Use of hyperbaric oxygenation as an adjunctive treatment for severe pernicious anaemia in a bloodless medicine patient

Abstract

Severe anaemia in patients who cannot receive blood transfusion is an indication for the use of hyperbaric oxygen therapy (HBO). Most reports of the use of HBO for anaemia involve patients with acute blood loss. This report details a case of HBO used for a patient with severe pernicious anaemia. A 35-year-old Jehovah’s Witnesses believer presented to a hospital with fatigue, dyspnoea and haemoglobin of 26 g/L. She was diagnosed with pernicious anaemia. As she could not receive blood transfusion due to her religious beliefs, vitamin B₁₂ supplementation and HBO were administered and resulted in significant improvement in her condition. The mechanisms of action of HBO, including increased systemic plasma oxygenation, can alleviate signs and symptoms of anaemia regardless of its aetiology. HBO administration can greatly enhance the plasma arterial oxygen content, leading to clinical improvement in patients with anaemia who cannot receive blood transfusion.

Background

Severe anaemia with inability to receive transfusion is an accepted yet underutilised indication for the administration of hyperbaric oxygen therapy (HBO). The use of HBO can alleviate signs and symptoms of oxygen debt which are often present in severely anaemic patients. Most reported cases of the use of HBO for severe anaemia involve patients who have sustained acute blood loss; however, anaemia may result from other causes, including increased red blood cell destruction or decreased red blood cell production. The following case report describes the use of HBO to treat a Jehovah’s Witnesses believer with profound and symptomatic anaemia due to iron deficiency and pernicious anaemia.

Case presentation

A 35-year-old woman presented to an emergency department (ED) for evaluation of a 1-week history of fatigue, cough, fever, dyspnoea and chest pain. She reported that she had also experienced recent diarrhoea and weight loss after taking a trip to Canada. She was otherwise healthy and took no medications. She was a Jehovah’s Witness and did not use tobacco products or consume ethanol.

In the ED, her vital signs revealed a temperature of 37.3°C, a heart rate of 126/min and blood pressure 132/71 mm Hg. Physical examination was unremarkable except for diffuse pallor.

Investigations

Laboratory testing revealed pancytopenia (white blood count 1.2 10⁹/L (range 4–10.8 10⁹/L), haemoglobin 26 g/L (range 110–145 g/L), platelets 76 10⁹/L (range 145–500 10⁹/L)). Her blood cardiac troponin was undetectable, blood lactic acid was 1.0 mmol/L (range 0.7–2.0 mmol/L), and automated reticulocyte count was 1.5% (range 0.5%–2.0%).

Differential diagnosis

She was admitted to an intensive care unit; the suppressed reticulocyte response noted on initial laboratory testing led to a differential diagnosis of aplastic anaemia or acute leukaemia. Due to her religious beliefs, the patient declined blood transfusion. A haematological consultation was obtained; additional laboratory studies were ordered, including iron studies which were borderline low and folate concentration which was unremarkable. Vitamin B₁₂ level was undetectable and whole blood erythropoietin concentration was elevated (4376 mU/L (reference range 4–27 mU/L)). Antibodies to intrinsic factor were positive, and she was treated with intramuscular vitamin B₁₂.

Treatment

The following morning, the patient’s haemoglobin fell to 21 g/L. She remained fatigued and tachycardic, and exhibited intermittent confusion. Her temperature rose to 38.4°C, and she was administered intravenous antibiotics for neutropenic fever prophylaxis. Flow cytometry was performed with no lymphoproliferative disorder identified; the patient declined to undergo bone marrow biopsy. Three doses of intravenous sodium ferric gluconate 250 mg were ordered for iron repletion, and the patient was also referred for hyperbaric medicine evaluation. She received five daily sessions of HBO and tolerated these without complications.

By hospital day 7, she was no longer febrile, although she remained tachycardic (heart rate 103/min). Her haemoglobin had improved to 42 g/L, and her automated reticulocyte count had increased to 13.8%. Her white blood count was 4.7 10⁹/L, and her platelet count was 150 10⁹/L. She remained fatigued but felt better overall; her mental status remained normal, and she was able to ambulate along the hospital hallways without significant dyspnoea. Due to her significant improvement in mentation and functional status, she requested discharge from the hospital despite her critically low haemoglobin concentration. She left the hospital on hospital day 7 with instructions to take oral vitamin B₁₂ supplementation and to follow-up for further outpatient care. At the time of discharge, the aetiology of her anaemia was believed to be multifactorial, related to pernicious anaemia as well as possible iron deficiency and gastrointestinal malabsorption.

