1. ACUTE NORMOVOLEMIC HEMODILUTION
Aryeh Shander, MD, FCCM, FCCP
Chief, Department of Anesthesiology, Critical Care and Hyperbaric Medicine
Englewood Hospital and Medical Center,
Englewood, New Jersey
Clinical Professor of Anesthesiology, Medicine and Surgery
Mount Sinai School of Medicine, New York

2. ANH The technique Formula or other targets
Fluid resuscitation, is there a difference?
Induced anemia – safe or risk?
Anemia, perfusion and organ function
ANH and PBM- outcomes

3. ANH
As a blood conservation technique it cannot stand alone and must be accompanied by
Treatment of ANEMIA
Cell salvage and possible fractionation
Post operative management of anemia and coagulation

4. ANH – The Debate ANH – controversial ANH – variety of methods
ANH – unclear indications
ANH – risk not quantified
ANH – more work

5. Acute Normovolemic Hemodilution (ANH)

6. ANH
Blood is collected in standard blood bags containing citrate as the anticoagulant. Hemodilution kits are available, that contain 2 blood bags, a Y-type connector with a Luer lock adapter and a patient identification bracelet, which simplifies the ANH process. Vascular access for the collection of blood may be obtained from an artery,usually the radial, or a large vein. The blood should be gently and intermittently agitated to ensure adequate mixing with the anticoagulant. Approximately minutes is required for the withdrawal of a unit of blood, and adequate time should be available to withdraw 3-4 units from anesthesia induction until major surgical blood loss occurs.

8. Practical Issues ANH Key Points: Vascular access - IV or arterial
Monitoring
GA and/or Regional
Fluid replacement
Key points in our success with ANH:
Vascular access - Whole blood can be removed either through a central line, large bore peripheral IV gauge with a tourniquet loosely applied or an arterial line. It is important to gently agitate the blood during the collection process to ensure adequate mixing with the anticoagulant.
Monitoring - In the majority of the cases an arterial line is utilized for “beat to beat” blood pressure monitoring. Other invasive monitoring depend on the patient’s associated comorbidities and are not dependent on the performance of ANH. A urinary drainage catheter is usually used secondary to anticipated blood loss and associated fluid shifts.
Anesthetic type - General anesthesia is the primary anesthetic in the majority of surgical procedures primarily because of the nature of the surgery. However, ANH has been successfully used in cases that are appropriate for regional anesthesia. Radical prostatectomies and lower extremity revascularizations have been performed with regional anesthesia and ANH for blood conservation. More vigilance is required during the ANH blood withdrawal process because of the sympathectomy obtained from neuraxial blockade.
Fluid replacement - It is crucial that the circulatory blood volume be maintained at all times during the hemodilution process. This can be achieved with either crystalloid or colloid solutions. We prefer to use Hetastarch initially, since it has the advantage of greater intravascular retention and smaller amounts are required to maintain euvolemia.

9. ANH indications and concerns
Relative Indications
Preop normal Hemoglobin levels
Anticipated intraop blood loss > ~1000ml
Moderate anticipated blood loss in patient refusing allogeneic transfusion
Ability to draw blood after anesthetic induction + before commencement of surgical bleeding
Concerns
Ability to tolerate blood withdrawal
Recurarization* (Br J Anaesth. 2006;97(4):482-8)
Coagulation
Fluid overload
Excluding contraindications for ANH as described earlier, relative indications for ANH include a Hct>34%, anticipated surgical blood loss >1000ml, and the ability to withdraw blood between the anesthetic induction + commencement of surgical blood loss. In the patient refusing allogeneic transfusion and moderate surgical blood loss is anticipated, we tend to be more aggressive with ANH and err on the side of withdrawing. In most cases, the withdrawal of blood and the hemodilution process can continue once surgery has started, since the majority of surgical blood loss does not occur in the early stages of surgery.
Hobisch-Hagen P et al. BJA;82(4):503-9

10. Outcome Measurement in Blood Conservation (ANH)
Reduced blood loss
Statistically significant reduction of blood loss
Clinically significant reduction of blood loss
Reduced blood loss and or eliminate patient’s exposure to allogeneic transfusions
Reduced or eliminate transfusions alone
Morbidity – perioperative infection, SIRS or MOF
Mortality

11. The Effect of Two Levels of Hypotension on Intraoperative Blood Loss During Total Hip Arthroplasty Performed Under Lumber Epidural Anesthesia
45-54 mmHg
55-64 mmHg
p value N= 20
Intraop BL
0.004
Post op BL NS
Total BL
Baseline Hb
Post op D1
Post op D2
Unit of allo 13
Shanrrock NE, et al.Anesth Analg Mar;76(3):580-4.

