Role of Blood Management in Optimizing Perioperative Outcomes in Patients With Secondary Anemia Undergoing Hysterectomy or Myomectomy for Abnormal Uterine Bleeding: A Proposed Randomized Control Trial
Phase: NA
Conditions: Abnormal Uterine Bleeding
Sponsor: The Cleveland Clinic

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Title :  Role of blood management in optimizing perioperative outcomes in patients with 
secondary anemia undergoing hysterectomy for abnormal uterine bleeding: A Proposed 
Randomized Control Trial  
 
Principal Investigators:   
Rosanne M Kho MD (Head, Section of Benign Gynecology) 
Morgan Gruner MD (PGY-2, Ob/Gyn Residency Program) 
 
Co-Investigators:  
 
Mark Dassel MD (Benign Gyn Surgery/MIGS staff) 
 
 
 
 
Lindsey Valentine (Benign Gyn Surgery/MIGS staff)  
Miguel Luna Russo MD (PGY-5, Fellowship in MIGS) 
Meng Yao MS (Statistician) 
Cara King DO (Director, Benign Gyn Surgery) 
Megan Orlando, MD (PGY-5, Fellowship in MIGS)  
 
 
I. Background/Introduction: 
 
According to the World Health Organization (WHO),  30.2 % of the world’s population of 
nonpregnant women are anemic (1), with a higher percentage of anemia being encountered in 
patients seeking surgical management of abnormal uterine bleeding (AUB). Age, gender, 
socioeconomic factors, nutrition, and certain pathologic states are associated with iron depletion 
and associated iron deficiency anemia. Uterine fibroid (or leiomyoma) is the most common 
diagnosis associated with hysterectomy, accounting for approximately 31% of all procedures 
performed. Abnormal uterine bleeding and endometriosis are the second and third most 
common diagnoses associated with hysterectomy, explaining 14% and 11%, respectively (2). 
Based on the diagnoses recorded in the medical record by providers, 48.7% of patients were 
presumed to have dysfunctional uterine bleeding (DUB) and 9% were presumed to have 
bleeding secondary to uterine fibroids. In this population of women with AUB, 350 (92.3%) had a 
hemoglobin concentration recorded. Thirty-five percent were anemic with a hemoglobin of 
<12g/dL and 13.7% had moderate to severe anemia with a hemoglobin of <10 g/dL (3).  
 
In addition to the high incidence of secondary anemia in patients with abnormal uterine 
bleeding and fibroids, surgeries for abnormal uterine bleeding and fibroids such as 
hysterectomy and myomectomy can involve a significant blood loss (4,5).  The overall rate of 
postoperative blood transfusion for hysterectomy in the cited study was 13.3% (5).  The need for 
packed red blood cell transfusion is one of the known complications of surgery and is increased 
in women who are noted to be anemic preoperatively.  Blood transfusions are associated with 
increased adverse surgical outcomes. Higher rates of morbidity and mortality have been 
reported in patients receiving one unit of packed red blood cells compared with patients who did 
not undergo transfusion (6). The WHO recommends, in compliance with their guide for optimal 
clinical use, “that before surgery every reasonable measure should be taken to optimize the 
patient’s own blood volume” (7). Pre-operative hemoglobin less than 10.6 g/dL versus greater 
than or equal to 13.1 g/dL had five times the odds of transfusion (5).  

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Anemia is a modifiable risk factor that can be assessed and optimized pre-operatively. 
Prior studies have evaluated preoperative blood management strategies in oncology patients, 
patients undergoing general surgery procedures, and orthopedic surgery. A systematic review 
of the management of perioperative anemia showed varying results in change in hemoglobin 
levels after blood management intervention, but all studies were able to show a decrease in 
postoperative blood transfusions (8). A randomized control trial evaluating oral iron 
supplementation preoperatively in patients undergoing colorectal surgery reported reduced 
blood transfusion rates in the group receiving this intervention (9). Froessler et al studied 
perioperative IV iron intervention in patients undergoing major abdominal surgery in a 
randomized control trial with using blood transfusions as a primary endpoint. They concluded 
that perioperative IV iron reduced the need for blood transfusion and was also associated with 
higher postoperative hemoglobin and shorter hospital stay (10). A blood management protocol 
implemented in the perioperative period also noted a decrease in perioperative blood 
transfusion and postoperative anemia in the orthopedic population. The interventions used in 
their blood protocol management included erythropoietin, ferric carboxymaltose, and tranexamic 
acid (11).   
 