Due to insurance limitations, the patient was unable to maintain her medical follow-up appointments for several months. She presented for re-evaluation 5 months after hospital discharge; at this time, she reported having persistent severe fatigue as well as exertional dyspnoea. She had experienced heavy and painful menstrual cycles since hospital discharge. She was unable to work due to these symptoms. Her haemoglobin was 48 g/L; platelet and white blood cell counts were within normal limits. Iron studies revealed severe iron deficiency (iron 9 μg/dL (range 27–159 μg/dL), ferritin 2 ng/mL (range 15–150 ng/mL), and the patient was scheduled for a series of iron infusions and hyperbaric treatments. She was evaluated by a haematologist, who referred her for a gastroenterology evaluation for possible malabsorption. She was also referred for gynaecological evaluation due to the reports of menorrhagia.

Outcome and follow-up

After completion of a second course of HBO and iron infusions, the patient’s haemoglobin rose to 74 g/L. She stated that she had only intermittent fatigue and reported resolution of her previously abnormal menstrual cycles. She felt well enough to return to her job as a teacher, as this position was virtual in nature due to the ongoing COVID-19 pandemic.

Discussion

Anaemia, the most frequent pathology in humans, is defined as a haemoglobin concentration of less than 120 g/L in women and 130 g/L in men.¹ Anaemia may occur secondary to blood loss, increased red blood cell destruction or decreased red blood cell production. Many cases of anaemia are multifactorial in aetiology, which may confound the diagnosis and treatment of this condition.¹

While severe or symptomatic anaemia is often treated by transfusion of blood products, some patients are unable to receive transfusions due to religious or medical limitations. Most patients who are unable to receive transfusions due to religious reasons are Jehovah’s Witnesses.² There are more than 8 million Jehovah’s Witnesses worldwide; members of this religion believe that the Biblical command to abstain from blood (Acts 15:20) requires them to avoid receiving transfusion of blood or its components. Management of severe anaemia in this patient population includes interventions to reduce blood loss, enhance red blood cell production and increase the oxygen carrying capacity of blood. Methods of reducing blood loss include use of paediatric phlebotomy tubes as well as reduction of unnecessary blood draws. Enhancement of red blood cell production can result from the administration of recombinant human erythropoietin, iron supplementation and correction of nutritional deficiencies. The oxygen carrying capacity of blood may be increased through the use of HBO or artificial blood substitutes; clinical implementation of the latter has been limited by unacceptable toxicities, including increased risk of cardiac disease and death.³

In 1959, the Dutch surgeon Boerema published ‘Life without blood’, a manuscript detailing the use of HBO for the treatment of anaemia.⁴ Boerema exsanguinated healthy piglets and replaced the blood volume with a plasma-like solution. The resulting haemoglobin concentration of the piglets was 4 g/L, a haemoglobin concentration which is incompatible with life. The piglets were then pressurised in a hyperbaric chamber for 45 min. The animals survived this exposure, despite having minimal haemoglobin, 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 can greatly 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 pressurisation, more of that gas dissolves in solution. Breathing normobaric room air (21% oxygen) results in a PaO₂ of approximately 100 mm Hg; breathing 100% oxygen under hyperbaric conditions results in a PaO₂ of greater than 1600 mm Hg.⁵ Under hyperbaric conditions, oxygen dissolved in the plasma can approximate or meet the body’s metabolic demands.⁶ Since Boerema’s initial publication on this subject, there have been multiple reported cases of the use of HBO for the treatment of acute blood loss anaemia in patients who are unable to receive transfusion of blood products.^5–7 In these cases, patients received one to three HBO treatments daily; the treatment frequency was based on the patient’s clinical presentation, and was titrated based on improvement or resolution of the signs and symptoms of oxygen debt.