12. Intraoperative – ANH Effectiveness of acute normovolemic hemodilution to minimize allogeneic blood transfusion in major liver resections
Liver resection – at least 30% transfusion requirements
Prospective, randomized
N = 78
ANH to target Hct 24% vs. controls
Transfuse at 20%
Matot I, et al. Anesthesiology 2002;97:

13. Matot I. et al. Anesthesiology 2002;97:794-800
Intraoperative – ANH
Matot I. et al. Anesthesiology 2002;97:

14. ANH The technique Formula or other targets
Fluid resuscitation, is there a difference?
Induced anemia – what’s the limit?
Anemia, perfusion and organ function
ANH and blood conservation - outcomes

15. V=EBV x Hi – Hf / Hav
ANH

16. Weiskopf R.B. Anesthesiology 2001;94:439-46
                                                                                                                         
The range (window) of fractional blood volume loss (area between the maximum allowable fractional blood volume loss without blood removed and with acute normovolemic hemodilution, where acute normovolemic hemodilution can obviate erythrocyte transfusion that otherwise would have been necessary to maintain the trigger hematocrits (Ht) of 0.21 and 0.30 had acute normovolemic hemodilution not been used, for initial hematocrit (Ho)
Weiskopf R.B. Anesthesiology 2001;94:439-46

17. ANH The technique Formula or other targets
Fluid resuscitation, is there a difference?
Induced anemia – what’s the limit?
Anemia, perfusion and organ function
ANH and blood conservation - outcomes

18. Choice of Fluid Crystalloid Colloid ‘Normal’ Saline
Physiologic solutions
Colloid HA
Penta-Starch
Solute

19. Normal Saline vs. LR in Gyn Surgery
Total n = 24
Scheingraber et al. Anesthesiology 1999

20. Anemia, viscosity and tissue oxygenation
OXYGEN TENSION, mm/hg
Tsai AG. Biorheology 38 (2000)

21. Acid-Base Changes Caused by 5% Albumin versus 6% Hydroxyl Starch Solution in Patients Undergoing ANH Rehm M, et. Al. Anesthesiology 2000;93:
N=20 Gyn surgery
ANH to HCT 22%
10 HES and 10 HA in NaCl solution
Blood volume well maintained in both groups
Metabolic acidosis (SID) with both after ANH

22. ANH The technique Formula or other targets
Fluid resuscitation, is there a difference?
Induced anemia – safe or risk?
Anemia, perfusion and organ function
ANH and blood conservation - outcomes

23. VO2 vs. DO2 Critical point of DO2 VO2 DO2 ml/m2/min
E.C.S.M. van Woerkens A&A 75, 1992

24. Normovolemic Anemia N=33
Variable
Beginning
Post ANH
Hemoglobin
13.1
5.0
Cardiac Index
3.05
5.71
Heart Rate 58 92
SVR
2372
1001
VO2
3.07
3.42
Lactate
Normal
Weiskopf et.al. JAMA 279, #3 1998

25. Critical Oxygen Delivery in Conscious Humans
DO2
and
VO2
ml O2 Kg-1
min-1 * *
time
N=8
Hb. 4.7+/- 0.2 g/dl
Lieberman JA Anesthesiology 2000; 92:407-13

26. ANH & Coagulation aPT, INR, aPTT, platelets and fibrinogen
No significant change at 500, 1000 ml
1500 ml, aPT and INR increased without increased in nonsurgical bleeding

29. Acute Severe Isovolemic Anemia Impairs Cognitive Function and Memory in Humans Weiskopf R.B. et.al., Anesthesiology 2000;92: N=9 volunteers - reaction time and calculation were impaired at Hb of 5.0gm/dl but not 7.0gm/dl No PET scan, tests min after anemia induction Impaired vs. protective Oxygen Reverses Deficits of Cong. Function and Memory and Increased Heart Rate Induced by Acute Severe Isovolemic Anemia Weiskopf R.B. et.al. Anesthesiology 2002;96: Acute Isovolemic Anemia Does Not Impair Peripheral or Central Nerve Conduction Weiskopf R.B., et.al. Anesthesiology 2003;99(3): Peripheral conduction but no CNS effect at 5.0gm/dl

30. Cardiovascular Disease

31. Coronary Flow
Flow resistance is primarily reduced by reduction of viscosity
Coronary flow is markedly increased with ANH - Subendo and Subepicardial, improved oxygen utilization
Increased myocardial O2 extraction
Active coronary vasodilatation
MVO2 (myocardial BF X CaO2) remain stable
Extraction ratio in severe ANH is UNCHANGED until Hct drops below 12.5% (Hgb 4.5)
Jan KM, Am J Physiol 1977;233:H106
Levy PS et al. Am J Physiol 1993;265:H340-9

