Hyperbaric Therapy in Blood Loss Anemia

Etiology

According to the Jehovah’s Witnesses religion, portions of the Bible (including Genesis, Leviticus, and Acts) state that its followers must abstain from receiving blood.[2] Jehovah’s Witnesses will not accept blood transfusions, and this religious belief has been upheld in the American legal system.[2]

Other patients are unable to accept blood products due to medical reasons. Examples include patients with hemolysis and antibody formation due to transfusion reactions or those with crossmatch incompatibility. 

Patients who cannot accept blood transfusions for medical or religious purposes are at increased risk of morbidity and death after acute and unexpected blood loss from conditions including postpartum bleeding, trauma, and intraoperative hemorrhage.

Epidemiology

Up to 1000 Jehovah's Witnesses die each year in part because they refuse to accept a blood transfusion.[2] Anemic patients who are elderly, obese, on hemodialysis, or have underlying heart disease are at increased risk for mortality.

Pathophysiology

Hyperbaric oxygen therapy is delivered in a hyperbaric (pressure) chamber with the patient breathing 100% oxygen at a pressure greater than 1.0 atmosphere absolute (ATA). Typically 2-3 ATA is used. Beyond 3 ATA, there are issues with oxygen toxicity.   

The amount of oxygen delivered to the body (DO2) is dependent on the arterial oxygen content (CaO2) and cardiac index (CI). The equation representing this is as follows:

• DO2 = CaO2 x CI

The arterial oxygen content primarily depends on hemoglobin concentration; each hemoglobin molecule can carry up to 1.38 ml of oxygen per gram of hemoglobin.[3] A tiny amount of the arterial oxygen supply is dissolved in the plasma and depends on the partial pressure of oxygen in the blood (PaO2). The following equation represents the arterial oxygen content:

• CaO2= (Hemoglobin [g/dL] x 1.38 ml O2 x %oxygen saturation) + (0.003 x PaO2)

The oxygen delivered to tissues is then extracted and used by the tissues. On average, the human body extracts 5% to 6% volume of oxygen from the blood.[3] As long as the oxygen supply equals or exceeds the amount of extracted oxygen, symptoms of oxygen debt do not occur. In anemic patients, oxygen delivery via hemoglobin may not be sufficient to compensate for oxygen extraction. When hemoglobin concentrations drop below 6 g/dL, oxygen delivery, and extraction become unequal, and when hemoglobin concentrations fall below 4 g/dL, tissue oxygenation delivery is significantly impaired.[2]

In 1959, the Dutch surgeon Boerema published “Life Without Blood,” a manuscript detailing the use of hyperbaric oxygen therapy (HBO) for treating anemia.[4] Boerema exsanguinated healthy piglets and replaced the blood volume with a plasma-like solution. The piglets’ resulting hemoglobin concentration was 0.4 g/dL, which is incompatible with life. The piglets were then pressurized in a hyperbaric chamber to 3 absolute atmospheres (ATA) for 45 minutes. The animals survived this exposure, despite having essentially no hemoglobin present and recovered uneventfully after they were re-infused with normal blood. Boerema noted that under hyperbaric conditions, the amount of oxygen dissolved in the plasma could significantly exceed the amount present while breathing air under normobaric conditions. This phenomenon is due to Henry’s Law, which states that the amount of gas dissolved in a solution is directly proportional to the partial pressure of the gas. When partial pressures of a gas increase, such as under hyperbaric pressurization, more of that gas dissolves in solution. Breathing room air (21% oxygen) under normobaric conditions results in a PaO2 of approximately 100 mmHg; breathing 100% oxygen under hyperbaric conditions results in a PaO2 greater than 2000 mmHg. Under hyperbaric conditions, oxygen dissolved in the plasma can approximate or meet the body’s metabolic demands of oxygen extraction.[5] At a treatment depth of 3 ATA, the plasma dissolved oxygen approximates 6% volume, equal to the body’s oxygen extraction.[6]

History and Physical

Anemia can present with a wide range of signs and symptoms. For example, anemic patients may be light-headed, confused, weak, fatigued, irritable, and have headaches, decreased exercise tolerance, palpitations, or dyspnea. Generally, symptoms do not occur until the hemoglobin level drops to less than 7 g/dL.  

The most common systems involved in hemorrhage are the gastrointestinal, genitourinary, and pulmonary systems. Therefore, menstrual history in women should be explored, as well as asking about hematemesis, hemoptysis, hematuria, hematochezia, and melena.