A Blood management protocol was recently developed at the Cleveland Clinic whereby 
either confirmed or suspected anemic patients with abnormal uterine bleeding scheduled for 
surgical management are referred to Blood Management for assessment of laboratory studies 
(CBC, Ferritin, iron, TIBC, %Sat) and a care plan is development.  Several factors are 
considered in designing a treatment plan including current blood loss, anemia symptoms, 
scheduled or upcoming procedures, and others.  Treatment plans may include observation 
alone or oral iron versus intravenous iron.  Iron deficiency is calculated using the Ganzoni 
calculation for patients receiving intravenous iron. Per the Blood Management Protocol: An 
anemia screening lab panel will be ordered, in combination with a referral to the Blood 
Management clinic via WHI Blood Management Referral Smartset. This order set will 
automatically preselect the lab panel — complete blood count (CBC), iron, total 
iron binding capacity (TIBC) and ferritin — and the referral to the Blood Management clinic. The 
patient will automatically receive information in the after-visit summary regarding the Blood 
Management clinic referral. Any correctable causes of anemia will be addressed preoperatively 
by the Blood Management group. Measures used may include the use of intravenous iron or 
oral iron. See Algorithm in Table 2.0.  
  
Using Ganzoni Formula Calculator: http://www.al-
nasir.com/www/PharmCalc/mob_exec_calc.php?ID=ganzoni 
  
Clinical data for calculator: 
a) Current hemoglobin 
b) Weight in kg 
c) Target hemoglobin (see table below) 
Ganzoni Target Hemoglobin 
Female 
High Blood Loss* (> 3 gm/dL) 
13 gm/dL 

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Low Blood Loss*  (1-2 gm/dL) 
12 gm/dL 
Non-surgical* 
12 gm/dL 
Unknown* 
12 gm/dL 
*High blood loss defined as expected drop in hemoglobin > gm/dL postoperatively i.e. CABG, 
Valve, AAA, lower extremity joint replacement,multi-level spine w/instrumentation; Low blood 
loss expected drop hemoglobin 1-2 gm/dL i.e. hysterectomy, simple colectomy, laparoscopic or 
robotic assisted procedures; Non-surgical is medical iron deficiency treatment; Unknown are 
default targets. 
 
There is currently limited information regarding the role of blood management in the 
benign gynecologic population and specifically, in patients who are scheduled to undergo 
surgery for fibroids and/or abnormal uterine bleeding. A thorough search through PubMed and 
clinicaltrials.gov did not reveal any studies on this issue. In 2019 at CCF only 2% of gyn patients 
at Main Campus were referred to blood management, but 12.6% of the main campus gyn 
population had a Hb of <10.0 g/dL. The overall goal of this study is to evaluate the role of 
preoperative blood management in optimizing surgical outcomes by reducing the co-morbidities 
associated with postoperative blood transfusion.    
 
Specific Aims/Objective:  
 
The primary objective of this study is to compare the change in baseline hemoglobin 
levels in patients in the study (Blood Management Protocol) and control (“usual 
care”)                                                                                                                                                                        
group who are undergoing hysterectomy for abnormal uterine bleeding.  Change in baseline 
hemoglobin levels is defined as the difference of the hemoglobin level obtained within 72 hours 
prior to surgery and the hemoglobin level at 4 weeks postoperatively.  
 
Our secondary objectives include 1. To evaluate the perioperative outcomes between the two 
groups including OR times, EBL, peri-operative transfusion rates, length of hospital stay, 
complications including intra-operative injuries, postoperative infection rates, readmission, and 
re-operation; 2. to assess patient satisfaction regarding their experience with the Blood 
Management protocol and extra outpatient infusion visits required using a patient questionnaire 
(PATSAT 35, Attached); and 3. to compare the quality of patient health and recovery between 
the two groups using the RAND-36 (Attached) assessment tool. The REDCap database will 
include potential identifiers to enable online surveys. The included potential patient identifiers 
include: date of birth, surgery date, and subject email (they provide for the study.)  
 
 
Data variables that will be collected in the study are visible in the following table.  
 
Patient Demographics:  
• 
MRN 
• 
Age/ Date of Birth 
• 
BMI 

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• 
Race 
• 
Gravidity/Parity 
• 
Prior abdominal surgery 
• 
Prior cesarean section 
• 
Diabetes 
• 
Hypertension 
• 
Current Smoker 
• 
Former Smoker 
• 
Menopause status 
• 
Type of surgery: Hysterectomy or myomectomy 
 Type: Vaginal, laparoscopic, open, laparoscopic assisted 
vaginal hysterectomy, robotic 
• 
Surgery date, discharge date 
• 
Surgery date/ Discharge date 
• 
Subject email 
Primary objectives:  
• 
Change in hemoglobin levels 
o Baseline Hemoglobin (pre-op) 
o Post Op Hemoglobin level 
Secondary objectives:  
• 
Operative time  
• 
Blood Loss 
• 
Perioperative transfusion rate 
• 
Length of hospital stay 
• 
Intraoperative Complications 
o Intraoperative injuries  
o Post-operative infection rates 
o Readmission 
o Reoperation  
• 
Patient Satisfaction  
• 
Quality of Health and Recovery 
• 
Number of infusions received 
• 
Days on PO iron therapy 
 
 
Table 1.0 -- Data Collection Variables 
We anticipate that patients undergoing blood management protocol will have a faster 
return to normal recovery and better quality of life scores during recovery using the RAND-36 
assessment questionnaire compared to patients undergoing usual care. We also plan to 
evaluate additional cost of blood management treatments for oral iron, IV iron, and blood 
transfusion in regards to feasibility, and from a health care utilization standpoint.   
 
