Blood Conservation Strategies and Liver Transplantation

Abstract

Red blood cell and component transfusions are a frequent and widely accepted accompaniment of surgical procedures. Although the risk of specific disease transmission via allogeneic blood transfusions (ABT) is very low, the occurrence of transfusion related immune modulation (TRIM) still remains a ubiquitous concern. Recent studies have shown that ABT are linked to increased morbidity and mortality across various specialties, with negative outcomes directly correlated to number of transfusions. Blood conservation methods are therefore necessary to reduce ABT.

Acute normo-volemic hemodilution (ANH) along with pre-operative blood augmentation and intraoperative cell salvage are blood conservation techniques utilized in tertiary and even quaternary (transplantation) surgery in Jehovah’s Witnesses with excellent outcomes. The many hematologic complications such as anemia, thrombocytopenia and coagulopathies that occur with liver transplantation present a significant barrier when trying to avoid ABT. Despite this, living donor liver transplantation (LDLT) has been successfully performed in a transfusion-free environment, providing valuable insight into the possibilities of limiting ABT and its associated risks in all patients.

Introduction

Allogeneic blood transfusions (ABT) have been routine practice during operations for many decades, well integrated into surgical standard of care guidelines. However, reducing blood transfusions in patients has both financial and clinical implications. The cost of blood products makes up a significant portion of a hospital budget and in the era of DRG reimbursement, these expenses no longer pass through to payers. Further, there are also hidden costs to blood transfusions related to the intrinsic immune-suppressing nature of allogeneic blood product administrations.¹

While the risk of disease transmission from banked blood is very low, there still remains a considerable risk of TRIM. This immune modulation has been shown to have a negative effect on a patient’s postoperative recovery. ABT has been linked to an increased risk of infection post-operatively.² These negative outcomes are directly proportional to the number of units transfused.³ Avoidance of blood transfusion is, therefore, key to improving patient outcomes following surgery. The aim of this paper is to: 1) Highlight the use of acute normovolemic hemodilution (ANH) as the most effective blood conservation strategy; 2) Examine successful blood augmentation and blood conservation strategies used during live donor liver transplantation (LDLT) to prevent blood loss; and 3) Demonstrate the results of a Jehovah’s Witness (JW) cohort study comparing transfusion-free and transfusion-eligible patients across multiple surgical specialties.

Increased Patient Risk With Blood Transfusions

While banked blood is safe, transfusion can be potentially quite harmful. The risk of contracting viral infections during an ABT is very low, with a 1:200,000–500,000 chance of HBV transmission and a 1:2 million chance of HIV transmission. The risk of CMV transmission is highest at 12:100.⁴ The real risk of transfusion for the patient is not disease transmission but rather immune suppression. ABT results in the infusion of large amounts of foreign antigens and WBCs, which modulate the recipient immune system. The severity of this immune suppression is correlated with the number of units of blood transfused⁵ and the WBC aliquot that accompanies it. Negative effects of TRIM include increased risk of infections, increased risk of cancer reoccurrence and increase in other post-operative morbidities.⁶

A meta-analysis of 23 peer-review articles published between 1986 and 2000 showed overwhelming evidence that ABT is associated with significantly increased risk of post-op bacterial infection in the surgical patient.⁷ Nosocomial infection rates are higher in transfused patients.⁸ In a study published by Crabtree et al. looking at 8,405 cardiac surgery patients between 1997 and 2004, blood product transfusion was shown to be an independent prognostic factor in elective cardiac procedures for C. Difficile infection (OR =3.277). Blood product transfusion had a greater odds ratio for C. Difficile infection than advanced age, female sex and increased cumulative days of antibiotic administration.⁹

Table 1 shows a compilation of comparative transfusion studies in cardiac surgery that all demonstrate an association between transfusion and increased morbidity and mortality. The 2006 cohort study of 11,963 patients by Koch et al. shows that transfusion is associated with an increase in serious complications such as renal failure, cardiac arrhythmias and neurologic events. Murphy et al. showed in their large 2007 cohort study that transfusions lead to increased length of hospital stay and short-term mortality with corresponding increased costs. This result challenged the long-held notion that older individuals with coronary disease should have a lower threshold for transfusion.¹⁰

Table 1.

