Sickle Cell Crisis – Home Oxygen and timely treatment prevent complications and change the trajectory of disease – Case reports and practice guidelines
July 4th, 2024
By
Dr Sota Omoigui MD
Division of Inflammation and Pain Medicine
L.A. Pain Clinic
4019 W. Rosecrans Ave, Hawthorne, CA 90250
Email: [email protected]
Website: www.medicinehouse.com
Author
Sota Omoigui’s Anesthesia Drugs Handbook
(translated into six languages)
Sota Omoigui’s Pain Drugs Handbook
The Biochemical Origin of Pain
Recipient of the US FDA Advisory Committee Service Award, in recognition of distinguished service to the people of the United States of America
Abstract:
Reversible sickle cells (RSC) can become irreversible sickle cells (ISC) after repeated episodes of sickling. The reversible sickle cells can revert to their original flexible discoid shape when reoxygenated, but repeated sickling can damage the cell membrane and make it impossible for the cells to return to their normal shape, becoming irreversible sickle cells. Oxygen therapy in the golden half hour onset of a crisis restores reversible sickle cells and prevents them from progressing to a critical mass of irreversible sickle cells, wherein the sickle cell crisis becomes established and intractable. Developing a medication to prevent and stop a sickle cell crisis within the golden half hour has been very difficult. The efficacy of oxygen therapy in preventing and aborting a crisis in the golden half hour is very promising. When you stop the crisis, you prevent severe pain, emergency care, hospitalization and multi-organ damage. It would reduce the complications, disability and mortality rates linked to this chronic condition.
Introduction:
The sickle cell mutation can be traced back to at least 7300 years. The first recorded cases of sickle cell disease were in Egypt during the predynastic period (∼3200 BC), in the Persian Gulf during the Hellenistic period (2,130 years before present), and in Ghana in 1670 AD.[i]
For thousands of years, sickle cell disease has been an inevitable sentence of recurrent excruciating pain crisis, resulting in complications, severe disabilities and death. In the modern era, the mortality rate for adults with the disease has risen one percent every year since 1979. The median age at death in 2005 was 42 years for females and 38 years for males [ii]. The dreaded feature of the disease is the sickle cell crisis. Developing a medication to stop a sickle cell crisis has proven difficult. On September 25th, 2024, Pfizer withdrew Oxbryta (Voxelotor) from the market as the patients on Oxbryta had more sickle cell crisis than those on placebo[iii]. Crizanlizumab-tmca (Adakveo), by Novartis, was approved by the United States Food and Drug Administration (US FDA) in November 2019 for reduction in frequency of sickle cell crises. In May 2023, The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) revoked Novartis’ approval for Adakveo[iv] because Adakveo couldn’t reduce the number of painful crises. We need to have another look at oxygen therapy in the early period of sickle cell crisis.
Irreversible sickle cell formation is time dependent and HbS sickling is reversible with re-oxygenation[v] and in our clinical experience within the first golden half hour (30 mins). When time progresses, the cells become irreversibly sickled. Irreversibly sickled cells (ISC’s) are circulating blood cells in patients with sickle cell disease that retain a sickled shape even when oxygenated[vi]. In these irreversibly sickled cells, the structure of the cytoskeleton network is permanently altered. These are the cells that cause obstruction of blood flow, severe pain and suffering and multi organ damage. By the time these patients seek medical care or arrive in the hospital, they are already experiencing irreversible sickling which can no longer be reversed by oxygenation12. These cells remain until they are removed by destruction (hemolysis), phagocytosis or sequestration when an excessive amount of blood becomes trapped in the spleen, causing a dangerous drop in the circulating blood volume (drop in hemoglobin of 2 g/dL) accompanied by enlargement of the spleen (splenomegaly). Clearing these sickled cells is a process that can take several weeks resulting in a prolonged sickle cell crisis with multi organ damage and increased risk of death[vii]
History
Sickle cell disease was first described by Herrick in 1910[viii] when he observed a dental student who presented with pulmonary symptoms. He further described the “peculiar sickle-cell shape” of the red blood cells of the patient. In 1927, Hahn and Gillespie[ix] suggested that hypoxia caused the sickling of red blood cells by saturating a cell suspension with carbon dioxide to induce shape changes. The level and effect of hypoxia in the causation of a sickle cell pain crisis depends on the degree of anemia, sedation, nocturnal hypoventilation as well as the presence of other triggers such as stress[x], exertion/exhaustion, alcohol ingestion, altitude, infection, cold, all of which can vary at any point in time [xi] [xii].