32. Cardioprotective effects of acute normovolemic hemodilution in patients with severe aortic stenosis undergoing valve replacement
N = 40 patients scheduled for elective AVR - randomly assigned to a control group (standard care) or an ANH group (target hematocrit level of 28%)
In the ANH group:
Postoperative release of troponin I (1.7 ng/mL) and myocardial fraction of creatine kinase (22 U/L) was significantly lower than in the control group (3.6 ng/mL and 45 [U/L, respectively)
Circulating levels of erythropoietin (EPO) were higher than in control patients (13.6 +/- 4.2 mUI/mL vs /- 2.4 mUI/mL; p < 0.05).
Fewer hemodiluted patients presented adverse cardiac events
Preoperative ANH further attenuates myocardial injuries
ANH-induced cardioprotection:
Optimization of preischemic myocardial oxygen delivery and/or consumption
Postconditioning effects of endogenous EPO
This study was a randomized controlled trial.
All patients were managed with standard myocardial preservation techniques (cold blood cardioplegia, anesthetic preconditioning). The outcome measures included the release of myocardial enzymes, perioperative hemodynamic changes, the need for pharmacologic cardiovascular support, and cardiac complications. the postoperative release of troponin I (mean peak plasma concentrations, 1.7 ng/mL) and myocardial fraction of creatine kinase (22 U/L; range, U/L) was significantly lower than in the control group (3.6 ng/mL and 45 [range, 39-51] U/L, respectively)
Licker M. et al. Transfusion Feb;47(2):341-50

33. Perioperative time course of serum concentrations of total CPK (A), CK-MB (B), and cTnI (C) in the control ( ) and ANH ( ) groups. *p < 0.05, between the two groups; #p < 0.05, compared with baseline
This study was a randomized controlled trial.
All patients were managed with standard myocardial preservation techniques (cold blood cardioplegia, anesthetic preconditioning). The outcome measures included the release of myocardial enzymes, perioperative hemodynamic changes, the need for pharmacologic cardiovascular support, and cardiac complications. the postoperative release of troponin I (mean peak plasma concentrations, 1.7 ng/mL) and myocardial fraction of creatine kinase (22 U/L; range, U/L) was significantly lower than in the control group (3.6 ng/mL and 45 [range, 39-51] U/L, respectively)
Licker M. et al. Transfusion Feb;47(2):341-50

34. ANH & CARDIAC DISEASE

35. Significant Intraoperative Predictors of Transfusion
Based on Patients With a Preoperative Estimated Risk of
Transfusion 5%a
Risk Factors OR CI Multivariate
p Value
CPB time –
No. of bypass grafts (3) –
Total crystalloid (2,500 mL) –
Total ANH –
n 145 observations; 5 were excluded because of missing values for a
covariate; Hosmer-Lemeshow statistic for lack of fit of this model has a p
value of 0.72, and the c statistic
ANH acute normovolemic hemodilution; CI confidence interval;
Moskowitz D, Klein J.J, Shander A et.al. Ann Thorac Surg 2004;77:626–34

36. Blood Conservation Englewood Hospital and Medical Center

37. CABG Outcomes PBMP vs Non-PBMP
Moskowitz et al Ann Thorac Surg 2010

38. Outcome of ANH Cost effective
Monk TG, et al. Transfusion 1996;36(6):849-50
ANH cost effective vs PAD in rad prostate surgery
Monk TG, et al. A&A 1997;85(5):953-8
ANH replaces PAD
Monk TG, et al. Anesthesiology 1999;(1):24-33
EPO, ANH and PAD – ANH least costly
Goodnough LT, et al. Vox Sang 1999;77(1):11-6
RT of ANH vs PAD TKA – ANH less costly
Goodnough LT, et al. Transfsion 2000;40(9):1054-7
RT ANH vs PAD in THA – ANH less $$

39. Clinical Studies
Meta-analysis of 24 randomized prospective studies of ANH in 1,218 patients
ANH reduced likelihood of allogeneic exposure and total units of allogeneic blood transfused
Bryson, G. L. et al., Anesth Analg 1998, 86: 9

40. Prospective randomized study N = 40 (over 2 years)
Evaluation of Acute Normovolemic Hemodilution and Autotransfusion in Neurosurgical Patients Undergoing Excision of Intracranial Meningiom
Prospective randomized study
N = 40 (over 2 years)
Group I (Control Group) - Group II (ANH Group)
Surgical blood loss in group I was ± ml vs ml in group II
Mean blood transfused in group I was ± ml vs. 165 ± ml in group II [statistically significant (p<0.05)]
ANH up to a target hematocrit of 30% is safe and effective in reducing the need for allogeneic blood
Parameters studied included changes in hemoglobin, hematocrit and hemodynamic parameters.
Group II (ANH Group), Acute Normovolemic Hemodilution (target hematocrit of 30%)
The mean value of blood withdrawn in ANH group was ± 208 ml
This was replaced simultaneously with an equal volume of 6% Hydroxyethyl starch to maintain normovolemia
5 patients (25%) required homologous blood in group II
Naqash IA. Et al. J Anaesthesiol Clin Pharmacol Jan;27(1):54-8