Outcomes in Cardiac surgery between transfusion-free and transfusion-eligible patients. Transfusion is associated with an increased number of major complications such as renal failure and serious infection as well as increased mortality.

Study	Results: Transfusion Associated With …
Engoren et al (2002) (n = 1915)	Mortality at 5 years: RR 1.7
Koch et al (2006) (n = 11,963)	Higher postoperative morbidity and mortality OR 1.77 Renal failure OR 2.06 Prolonged ventilator support OR 1.79 Serious infection OR 1.76 Cardiac complications OR 1.55 Neurologic events OR 1.37
Murphy et al (2007) (n = 8,598)	Infection and ischemic outcomes Adjusted OR 3.38 and 3.35 Increased length of stay HR 0.63 Death within 30 days HR 6.69

Increased cancer recurrence and decreased survival in patients with transfusion during surgery has also been shown in studies across different cancer types including colorectal¹¹ and hepatocellular carcinoma.¹²

With ABT linked to increased morbidity and mortality, appropriate blood conservation measures are essential to decrease post-operative risk in patients. Blood conservation strategies are associated with similar or better clinical outcomes as well as decreased costs.

ANH is the Best Blood Conservation Tool

Acute normovolemic hemodilution (ANH) involves placement of a large-bore IV with gravity drainage of whole blood into a CPD bag following anesthesia induction. Whole blood is removed while albumin or crystalloid IV restoration of intravascular volume occurs simultaneously. This is maintained until the patient’s hematocrit drops to a level between 18–30%. Any blood loss that occurs during surgery results in the loss of diluted blood. The whole blood collected pre-operatively stays in the operating room and all ANH blood is returned to the patient as needed during the procedure and all is returned by the end of the operation¹³.

The major benefits of ANH include: 1) Simplicity- it does not require any preoperative preparation whereas with blood augmentation using erythropoietic drugs there is a time delay for erythropoiesis as well as a pharmaceutical cost increment. 2) ANH contains whole blood including platelets and coagulation factors. It takes advantage of the natural redundancy of the coagulation system which allows removal of a significant portion of the protein pro-coagulant and platelet compartments while preserving 100% platelet and plasma protein clotting system activities. 3) ANH provides a valuable cushion for safety, usually 400–800 cc, in the event of unexpected blood loss.

The basic principle behind ANH is that isovolemic anemia is a safe situation in most patients and that it will be well tolerated. ANH builds upon the concept that hematologic redundancy, in this case of the red cell mass, is present and allows manipulation of this red cell mass compartment to the benefit of the patient.

Vascular volume is preserved so cardiac output and oxygen delivery are maintained. ANH to a hemoglobin level as low as 5gm/dl in conscious healthy resting humans did not produce inadequate systemic oxygenation. Studies have shown that ANH decreases systemic vascular resistance (SVR) and increases heart rate (HR) and stroke volume (SV). Plasma lactate levels stay constant over a wide range of hemoglobin.¹⁴ Even in the event of significant blood loss, post-operative anemia is safe. A 2005 study conducted by the American Society of Hematology found that six out of seven patients (85.7%) with a hemoglobin as low as 2.5–3.0 g/dL survived. Out of a total of 128 patients with profound anemia (hemoglobin ranging from 2.5–7.0 g/dL), 95.3% survived¹⁵. Patients with profound post-operative anemia treated without blood transfusions have a high survival rate.

Blood Conservation Strategies in LDLT

Transfusion-free techniques were first performed on Jehovah’s Witnesses (JW) because of their religious beliefs that do not allow them to accept whole blood transfusions. Solid organ transplantation, ANH, heart lung bypass and intraoperative cell saver are considered a matter of personal choice under JW religious guidelines.¹⁶ Blood conservation strategies used on JW cohorts serve as a valuable prototype for transfusion-free surgery in a secular population.

Several blood conservation strategies are currently used in JW during live donor liver transplantation (LDLT). These are either pre-operative, intraoperative or postoperative. Pre-operative strategies consist of raising hemoglobin through blood augmentation using iron, folate and EPO. Post-operative blood conservation involves limited blood draws and the use of pediatric drainage tubes. Intraoperative techniques include ANH, cell salvage, and specialized surgical techniques. Combining pre-operative blood augmentation with ANH can be especially effective in LDLTs, allowing the removal of greater quantities of whole blood without causing significant pre-operative anemia.