In a low oxygen environment, the sickle hemoglobin undergoes formation of a sticky gel, with a network of closely packed parallel rod like structures, a process that is known as polymerization. With polymerization, the sickle hemoglobin cells become more rigid and change their shape to a sickle shape. The red blood cells are trapped and easily destroyed during their passage through the blood vessels and capillaries resulting in anemia and a complex cascade of processes that include inflammation, and ultimately, blood vessel occlusion (obstruction of blood vessels in almost every organ) with interruption of the blood supply and excruciating pain12
In 1930, Scriver and Waugh in Canada reported, a case of sickle-cell anemia, wherein the number of sickle cells in the blood may be varied by the change of the partial oxygen (O2) pressure; that this is a reversible reaction; and that sickling takes place when the O2 pressure falls below a pressure of 45 mm. Hg[xiii]. In 1983, an article by Franck and Chiu[xiv] stated as follows:
“Abnormalities in the availability of the phospholipids to exogenous probes have also been shown to occur in sickled erythrocytes. The accessibility of both aminophospholipids for chemical as well as enzymatic probes appears to be increased, not only in irreversibly sickled cells, but also in deoxygenated reversible sickle cells (RSCs), when compared to both normal cells or oxygenated (discoid) RSCs). Furthermore, it is of interest that RSCs not only possess the ability to readopt their discoid shape upon reoxygenation, but that this process also for the greater part restores the degree of accessibility of the glycerophospholipids to exogenous probes to the levels found in normal erythrocytes”
In 1991, another article by Robert Hebbel stated[xv].: “More precisely, sickling results in elevated translocation rates for added Phospatidylcholine ( PC) or lysoPC. For reversibly sickled cells this destabilization is reversible, with reoxygenation allowing a return to normal PC translocation rates and near-normal Phosphatidyl serine (PS) availability to phospholipase.
In a clinical trial by Zipursky et al in August 1992, the effect of oxygen therapy on the number of irreversibly (ISC) and reversibly (RSC) sickled cells was studied in patients with sickle cell anemia[xvi]. Inhalation of 50% oxygen in patients who were not in crisis produced a significant fall in RSCs and a lesser fall in ISCs. Inhalation of 50% oxygen in patients who were in crisis, showed a significant reduction in RSCs, but not in ISCs. In the group of patients that receive air (no supplemental oxygen) there was no significant change in RSCs or ISCs. In patients that were in a crisis, despite the reduction in RSCs in the oxygen-treated group, there was no significant difference between the air and oxygen groups in the duration of severe pain, opioid administration, and hospitalization. As mentioned previously, oxygen therapy when a sickle cell crisis is already established, does not affect the population of ISC as those have to be cleared by hemolysis, phagocytosis or sequestration. Reversible sickle cells (RSC) can become irreversible sickle cells (ISC) after repeated episodes of sickling. During sickling, red blood cells become rigid and sickle-shaped and obstruct the blood flow to the organs. The reversible sickle cells can revert to their original flexible discoid shape when reoxygenated, but repeated sickling can damage the cell membrane and make it impossible for the cells to return to their normal shape, becoming irreversible sickle cells 16. Thus, oxygen therapy in the golden half hour onset of a crisis restores reversible sickle cells and prevents them from progressing to a critical mass of irreversible sickle cells, wherein the sickle cell crisis becomes established and intractable.
What this means is that if we can reverse the low oxygen environment, by providing home inhalation oxygen within the first golden half hour of a sickle cell crisis, we may be able to stop the crisis. We have seen this work in a few sickle cell patients treated in our practice, as long as there are no other triggers involved such as cold and infection.
