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* From the Pulmonary and Critical Care Section, Medical College of Georgia, Augusta, GA.
Correspondence to: Thomas A. Dillard, MD, FCCP, Medical College of Georgia, 1120 15th St, Room BBR5513, Augusta, GA 30912-3135; e-mail: T.Dillard{at}mail.mcg.edu
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Physical Examination
The patient was alert with a BP of 103/52 mm Hg and a pulse rate of 113 beats/min. Lungs were clear to auscultation. Cardiac examination revealed tachycardia with regular rhythm. The abdomen was soft, not tender, with normal bowel sounds. Pelvic examination showed a large amount of dark blood and clots in the vagina. The uterus was enlarged and estimated to be equivalent to 18 weeks’ gestation in size.
Laboratory Findings
Admission data showed a hemoglobin concentration of 5.8 g/dL, hematocrit of 18.2%, and WBC count of 11,700/µL with normal differential. The platelet count was 242,000/µL. Coagulation profile showed prothrombin time of 17.7 s, international normalized ratio of 2.5, and activated partial thromboplastin time of 22.8 s. The serum sodium level was 138 mEq/L; chloride, 109 mEq/L; bicarbonate, 19 mEq/L; BUN, 11 mg/dL; and creatinine, 0.8 mg/dL.
Hospital Course
The patient refused blood transfusion for religious reasons. The gynecology service evaluated the patient and decided that the surgical risk was excessive. She continued to have uterine bleeding and had another syncope episode with transient myoclonic activity. The hemoglobin level fell to 3.5 g/dL and later to 2.5 g/dL. The patient was transferred to the medical ICU, where hypotension subsequently developed. Her lactic acid was 5.7 mg/dL. She received vigorous volume expansion by administration of IV crystalloid fluids. She was intubated and received mechanical ventilation with 100% fraction of inspired oxygen, sedation, and neuromuscular blockade. She later received a low-dose norepinephrine infusion to sustain mean arterial BP > 60 to 65 mm Hg.
What interventions should be used in this patient?
Answer: Control of the uterine bleeding site, reversal of anticoagulation, parenteral iron, and high doses of recombinant human erythropoietin.
The Jehovah’s Witness with life-threatening anemia represents a special challenge to the critical care physician. Acute reduction of blood hemoglobin concentration < 5 g/dL may result in inadequate oxygen delivery and severe tissue hypoxia; however, there are a few reports of Jehovah’s Witnesses who survived with a hemoglobin concentration < 3 g/dL. The treating physician needs to formulate a clinical management plan to minimize blood loss, maximize oxygen delivery, and minimize oxygen comsumption.
Essential management includes controlling the bleeding and correcting coagulopathy if present. When surgical intervention is required, the patient’s risk must be minimized before surgery. Effort must also be taken to limit intraoperative blood loss by using several techniques. These techniques include normovolemic hemodilution, controlled hypotensive anesthesia, meticulous hemostasis, and red cell salvaging devices. In a patient with an excessive surgical risk, an alternative approach should be taken. Hemostatic drugs provide useful therapy in treating coagulopathy. The currently available hemostatic drugs are antifibrinolytics (aprotinin, tranexamic acid, and aminocaprioc acid), recombinant coagulation factors (VIIa, VIII, and IX), and desmopressin. Administration of vitamin K plays a role in hemostasis by increasing the levels of vitamin K-dependent factors. Some Jehovah’s Witnesses agree to receive cryoprecipitate.
Iatrogenic blood loss should be minimized by ordering only essential laboratory tests and using microsample analyzers. If these analyzers are not available, small samples should be drawn by using pediatric-sized tubes.
When oxygen delivery is compromised, the reduction of nonessential oxygen uptake plays an important role to prevent significant tissue hypoxia. Muscle paralysis with sedation and ventilatory support is effective in minimizing the oxygen uptake. Controlled mild hypothermia with target core temperature of 30°C to 32°C has been successfully used in the management of anemic Jehovah’s Witnesses to reduce metabolic rate and oxygen uptake.
Oxygen delivery is defined as the product of cardiac output and the arterial oxygen content. Arterial oxygen content (CaO2) is calculated by the following equation:
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where SaO2 is arterial oxygen saturation, and Hb is hemoglobin.
