kramer JH, Viele M, Neumann M, Feiner JR, Watson JJ, Hopf HW, Toy P. Acute severe
isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology
2000;92:1646–1652.
Weiskopf RB, Viele MK, Feiner J, Kelley S, Lieberman J, Noorani M, Leung JM, Fisher DM, Murray WR,
Toy P, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia.
JAMA 1998;279:217–221.
Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352:1011–1023.