By the time sickle cell patients seek medical care or arrive in the hospital, they are likely already experiencing irreversible sickling which can no longer be reversed by oxygenation. Based upon our clinical experience, the time dependent golden half hour intervention for a sickle cell crisis, which can damage multiple organs is similar to that of the golden hour for stroke when there is the best chance of restoring blood flow and saving brain tissue or that for myocardial infarction wherein timely intervention impacts a patient’s survival and quality of life following a heart attack.
Discussion
In our practice, we have been able to reduce the incidence of sickle cell crisis as well as reduce hospitalizations by 90% in seven patients. This is of immense significance. The sickle cell crisis results in obstruction of blood flow, severe pain and suffering and damage to organs. It results in severe life threatening and disabling complications including acute chest syndrome, avascular necrosis of the hips (death of bone tissue due to lack of blood supply) with bone destruction, stroke, brain damage, priapism, kidney damage that may result in dialysis and increased risk of death. Thus the key to the disease is stopping the crisis, at the first sign of the crisis.
Now we know that a low oxygen environment will cause a crisis and re-oxygenation within several minutes of the crisis will reverse the sickling. The next question will be when and where do the majority of crisis occur. And research as well as clinical history already provided us the answer. In one study of 21 screened participants, nine (43%) had sufficient nocturnal hypoxaemia to warrant oxygen therapy (≥5 min at SpO2 ≤ 88%)11 In our clinical experience, the majority of crisis (90%) occur during sleep either at bedtime or in the daytime. Patients with sickle cell disease are fearful of going to sleep, because they never know if they would wake up in a crisis. The literature is replete with similar stories. An article in the New York Times, about a patient with sickle cell disease, stated: “She struggled through the night as she had so many times before, restless from sickle cell pain that felt like knives stabbing her bones. When morning broke, she wept at the edge of her hotel-room bed, her stomach wrenched in a complicated knot of anger, trepidation and hope”[xvii]. In another article in CNN, a different patient recollected as a child, fearing the night because that’s when her sickle cell crises most often hit. “I thought there was something about the hours between 2 and 5 a.m. that was just dangerous,” she said.[xviii] And what happens during sleep. People do not breathe as well during sleep as they do when they are wake. They have shallow or slow breathing that reduces oxygen intake during sleep. This is called nocturnal (nighttime) hypoventilation19. Unless it is very severe, people with normal hemoglobin do not suffer any bad effects. However, people with sickle cell anemia are at a greater risk from the low oxygen environment during sleep. Studies have linked nocturnal hypoventilation with sickle cell hemoglobin polymerization, and sickle cell pain crisis. In a study titled “Nocturnal oxygen saturation and painful sickle cell crises in children” [xix] the authors concluded that low nighttime oxygen saturation was highly significantly associated with a higher rate of painful crisis in childhood.
So, we know that a low oxygen environment causes sickle cell crisis and the greatest occurrence of a low oxygen environment occurs during sleep[xx]. Therefore, we can prevent it by having sickle cell patients sleep with oxygen when they go to sleep. Such a low oxygen environment is made worse when there are one or more triggers such as increased anemia, stress, exertion/exhaustion, infection, increased sedation, alcohol ingestion, altitude (>2000ft), infection, cold environment, a feeling of being unwell etc. Therefore, all patients will need to have home oxygen available to them for use as needed. In the absence of triggers, patients with sickle cell disease do not have to sleep with oxygen. Now to a very important point. Should the patient wake up in a crisis, they should immediately turn on their oxygen machine or cylinder and apply oxygen as we have found that the administration of oxygen within the golden half hour of a crisis, can abort the crisis, because HgbS sickling is reversible with re-oxygenation in the early stages[xxi].
Providing sickle cell patients with the scientific basis for their nighttime crisis, and the use of oxygen to prevent those crises, gives them control over their illness and significantly allayed their anxiety and fear of waking up in pain. If they use oxygen at bedtime, they will never wake up in a crisis.