Strategies to improve oxygen delivery include maximizing blood production, cardiac output, and dissolved oxygen. Intravascular volume and cardiac output should be maintained in optimal state to ensure adequate tissue perfusion and oxygenation. In severe anemia, dissolved oxygen may contribute 25% of the oxygen content. Increased oxygen tension can be achieved by mechanical ventilation with high fraction of inspired oxygen.
Hyperbaric oxygen therapy substantially enhances tissue oxygen delivery and has been used in severely anemic patients who refuse blood transfusion. The potential benefit must be weighed against the risk of this therapy, including pulmonary oxygen toxicity and barotrauma. The benefit dissipates rapidly when the patient returns to atmospheric pressure requiring multiple treatments to minimize toxicity.
Hemoglobin-based oxygen carriers, cell-free hemoglobin solutions extracted from human or bovine RBC or produced by using recombinant technology, are a promising future substitute therapies for blood. At present these products can only be obtained from the developers on a case-by-case basis through compassionate-use research protocols. Compassionate use of stroma-free hemoglobin was not available for use in our patient. The physician should carefully counsel Jehovah’s Witnesses individually to ensure acceptability of these treatments.
Polymerized bovine hemoglobin has been used in a clinical trial of sickle-cell patients and a patient with severe, autoimmune, hemolytic anemia. The use of polymerized bovine hemoglobin in the management of a Jehovah’s Witness with profound anemia has been reported; however, the patient died from abdominal sepsis. Cell-free hemoglobin substances may support bacterial virulence by inhibiting neutrophil function and providing substrate for bacterial replication. Vasoconstriction in the peripheral circulation, which may occur with bovine hemoglobin more than other free hemoglobins, may decrease cardiac output and thus impair oxygen delivery.
Human polymerized hemoglobin (PolyHeme; Northfield Laboratories; Evanston, IL) has been found to be safe and effective in the treatment of acute blood loss in trauma and emergent surgery.5 Human polymerized hemoglobin appears to produce less vasoconstriction. Randomized, controlled phase III studies are currently under way to determine the potential role of human polymerized hemoglobin in the treatment of acute blood loss. Human polymerized hemoglobin was used in a Jehovah’s Witness who survived a hemoglobin level of 3.2 g/dL.
Recombinant human erythropoietin enhances erythropoiesis to compensate for blood loss, and is accepted by most Jehovah’s Witnesses. A randomized clinical trial demonstrated that administration of recombinant human erythropoietin in critically ill patients was effective in raising hematocrits. Erythropoietin therapy has been successfully used in a severely anemic Jehovah’s Witness. The optimal dose of recombinant human erythropoietin remains unclear. Those patients usually require a high dose of recombinant human erythropoietin, 300 to 500 U/kg/d, for several days and then three times a week. In most cases, the hemoglobin rises to an acceptable level within 2 to 3 weeks. Because of enhanced erythropoiesis with recombinant human erythropoietin, iron supplementation and other cofactors should be administered routinely during the treatment. Adequate nutrition is important in sustaining the erythropoieses.
In the present patient, the uterine bleeding was successfully controlled by endometrial tamponade by Foley catheter, and treatment with conjugated estrogens and methylergonovine beginning on hospital day 1; this was followed by external-beam radiation therapy to the uterus with 1,200 rad in divided doses over 3 days beginning on hospital day 2. She received an initial dose of 60,000 U of recombinant human erythropoietin, followed by 40,000 U/d for 3 days, and then 40,000 U every other day for 1 week. She received IV iron dextran, and folic acid was also administered. Anticoagulation was reversed with vitamin K IV, desmopressin, recombinant factor VIIa, and cryoprecipitate after obtaining surrogate informed consent for the plasma products. Neuromuscular blockade was discontinued after 24 h. Mechanical ventilation was continued with decreasing fraction of inspired oxygen to 40% over 4 days. She was extubated on hospital day 8 and was discharged home on day 17 with a hemoglobin level of 7.2 g/dL (Fig 1 ).
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2. Mechanical ventilation and muscle paralysis are indicated in a life-threatening anemia to maximize oxygen delivery and minimize oxygen uptake.
3. Hemoglobin-based oxygen carriers are promising therapies as substitutes for blood transfusion but may not be accepted by all Jehovah’s Witnesses and are available only on a case-by-case basis for compassionate use.
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