A thorough past medical history should include the following:

• Medications such as aspirin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, bisphosphonates,carbamazepine, cephalosporins, nonsteroidal anti-inflammatory drugs, phenytoin, sulfa drugs, and chemotherapy agents
• Supplements such as iron, folate, and B12,
• Family history such as Sickle cell anemia, glucose-6-phosphate deficiency, spherocytosis

On exam, signs of acute blood loss associated with emergent anemia can include hemodynamic abnormalities such as hypotension, tachycardia, and tachypnea. In addition, the patient may experience decreased urine output, increased thirst, and altered mental status. These clinical manifestations depend on factors such as patient comorbidities, age, baseline medications, and severity of illness or injury. For example, younger adults may be able to compensate with an increased heart rate. However, older patients with baseline medical problems are more commonly unable to compensate. This may be especially true if they are chronically on beta-blockers. The examination is often normal in patients with chronic anemia, although several findings suggest specific causes. Pallor, scleral icterus, and jaundice are associated with hemolytic anemia.

In addition, physicians should assess for evidence of cardiac murmur, crackles, hepatomegaly or splenomegaly, thyromegaly, and lymphadenopathy. On rectal examination, evaluation for tenderness, joint deformities, rashes, and melena or blood is essential. Evidence of bleeding with chronic anemia suggests a coagulation disorder. As discussed, patients can adapt to low hemoglobin levels, such as 5 to 6 g/dL, if anemia is slow in onset.

Evaluation

Patient evaluation should focus on signs and symptoms of decreased oxygen delivery to tissues. Vital signs may show tachycardia and hypotension. The patient’s mental status may be altered; cerebral infarcts may occur secondary to decreased oxygen delivery to the brain. Ischemic changes may be present on electrocardiography, and decreased urine output may be due to hypoperfusion. Laboratory studies may reveal metabolic acidosis, abnormal cardiac enzymes, or a base deficit.

Treatment / Management

The physiologic effects of hyperbaric oxygen therapy in anemic patients are short-lived; the elevated tissue partial pressures of oxygen last only minutes to hours after each hyperbaric exposure.[5] The frequency of hyperbaric oxygen therapy should be tailored to the patient’s clinical status.[7] More symptomatic patients may require treatments administered two or three times daily.  Typically treatments are at 2 to 3 ATA for 3 to 4 hours 3 or 4 times daily.  Volume status should be maintained, as well as nutritional support, folic acid, vitamin B, iron, and other hematinics.[8](B3)

Treatments can be administered in a monoplace (holding a single person) or multiplace (accommodating multiple people) hyperbaric chamber.  Treatment depths depend on the individual hyperbaric unit’s clinical procedures.  Still, increased treatment depths will result in higher partial pressures of oxygen and likely increase relief of the symptoms of oxygen debt.  Other modalities which can reduce oxygen consumption, including sedation, neuromuscular paralysis, and cooling, can also be utilized as adjunctive therapy.[9] Blood should be minimized whenever possible; pediatric tubes can be used for phlebotomy to reduce unnecessary blood loss.[9] Consultation with a bloodless medicine specialist for recommendations for using iron supplementation and erythropoietin may also be considered.(B3)

Differential Diagnosis

Differentials include the following conditions:

• Alpha thalassemia

• Aplastic anemia

• Beta thalassemia

• Hemolytic anemia

• Iron deficiency anemia

• Low LDL cholesterol

• Megaloblastic anemia

• Myelophthisic anemia

• Pernicious anemia

• Sickle cell anemia

• Spur cell anemia

Prognosis

Several case reports and series support HBO's efficacy and other "bloodless" modalities for acute and chronic blood loss anemias.[10][11][12][13]

Complications

Mild middle ear barotrauma is not uncommon.  Serious complications of HBO are rare.[14] These include:

• Eustachian tube dysfunction
• Tympanic membrane rupture
• Oxygen toxicity
• Ear, sinus, or tooth pain
• Decompression sickness
• Pneumothorax
• Arterial gas embolism
• Nitrogen emboli to the central nervous system, lung, or joints
• Middle ear hemorrhage
• Deafness
• Changes in vision
• Certain types of hemolytic anemia
• Fire hazard
• Nausea, fatigue, malaise
• Claustrophobia
• Equipment malfunction