Let Oxygen be your medicine
By Dr Sota Omoigui MD, Division of Inflammation and Pain Medicine, L.A. Pain Clinic
Introduction:
For too long has sickle cell disease been an inevitable sentence of severe pain and suffering. For too long have patients with sickle cell disease had to writhe in excruciating pain crisis, to suffer severe disabilities and die with no hope.
For the first time in almost 100 years, we describe herein, a home intervention that can prevent and stop a sickle cell crisis. We also include in this article, a video presentation of a patient with sickle cell disease, who received this intervention and experienced an immediate decrease in pain crisis, a decrease in hospitalizations and a change in the quality of his life (https://youtu.be/cfoOz1CLX7I?si=Ixs6AZWeTLUzVGHe) Empowered by knowledge, over the last hundred years, we can shine a light and dispel the darkness of despair, disability and death.
This intervention will change lives of patients with sickle cell disease together with their families and caregivers. It will decrease the illness and hospitalization burden not just in Africa but all over the world.
Sickle cell disease was first described by Herrick in 1910 (https://www.scirp.org/reference/referencespapers?referenceid=590342) 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 suggested that hypoxia caused the sickling of red blood cells by saturating a cell suspension with carbon dioxide to induce shape changes (https://www.deepdyve.com/lp/american-medical-association/sickle-cell-anemia-report-of-a-case-greatly-improved-by-splenectomy-Uc0OCwdBPp)
In 1930, Scriver and Waugh in Canada reported, a case of sickle-cell anaemia, wherein the number of sickle cells in the blood “in vivo” may be varied by the change of the partial oxygen (02) pressure; that this is a reversible reaction; and that sickling takes place when the 02 pressure falls below a pressure of 45 mm. Hg.
(https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC382053&blobtype=pdf) Hypoxia means low oxygen. So 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.
This represents the underlying pathology of sickle cell disease which we have known for almost one hundred years. Very importantly, 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, exertion/exhaustion, alcohol ingestion, altitude, infection, cold, all of which can vary at any point in time.
As stated before, polymerization is the sickling process. This means the sickle hemoglobin cells become more rigid and change their shape to a sickle shape. In a low oxygen environment, the sickling process causes secondary changes in cell shape, size, water content, and membrane structure that contribute to the impairment of intrinsic cell deformability which is the flexibility of the red blood cell to pass through blood vessels.
The red blood cells are trapped and easily destroyed during their passage through the blood vessels and capillaries resulting in anemia. Thus Hemoglobin S (HgbS) sickling results in a very 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.
Now, here is the most important knowledge in this process that has been overlooked over all these years. Irreversible sickle cell formation is time dependent. HgbS sickling is reversible with re-oxygenation within the first several minutes.
As stated in this article by Robert Hebbel: “More precisely, sickling results in elevated translocation rates for added Phospatidylcholine ( PC) or lysoPC.110., 121., 122.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. (https://www.sciencedirect.com/science/article/pii/S0006497120777840?via%3Dihub) Another article by Franck and Chiu (https://www.sciencedirect.com/science/article/pii/S0021925820820833) 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”
What this means is that if we can reverse the low oxygen environment, by providing home oxygen within the first 15-30 minutes of a sickle cell crisis, we can stop the crisis. And we have seen this work in every sickle cell patient that we have treated, as long as there are no other triggers involved such as cold and infection.
We have been able to reduce the incidence of sickle cell crisis as well as reduce hospitalizations by 90%. 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, kidney damage that may result in dialysis. 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.
Most crises 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. One of our patients stated that she stayed up late in the night to shorten the duration of sleep.
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” (https://www.nytimes.com/2021/05/30/us/sickle-cell-black-women.html) . 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. (https://www.cnn.com/2021/06/18/health/world-sickle-cell-day-human-factor-wellness/index.html)
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 (night time) hypoventilation. 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” (https://pubmed.ncbi.nlm.nih.gov/12393400/) the authors concluded that low nighttime oxygen saturation was highly significantly associated with a higher rate of painful crisis in childhood.
Therefore, we know that a low oxygen environment causes sickle cell crisis and the greatest occurrence of a low oxygen environment occurs during sleep. 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.
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 and apply oxygen as we know that the administration of oxygen within several mins of a crisis, can abort the crisis, because HgbS sickling is reversible with re-oxygenation in the early stages.
Providing sickle cell patients with the scientific basis for their night time 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.
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. Once again, we mention oxygen. Hydroxyurea increases Hemoglobin F (HbF) production in RBCs and decreases sickling of HbS (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, resulting in a decreased concentration of deoxygenated sickle hemoglobin, and thereby inhibiting sickling, reducing the amount of red blood cell destruction and increasing hemoglobin levels (https://www.medcentral.com/pain/how-manage-acute-pain-crisis-sickle-cell-disease-practical-recommendations) (https://pubmed.ncbi.nlm.nih.gov/31199090/)
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 to near normal levels – almost as fast as a blood transfusion, and without the possible complications.
Oxbryta medication results in an increase of oxygenated sickle cell hemoglobin and patients on Oxbryta have a decreased need for supplemental oxygen at bedtime. Oxygen should however be utilized in the presence of crisis triggers. Oxbryta improves hemoglobin levels and reduces the frequency of oxygen use. However, unlike oxygen you breathe in, these medications decrease the incidences of sickle cell crisis but do not abort a crisis so there is still a need for oxygen both for prevention as well as timely abortion of a pain crisis. Only oxygen used in a timely manner can abort a sickle cell crisis.
All of our patients were able to abort a crisis by administering oxygen at the first sign of the crisis. The only exceptions to timely aborting a crisis are when the crisis occurs outside the home or was due to infection or cold weather. Once hemoglobin sickling is irreversible, oxygen will not abort the crisis.
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.