41. ANH did not reduce allogeneic transfusions
Relationship Between Intraoperative Fluid Administration and Perioperative Outcome After Pancreaticoduodenectomy Management
N = 130 (July 2005 to May 2009) randomized to ANH or standard management (STDM)
Transfusion rates were similar (ANH = 16.9%, 30 units vs STD = 18.5%, 33 units; P = 0.82)
Morbidity (ANH = 49.2% vs STD = 47%, P = 0.86)
More grade-3 complications in patients undergoing ANH (32% vs 23.1% STD, P = 0.17)
Pancreatic anastomosis complications higher in the ANH group (21.5% vs 7.7%, P = 0.045)
ANH did not reduce allogeneic transfusions
Restrictive intravenous fluid management during PD may help improve postoperative outcome
ANH group, intraoperative blood collection was performed to a target hemoglobin of 8.0 g/dL
Pancreatic anastomosis complications (leak/fistula/abscess) were significantly higher in the ANH group (21.5% vs 7.7%, P = 0.045)
The benefits of ANH do not necessarily extend to all procedures
Fischer M. et al. Ann Surg Dec;252(6):952-8

42. A Prospective Randomized Trial of Acute Normovolemic Hemodilution Compared to Standard Intraoperative Management in Patients Undergoing Major Hepatic Resection
N = 130 undergoing major hepatic resection (> or =3 segments) (From April 2004 to March 2007)
Randomly assigned to ANH Group or Standard anesthetic management (STD) group
ANH reduced the overall allogeneic red cell transfusion rate by 50% compared with STD
ANH patients were less often transfused intraoperatively (n = 1, 1.6%) compared with the STD group (n = 7, 10.4%) (P = 0.036)
ANH group had higher postoperative hemoglobin levels (P = 0.01)
ANH group required fewer red cell units overall (28 vs. 47 units)
Intraoperative blood loss > or =800 mL:
ANH reduced ABT (18.2% vs. 42.4%, P = 0.045) and FFP (21.1% vs. 48.3%, P = 0.025)
ANH is safe, effectively reduces the need for allogeneic transfusions, and should be considered for routine use
In the ANH group, intraoperative blood collection was performed to a target hemoglobin of 8.0 g/dL. Low central venous pressure anesthetic technique was used intraoperatively for both groups. A standardized transfusion protocol was applied to all patients intraoperatively and throughout the hospital stay. ANH reduced the overall allogeneic red cell transfusion rate by 50% compared with STD [12.7% (n = 8) vs. 25.4% (n = 17), respectively; P = 0.067
ANH patients were less often transfused intraoperatively (n = 1, 1.6%) compared with the STD group (n = 7, 10.4%) (P = 0.036)
ANH group had higher postoperative hemoglobin levels (P = 0.01)
ANH group required fewer red cell units overall (28 vs. 47 units)
In patients with intraoperative blood loss > or =800 mL, ANH reduced not only the allogeneic red cell transfusion rate (18.2% vs. 42.4%, P = 0.045) but also the proportion of patients requiring fresh frozen plasma (21.1% vs. 48.3%, P = 0.025)
Jarnagin WR. Et al. Ann Surg Sep;248(3):360-9

43. N = 155 patients undergoing elective hip surgery
Acute normovolemic hemodilution in moderate blood loss surgery: a randomized controlled trial
N = 155 patients undergoing elective hip surgery
Groups "ANH" (n = 78) or "standard transfusion" (n = 77)
Allogeneic transfusion was necessary in 22 (29%) standard transfusion patients and 15 (19%) ANH patients
Postoperative complications:
30 (38%) standard transfusion patients compared with 14 (18%) assigned to ANH group (OR, 0.3; 95% CI, ; p = 0.009)
The major difference between the groups was the frequency of infective complications
ANH reduced postoperative complications
ANH on induction of anesthesia was to a target hemoglobin (Hb) level of 110 g per L with return of autologous blood on wound closure. Allogeneic blood was prescribed by an objective transfusion trigger based on an Hb level of less than 80 g per L. Transfusion requirements and postoperative complications were recorded.
Allogeneic transfusion was necessary in 22 (29%) standard transfusion patients and 15 (19%) ANH (odds ratio [OR], 0.6; 95% CI, ; p = 0.23) with 63 and 33 units transfused, respectively (p = 0.1)
Bennett J. et al. Transfusion Jul;46(7):

44. Acute Normovolemic Hemodilution (ANH)
Safely reduces allogeneic transfusions and associated complications
Cost effective procedure
Effective in all surgical procedures – method dependent
Dramatically underutilized
No standard approach to date

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