Methods and Study Design:  
 
This will be a prospective randomized control trial conducted in a single large-referral 
center where anemic patients undergoing hysterectomy for fibroids or abnormal uterine bleeding 
will be recruited and randomized to undergo Blood Management protocol or usual care.    

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Inclusion criteria are anemic patients (defined as Hgb ≤ 11g/dL within 30 days of initial 
MIGS consult visit), greater than 18 years of age, with abnormal uterine bleeding, or fibroids 
undergoing hysterectomy by laparoscopic, robotic, vaginal or open routes. Exclusion criteria are 
malignancy, pregnancy, sickle cell anemia or other blood dyscrasias, women who received 
blood transfusions in 30 days prior to surgery, women receiving EPO therapy, women who have 
undergone gastric bypass surgery, and women on therapeutic/full anticoagulation. Patients 
undergoing hysteroscopic myomectomy alone without will not be included in the study.  
 
Women meeting the above inclusion criteria who are undergoing elective surgery 
(hysterectomy) at the Cleveland Clinic Main Campus will be randomly allocated to receive pre-
surgical optimization blood management referral versus usual care - defined as expectant 
management with no therapy, or PO iron therapy at the primary surgeon’s discretion. 
Randomization following a computer generated number sequence and allocation will occur in 
person. Patients will be screened from multiple minimally invasive gynecologic providers with 
high volume surgical practices at a large teaching institution, and consented on their initial 
preoperative visit. (These MIGS surgeons are Dr. Rosanne Kho, Dr. Mark Dassel, Dr. Cara 
King, Dr. Lindsey Valentine.) Patients will be randomized to receiving a blood management 
referral or usual care. Patients will be randomized with permuted block randomization with block 
size 2 and stratified on care providers. Blood management work up protocol is visible in Table 1.  
Patients receiving usual care will receive anemia management provided by the primary 
physician that may include no treatment, continued observation, or oral iron recommendations 
in the pre-operative time.  
 
The intervention will include pre-surgical optimization blood management referral based on pre-
operative Hb levels ≤11.0. Currently it is not standard of care at the Cleveland Clinic to send all 
patients with Hb ≤11.0 due to secondary anemia to blood management. It is done currently at 
the provider/surgeons preference alone and not through a research protocol or guidelines.  At 
the initial consultation visit a CBC will be drawn, patients will be given a consent form for the 
study and asked to review it. If a Hb ≤11.0 within 30 days of consultation visit is documented in 
EPIC, they will be consented and randomized at the consultation visit. All patients after initial 
consultation visit will be immediately sent to the lab for blood draw if they have not had Hb 
drawn within 30 days. Lab draw includes: CBC + differential, iron studies: iron, TIBC, ferritin, 
optional B12. If the initial consult visit occurs at Fairview or Hillcrest Hospital, the patient's follow 
up preoperative visit will be scheduled at the main campus where consent will be obtained. The 
blood management team then will receive the referral from primary surgeon’s office via EPIC in-
basket. Blood management coordinator will assess patient, arrange treatment, and orders will 
be cosigned by surgeon/referring provider. Blood management may further assess for 
symptoms of PICA, restless legs, and cold intolerance as symptomatic indicators of anemia. 
The Rand 36 study will be administered at either the consultation or the pre-operative visit. The 
PATSAT 35 will be administered at the postoperative visit only. Postoperative Hb levels will be 
collected by a CBC at the post-operative visit. All postoperative visits will be scheduled at the 
main campus. All surveys and consents will be obtained at visits that occur at the main campus.  
 

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Table 2: Blood Management Preoperative Iron Deficiency Algorithm  
 
Blood loss intraoperatively will be measured as accurately as possible with suction 
device recording and quantitative blood loss and tapes/packs by weighing instead of only visual 
assessment.  
 

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Image: 1.0 -- Patient Flow Sheet  
 
Justification for Sample Size:  
 
Power Calculation:  
 
Sample size was calculated to have 80% power to detect a difference between groups using a 
T-test at a significance level of 0.05. We assume that patients at 4 weeks will have a standard 
deviation in hemoglobin values of 1.2 g/dL (8) to detect a 1 g/dL difference between groups, we 

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will need 48 patients total (24 per group) if the groups are of equal size. Assuming a 20% 
dropout rate, 60 patients total (30 per group) will be the target enrollment.   
 