Surgical techniques to control portal hypertension and blood loss during LDLT operations in recipients are also essential for blood conservation. Hepatic congestion is a problem unique to LDLT and is associated with impaired function of the transplanted lobe. A temporary left portahepatic shunt – constructed by doing an end-to- end anastomosis of the left branch of the portal vein to the left hepatic vein - relieves the intra-abdominal hypertension while volume homeostasis is restored.¹⁷ The completed shunt is shown in Figure 1.

Figure 1.

Completed left portahepatic shunt in transfusion-free recipient of a live donor liver transplant. The portahepatic shunt reduces blood loss and helps control intra-abdominal hypertension.

A comparison between transfusion-free (JW) patients and transfusion eligible recipients in LDLT showed decreased estimated blood loss, decreased ICU stay and decreased need for reoperation in those who did not receive blood. There was a 100% survival in the JW liver recipients compared to 90% in the transfusion-eligible patients. All of the transfusion free patients received ANH as well as cell saver.¹⁸

JW Cohort studies across surgical specialties

Beginning in 1997, Keck Hospital of USC has tracked cohorts of JW that underwent major elective surgeries across multiple specialties (See Table 2). The results were compared to the outcomes for transfusion-eligible patients in 25 different operations where there is an anticipation of significant blood loss (between 300–500cc). There was no mortality in any of the elective cases in transfusion-free patients. Transfusion-free patients who received cadaveric liver transplants had the worst outcomes (50% survival) but also had the most severe pre-operative liver disease.¹⁹

Table 2.

Tertiary and quaternary surgical procedures associated with substantial blood loss and likelihood of blood product transfusions that have been performed at Keck Hospital of USC on Jehovah’s Witness patients between 1997 and 2013.

Procedure	N	Procedure	N
Liver Transplantation	31	Major Liver Lobectomy	48
Kidney Transplantation	27	Distal Pancreatx-Splenx	4
Heart Transplantation	5	Whipple Procedure	12
CABG	13	Total Hysterectomy	24
Valve Replacement	21	Pelvic Floor Reconstruction	7
Cardiac Resection	2
		Radical Cystectomy	6
Esophagectomy	2	Radical Prostatectomy	12
Radical Gastrectomy	2	RP Lymph Node Dissection	5
Esophageal Fundoplication	26	Robotic Nephrectomy	23
Abdomino-Perineal Resection	7	Pneumonectomy/Lobectomy	4
Colectomy	26	Diaphragm Hernia Repair	4
Total Knee Replacement	46	AAA repair-Open	3
Redo Total Knee Replacement	38	Carotid Endarterectomy	5
Total Hip Replacement	11	Renal or Fem-Tib repair	3
Redo Total Hip Replacement	16
		Radical Neck Dissection	9
Craniotomy w Resection/Clipping	6	Pharyngectomy/Laryngectomy	4
Pituitary Excision	15	Sinusectomy	18
Cervical Spinal Fusion	18	Mandibulectomy	5
Lumbar Spinal Fusion	31

Future Implications for Blood Conservation

Successfully performing major operations in a transfusion-free setting opens the door for implementing blood conservation in transfusion-eligible patients.

Mainstream transfusion avoidance strategies are important to implement in order to decrease costs and improve clinical outcomes. Blood loss by surgical case type is now predictable and transfusions are coming under increased scrutiny as a quality metric-likely to be a core measure in the near future.

Biography

Mansi Sheth, BS, is a Medical Student, Keck School of Medicine, University of Southern California, Los Angeles. Sujit Kulkarni, MD, Assistant Professor of Surgery, Kiran Dhanireddy, MD, Assistant Professor of Surgery, and Rick Selby, MD, (above), Professor of Surgery, Division Chief, are in the Division of Hepatobiliary, Pancreas and Abdominal Organ Transplant Surgery, Department of Surgery, University of Southern California, Los Angeles. Alexander Perez, Program Coordinator, Transfusion Free Surgery and Patent Blood Management, and Randy Henderson, Director, Transfusion Free Surgery and Patent Blood Management, are at the Keck Medical Center, University of Southern California, Los Angeles. Based on a presentation given at Missouri University School of Medicine Alumni Meeting 2014.

Contact: Rick.Selby@med.usc.edu