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 (https://www.ncbi.nlm.nih.gov/books/NBK560867/) 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. The oxygen concentrator should be set as continuous flow and not pulse dose which is triggered by breath and fails to provide enough oxygenation.
Oxygen concentrators range from cheaper home units to more expensive portable units certified for flight. In Nigeria, low priced Chinese home oxygen concentrators may be purchased over the internet or on websites like Konga.com. Prices range from N400,000.00 to N700,000.00 which is cheaper than the cost of one hospitalization. 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, (https://www.medcentral.com/pain/how-manage-acute-pain-crisis-sickle-cell-disease-practical-recommendations) (https://pubmed.ncbi.nlm.nih.gov/12677546/) (https://pubmed.ncbi.nlm.nih.gov/13292838/) 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%. (https://openhematologyjournal.com/VOLUME/4/PAGE/15/FULLTEXT/) 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. Other airlines require the patient to bring an oxygen concentrator that is certified for flight such as a Sequal Eclipse. This is much more cumbersome, and may get the patient stranded far from home, if there is any mechanical damage to the concentrator and we advocate for all airlines 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 15-20 minutes before severe pain produces chest splinting, inadequate respiration, further hypoxic sickling and a prolonged crisis requiring hospitalization.
The patient’s physician or hospital should have a standing order for the Emergency Medical Service (EMS) ambulance team or a home health nurse to administer at home, the first dose of opioid and anti-inflammatory injections that the patient has previously tolerated, together with oxygen, pulse oximetry and vital sign monitoring.
Only strong injectable opioids (e.g. Morphine, Pethidine injection) and injectable NSAIDs (e.g. Ketorolac, Diclofenac injection) that the patient has previously tolerated in a hospital setting, should be used. Weak opioids like Pentazocine or Tramadol are ineffective and will only prolong a crisis.
(https://www.medcentral.com/pain/how-manage-acute-pain-crisis-sickle-cell-disease-practical-recommendations) Where available, patients are advised to call an ambulance and proceed to the hospital should oxygen fail to abort the crisis, because severe anemia and infection including malaria may be the cause of the crisis.
Case Presentation
We have had seven patients with sickle cell anemia over the last 20 years. Their ages range from 25 to 67 years. They were all African American with five males and two females. Pain crisis with excruciating pain scores of 10/10 occurred on average once every 2 months with hospitalizations about once every 3-6 months. All of our patients had the majority 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 are prescribed an oxygen concentrator to use at home. They are 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 of 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 night time 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) (https://www.bluebirdbio.com/-/media/bluebirdbio/Corporate%20COM/Files/Lyfgenia/LYFGENIA_Prescribing_Information.pdf) , also known as lovo-cel and CASGEVY (exagamglogene autotemcel) (https://www.drugs.com/newdrugs/fda-approves-lyfgenia-lovotibeglogene-autotemcel-patients-ages-12-older-sickle-cell-history-vaso-6158.htm) 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. (https://stateline.org/2024/03/14/new-way-for-states-to-cover-pricey-gene-therapies-will-start-with-sickle-cell-disease/#:~:text=The%20two%20gene%20therapy%20treatments,%243.1%20million%20per%20patient%2C%20respectively.)
It is important to highlight that these curative therapies do not reverse pre-existing end organ complications. Oxygen and timely treatment are still mandatory in preventing 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:
Intervention with home inhalational oxygen that can prevent and timely abort a sickle cell crisis, is immediately available and accessible, to the global population of 6.51-9.2 million patients with sickle cell disease, and a sickle cell disease mortality burden at 376 000 in the year 2021 (https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(23)00118-7/fulltext).
The provision of inhalational oxygen is easily implemented and the benefits will be immediately obvious to both physician and patient. The cost of an in home oxygen concentrator, with an average duration of device use of 32.4 ± 30.7 months (https://pubmed.ncbi.nlm.nih.gov/24482704/) and even longer with proper maintenance, is often less than the cost of one hospital admission.
It will significantly reduce the burden of illness, disability and death in patients with sickle cell disease. The addition of inhalational oxygen with molecular oxygen directly by Voxelotor (Oxbryta) or indirectly by Hydroxyurea will change lives. Studies have shown that there are no deleterious effects from long term use of oxygen (https://pubmed.ncbi.nlm.nih.gov/32878859/)
It is imperative that the Federal and State Ministries of Health come to the assistance of sickle cell patients by providing oxygen concentrators to those who cannot afford it. The Government should also make arrangement with Pfizer, the manufacturer of Oxbryta to provide Oxbryta at a significantly reduced cost than the present cost of $100,000.00 for one year prescription.
Or alternatively make arrangements with the World health Organization (WHO), NGOs and Indian manufacturers to provide generic Oxbryta. It will decrease the costs of hospitalizations as well as the need and costs for repeat blood transfusions for sickle cell patients.
Strong opioid medications should also be made available to clinic and hospitals all over the country for the treatment of patients with severe pain as in sickle cell crisis.
As Hippocrates stated in 400 BC, let food be your medicine, Sota Omoigui declares in 2024 AD, that the guiding principles in the management of sickle cell disease shall be: Let Oxygen be your medicine – whether provided by breathing oxygen or at the molecular level with Oxbryta.
Acknowledgements:
Isiuwa Omoigui BA, Political Science, Ethnicity, Race and Migration (Yale’23), (Columbia Law School, New York) for designing the educational poster titled: Ending the Pain.
Dr Sota Omoigui is MD, Division of Inflammation and Pain Medicine L.A. Pain Clinic 4019 W. Rosecrans Ave, Hawthorne, CA 90250 Email: Medicinechief@aol.com 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
Dr. Omoigui is a recipient of the US FDA Advisory Committee Service Award, in recognition of distinguished service to the people of the United States of America.
Comment here