Cost and Payments to Subjects 
The patients will have no additional costs due to participating in the study beyond the usual 
insurance copays and standard costs for appointments.   
 
Quality Control Procedure:  
Information will be provided to all department members involved in administration of the study. 
Follow up, data entry, and patient follow up will be closely followed by the research team 
(resident, fellow, staff physicians, MIGS NP’s, Lead research nurse)  
 
Process of Consent  
Patients would be consented for participation in the study at their primary surgeon’s office when 
shared decision making for proceeding with surgery is performed.  Patients will receive no 
difference in care based on their participation in the study apart from the study protocol  
 
Risks and Discomfort of the Project  
The study has been designed to minimize as much risk as possible, and participants will be 
subjected to no more than minimal or standard risk for undergoing the intervention. Breach of 
confidentiality is a small risk. Physical risk are rare and unanticipated but would be limited to 
transfusion reaction to the IV iron therapy. There are no psychological risks for patients who 
participate in this study. Participants can also benefit from their participation in this study due to 
their altruistic motivation for partaking in research study they have contributed to scientific 
advancement.   
 
Analysis plan 
Approximately normally-distributed continuous measures will be summarized using means and 
standard deviations and will be compared using two-sample t-tests. Continuous measures that 
show departure from normality and ordinal measures will be summarized using medians and 
quartiles and will be compared using Wilcoxon rank sum tests. Categorical factors will be 
summarized using frequencies and percentages and will be compared using Pearson’s chi-
square tests or Fisher’s Exact tests. All analyses will be done using SAS (version 9.4, The SAS 
Institute, Cary, NC) and a p < 0.05 will be considered statistically significant.  
 
Timetable:  
The IRB will be submitted in April 2020. Upon approval of the IRB, it is estimated that data 
analysis can begin shortly after. It is estimated that it will take 6 months to enroll the 60 patients 
required. The study will be registered on clinicaltrials.gov after approval of the IRB and prior to 
enrollment.  
 
 
 
 

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References:  
 
1. Worldwide prevalence of anaemia 1993–2005 : WHO global database on 
anaemia / Edited by Bruno de Benoist, Erin McLean, Ines Egli and Mary 
Cogswell.  
 
2. Merrill RM. Hysterectomy surveillance in the United States, 1997 through 2005. 
Med Sci Monit. 2008;14(1):CR24–CR31. 
 
3. Matteson KA, Raker CA, Pinto SB, Scott DM, Frishman GN. Women presenting 
to an emergency facility with abnormal uterine bleeding: patient characteristics 
and prevalence of anemia. J Reprod Med. 2012;57(1-2):17–25. 
 
4. Gingold, JA et al. The effect of cell salvage on blood transfusion practices during 
abdominal myomectomies. American Journal of Obstetrics & Gynecology, 
Volume 218, Issue 2, S904 
 
5. Zitsman et al. Hysterectomy and Perioperative Blood Transfusion: Identifying 
Modifiable Risk Factors. Obstetrics and Gynecology: 2017. Volume 129, Issue 5, 
p90S. doi: 10.1097/01.AOG.0000514933.34242.2a 
 
6. Ferraris VA, Davenport DL, Saha SP, Austin PC, Zwischenberger JB. Surgical 
outcomes and transfusion of minimal amounts of blood in the operating room. 
Archives of Surgery 2012; 147: 49–55.  
 
7. World Health Organization. Availability, safety and quality of blood products. 
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22/03/2018).  
 
8. Borstlap W.A., Stellingwerf M.E., Moolla Z., Musters G.D., Buskens C.J., Tanis 
P.J., Bemelman W.A. Iron therapy for the treatment of preoperative anaemia in 
patients with colorectal carcinoma: A systematic review. Colorectal Dis. 
2015;17:1044–1054. doi: 10.1111/codi.13110. 
 
9. Lidder P.G., Sanders G., Whitehead E., Douie W.J., Mellor N., Lewis S.J., Hosie 
K.B. Pre-operative oral iron supplementation reduces blood transfusion in 
colorectal surgery—A prospective, randomised, controlled trial. Ann. R. Coll. 
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10. Froessler et al, “The Important Role for Intravenous Iron in Perioperative Patient 
Blood Management in Major Abdominal Surgery: A Randomized Control Trial,” 
Ann Surg 2016; 264;41-46 
 

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11. Rineau E., Chaudet A., Chassier C., Bizot P., Lasocki S. Implementing a blood 
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transfusion rate in major orthopedic surgery: A before-after study. Transfusion. 
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