Proof of Concept
The disease burden of sickle cell anemia has improved with the advent of medications like hydroxyurea and Voxelotor. These medications target the availability of oxygen at the molecular level to the sickle hemoglobin. Hydroxyurea increases Hemoglobin F (HbF) production in RBCs and decreases sickling of HbS[xxii] (https://www.oaepublish.com/articles/jtgg.2020.45) Hb F evolved to potentiate the transfer of oxygen (O2) from a mother’s blood to fetal tissues, a goal achieved by the higher Oxygen affinity of Hb F compared with adult Hb A. Oxbryta (Voxelotor) increases the affinity of the sickle hemoglobin for oxygen, thereby inhibiting sickling, reducing the amount of hemolysis and increasing hemoglobin levels[xxiii] [xxiv] Oxbryta taken orally (at 500 mg, three tablets once daily) can raise the hemoglobin level of a person with sickle cell anemia, by 2-3 g/l (Hematocrit increase of 6-9 %), within just a few days and in some cases can return close to normal levels[xxv] – almost as fast as a blood transfusion, and without the possible complications. However, at that dose, if administered long term, it raises the hemoglobin too high to a level that increases blood viscosity and in sickle cell increases the risk of a vaso-occlusive crisis. In the clinical trial, Oxbryta did not have a significant effect on reduction in pain crisis compared with placebo18.
The only exception in our current advances is the Novartis $665 million drug, Crizanlizumab-tmca (Adakveo), a humanized monoclonal antibody against P-selectin which inhibits the adhesion of sickle erythrocytes and leukocytes to the endothelium.[xxvi] Crizanlizumab was approved by the FDA in November 2019 for reduction in frequency of vaso-occlusive crises. In May 2023, The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) revoked Novartis’ approval for Adakveo[xxvii] after concluding that the med’s benefits did not outweigh the risks. The decision was based on the results[xxviii] of the global phase III study STAND (NCT03814746) trial, in which the drug didn’t outperform placebo. Specifically, Adakveo (crizanlizumab) couldn’t reduce the number of painful crises leading to a healthcare visit. Adakveo-treated patients saw an average of 2.5 painful crises resulting in a healthcare visit over their first year of treatment, while patients in the placebo group had an average of 2.3. Furthermore, the average number of crises requiring a home healthcare visit or treatment, which was 4.7 in the Adakveo group compared with placebo’s 3.9. On January 10th, 2024, the UK Medicines and Healthcare products Regulatory Agency (MHRA), based on the same Phase III STAND study, revoked a conditional marketing authorization for Adakveo to treat sickle cell disease[xxix].
The failure of this multimillion-dollar drug was predictable because the drug failed to target the hypoxic (low oxygen) milieu wherein Hgb polymerization is initiated. Instead, the drug targeted downstream of the subsequent inflammatory cascade, by which time Hgb polymerization is irreversible[xxx].
Inhalational Oxygen
Oxygen may be obtained from oxygen cylinders or, more conveniently, and with less maintenance, from portable or home oxygen concentrators such as the SeQual Eclipse, Inogen, Respironics, AirSep or many other lower priced Chinese brands (prices as low as $250.00). An oxygen concentrator is a device that intakes the surrounding air to produce an inspired oxygen concentration (FiO2) of 24% to 28% at 1-2 liters per minute flow by nasal cannula[xxxi] [xxxii] The concentrator, using battery or electrical power, takes in air, compresses the air and passes it over a sieve bed containing zeolite. The zeolite adsorbs the nitrogen from the air and the remaining gas, which is mostly oxygen is sent out of the concentrator through a plastic tubing to reach a nasal canula or mask. The nitrogen desorbs from the zeolite under the reduced pressure and is vented into the atmosphere. Avoid smoking or use of any electrical objects such as electric blankets, hair dryers or flammable materials near an oxygen concentrator.