Although acute blood loss may account for most of the patients who are referred for HBO due to symptomatic anaemia, patients with other types of anaemia may also be appropriate candidates for administration of hyperbaric oxygenation. Decreased red cell production may occur secondary to aplastic anaemia, nutritional deficiencies or drug-induced bone marrow suppression. Increased red blood cell breakdown can occur due to intravascular or autoimmune haemolysis. Patients with anaemia due to any of these conditions may also be candidates for HBO if they are unable to receive blood transfusions. The systemic hyperoxygenation that occurs as a result of HBO administration can improve the signs or symptoms of oxygen debt regardless of the aetiology of the anaemia.

In the case described above, HBO was used to treat a patient with profound anaemia of multifactorial aetiology, including iron deficiency and pernicious anaemia. Pernicious anaemia is a condition characterised by gastritis and development of autoantibodies to intrinsic factor.⁸ Intrinsic factor, which is secreted by the gastric parietal cells, is required for normal absorption of vitamin B₁₂ from the gastrointestinal tract; the presence of intrinsic factor antibodies leads to decreased vitamin B₁₂ absorption.⁹ The signs and symptoms of pernicious anaemia may vary in severity from mild fatigue to significant neurological impairment, including peripheral neuropathy, areflexia and cognitive impairment.¹⁰ Pancytopenia, which was present in the patient described in the above case, is an infrequent manifestation of vitamin B₁₂ deficiency.¹¹ The diagnosis of pernicious anaemia is established by identification of intrinsic factor antibodies; treatment involves lifelong administration of vitamin B₁₂.⁹

The patient in this case survived despite a nadir haemoglobin concentration of 21 g/L. Although this represents a critically low haemoglobin level, utilisation of patient blood management strategies can result in enhanced survival, without the use of blood product transfusion, in patients with haemoglobin concentrations as low as 25 g/L.¹² While the minimum haemoglobin concentration required to sustain life has not been defined, thresholds for blood transfusion have declined in recent years as the medical community has accepted tolerance of lower haemoglobin concentrations in the daily care of hospitalised patients.¹³ The risks of anaemia in the hospitalised patient population have been well described in the medical literature. In the postoperative patient population, the odds of death increase by a factor of 2.5 for every 100 g/L decrease in postoperative haemoglobin.¹⁴ In Jehovah’s Witnesses, anaemia-related mortality risk factors include shock, acute gastrointestinal bleeding, pneumonia, a nadir haemoglobin of less than 70 g/L, sepsis, worsening congestive heart failure and neurological complications.¹⁵ In this case, the patient’s lack of significant medical comorbidities increased her likelihood of survival despite the presence of severe anaemia.

In this case, the patient’s absolute reticulocyte count increased dramatically after she received sequential HBO treatments. In humans, endogenous erythropoietin production is stimulated by the presence of renal tissue hypoxia, and intermittent hypoxia involving normobaric hyperoxygenation has been studied as a potential catalyst for the release of endogenous erythropoietin.¹⁶ Only one study has explored the use of intermittent relative hypoxia after hyperbaric-induced hyperoxia as a stimulus for erythropoietin secretion. The results of that study revealed a decrease in endogenous erythropoietin production after administration of a single hyperbaric exposure.¹⁷ A significant increase in the absolute reticulocyte count was noted after the patient in this case received five hyperbaric treatments. This suggests that there may be a favourable effect on endogenous erythropoietin production after administration of serial hyperbaric exposures.

Learning points.

• Hyperbaric oxygen therapy (HBO) administration can greatly enhance the plasma arterial oxygen content, leading to clinical symptomatic improvement in severely anaemic patients who are unable to receive blood transfusion.

• While many patients who are referred for hyperbaric medicine due to a diagnosis of severe anaemia may have acute blood loss, patients with other types of anaemia may also be candidates for HBO.

• The mechanisms of action of HBO in the treatment of severely anaemic patients, including significant increase in systemic plasma oxygenation, can improve the signs and symptoms of oxygen debt in patients who have anaemia of any aetiology.

• By maintaining an enhanced awareness of the different types of anaemia and understanding the mechanisms of action of HBO in the severely anaemic population, hyperbaric medicine clinicians will be optimally prepared to promote enhanced outcomes in this patient population.