Air Travel and High Altitudes
Air travel is a hidden danger for sickle cell patients. During and following commercial airline flights, patients with sickle cell disease are known to experience complications such as bone pain, splenic infarction, [xxxiii] [xxxiv] [xxxv] osteonecrosis (avascular necrosis) of the hip, and, in some cases, prolonged crisis resulting in death. These complications have been linked to prolonged oxygen desaturation at high altitudes, with oxygen saturations measured as low as 77%, instead of the normal of 95%-100%. [xxxvi] Oxygen supplementation should be prescribed to ameliorate the low oxygen environment that occurs at high altitudes during airline flights, which does result in considerable harm to sickle cell patients who continue to have injury and death after such flights. Some airlines will provide compressed medical oxygen for flights while others require the patient to bring an oxygen concentrator that is certified for flight, which is more onerous, cost prohibitive for many patients and as a mechanical device can fail during flight or at the destination. All airlines should be mandated as a matter of human rights, to provide compressed medical oxygen to patients with respiratory disabilities such as sickle cell disease.
Treatment of a Crisis
Time is of essence to abort the crisis within the golden half hour before severe pain produces chest splinting[xxxvii], inadequate respiration further hypoxic sickling and a prolonged crisis requiring hospitalization. Consequently, home oxygen therapy, pulse oximetry and vital sign monitoring along with the first dose of opioid and anti-inflammatory injections that the patient has previously tolerated should become standard initial treatment by the Emergency Medical Service (EMS) ambulance team or a home health nurse.
Case Presentation
We have applied the principle described above to seven patients with sickle cell anemia over the last 20 years who have come to our specialist pain clinic for pain control. Their ages ranged from 25 to 67 years, African Americans, five males and two females. All our patients had most of their crises occurring at night, waking them up from sleep or occurring after they took plane flights or visited cities at high altitudes such as Vail and Denver Colorado or Las Vegas, Nevada.
Our patients were prescribed an oxygen concentrator to use at home. They were advised to sleep with oxygen (1.5-2 liters /min by nasal canula) only when there are one or more triggers such as increased anemia, stress, exertion/exhaustion, infection, increased sedation, alcohol ingestion, altitude (>2000ft), infection, cold environment, a feeling of being unwell etc. In the absence of triggers, they do not have to sleep with oxygen. All our patients were able to abort a crisis by administering oxygen at the first sign of the crisis. The only exceptions were when the crisis occurred outside the home or was induced by infection or hypothermia.
Before our intervention, with provision of an oxygen concentrator for administration of oxygen before sleep, they had regular episodes of sickle cell crisis, on average one every two months, with hospitalizations about once every 3-6 months, despite being on hydroxyurea. During these crises, they experienced disabling pain scores of 10/10, requiring prolonged hospital admissions ranging from 3 days to 3 weeks. The prolonged hospital stays occurred with development of acute chest syndrome or other complications.
After implementation of nighttime inhalational oxygen, pain crisis reduced in frequency to once every 6 months to 1 year. Hospitalizations were reduced from once every 3-6 months to once every 3-5 years. Most of those few and far between hospitalizations were due to cold or infection.
Cure – Bone Marrow Transplant and Gene Therapy
There are now several curative options for sickle cell disease. The essence of these cures is to reduce sickle hemoglobin and provide increased oxygen capacity of the replacement hemoglobin. Two therapies LYFGENIA™ (lovotibeglogene autotemcel)[xxxviii] [xxxix], also known as lovo-cel and CASGEVY (exagamglogene autotemcel)[xl] have recently been approved.
Casgevy and Lyfgenia, cost $2.2 million and $3.1 million per patient, respectively for a course of treatment, which can take up to a year. The therapies require several other procedures — including chemotherapy prior to the treatments, which involve removing blood cells from a patient and modifying the DNA before re-introducing them in the body. The United States government has stated that it will negotiate an “outcomes-based agreement” with the companies, meaning the prices for treatments will be tied to whether the therapy improves health outcomes[xli].
It is important to highlight that these curative therapies do not reverse pre-existing end organ complications. Oxygen and timely treatment is more likely to prevent end organ complications even for patients that will subsequently undergo gene therapy. Costs and availability of these new therapies will limit their global application, even in high-income countries. Capacity is limited. Bluebird Bio, the company that makes Lyfgenia, estimates that it can treat 85–105 patients per year with the gene therapy. The process is complex and time-consuming, and medical centers can only handle a limited number of patients because each person needs intensive care. Oxygen combined with Oxbryta will be the closest, most affordable and accessible alternative to gene therapy.
Conclusion:
There is evidence that intervention with home inhalational oxygen can prevent and timely abort a sickle cell crisis. The estimated global population of patients with sickle cell disease is 7.74 – 20 million with a sickle cell disease mortality burden at 376 000 in the year 2021[xlii] The mortality rate for adults with the disease has risen 1 percent every year since 19792. Half of adult sickle cell patients are dead by their early 40s.[xliii] The Healthcare Cost and Utilization Project (HCUP) Statistical Brief presented statistics on inpatient stays among patients with sickle cell disease (SCD) from 2000 through 2016 43. The number of hospital stays involving SCD for patients older than 45 years of age more than doubled between 2000 and 2014. Over 70 percent of SCD-related stays had a principal SCD diagnosis. Nearly all stays for SCD and one-third of stays with a secondary diagnosis of SCD involved a pain crisis. Black patients accounted for 88.7 percent of stays with a principal diagnosis of SCD (nearly all of which involved a pain crisis). Of 134,000 stays involving SCD in 2016, 71.3 percent were for SCD specifically (i.e., SCD was the principal diagnosis). Nearly all stays with a principal diagnosis of SCD involved a pain crisis (96.0 percent). The leading reason for stays for patients with a secondary diagnosis of SCD was respiratory system related illnesses, constituting 14.3 percent of those stays. Infectious and parasitic diseases and pregnancy were the second and third most common reasons for stays for patients with a secondary diagnosis of SCD, constituting 13.2 and 12.8 percent of those stays, respectively. In 2016, the aggregate cost of inpatient hospital stays for patients with a principal diagnosis of SCD was $811.4 million. Among stays for SCD, the mean length of stay was around 5 days for adults and was approximately 1 day shorter for children[xliv]. Sickle cell disease imposes a recognized economic burden on the US Healthcare system and society, primarily owing to inpatient hospitalizations and impaired quality of life. Sickle cell disease is not only an important medical problem, it is an economic one that causes $1.5 billion in lost wages and productivity each year in the U.S. alone, according to the first study of its kind. That comes to more than $650,000 lost over the average working life of a person living with the painful genetic disorder[xlv] [xlvi]
The provision of inhalational oxygen can be easily implemented and the benefits will be immediately obvious to physician, patient, their families and caregivers as well as the community and the nation. The cost of an in home oxygen concentrator, with an average duration of device use of 32.4 ± 30.7 months[xlvii] and even longer with proper maintenance, is often less than the cost of one hospital admission. The cost of an oxygen cylinder in the United States varies and in one supplier was $234.00 with refill cost of $14.30[xlviii]. In Nigeria, the cost of an oxygen cylinder is an average of $100.00 with refill cost of $15.00. That should last an average of 2-4 months depending on usage, which refill will be about $1.00 per week. For such a low cost, inhalational oxygen will significantly reduce the burden of illness, disability and death in patients with sickle cell disease. The addition of inhalational oxygen will change lives for both patients and their families. Studies have shown that there are no deleterious effects from long-term use of oxygen[xlix] .
There is good literature evidence that reoxygenation with inhalational oxygen at the early stages of a sickle cell crises is beneficial in restoring reversible sickle cells to normal and preventing irreversible sickling and the consequent blood vessel occlusion, severe pain, severe anemia from hemolysis of the irreversible sickle cells and end organ injuries. While we have found very good results in seven patients over twenty years, but how this translates to an estimated 7-20 million patients globally should be readily proven by its application. We recommend the reproducibility of our findings in a larger cohort of patients. Oxygen gas is cheaper than any other medication for a chronic disease. The cost savings will be significant in human, emotional and economic terms from, preventing severe pain and suffering, subsequent hospitalization and treatment of complications.. Oxygen can be dangerous and patients are advised to avoid smoking, or use of any electrical objects such as electric blankets, hair dryers, open flames or flammable materials near an oxygen concentrator or cylinder.
Acknowledgements:
Isiuwa Omoigui BA, Political Science, Ethnicity, Race and Migration (Yale’23), (Columbia Law School, New York)
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