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What exactly causes cyanosis?
Editor's Note
"Pediatrics, Big Cases" is a new case learning mode launched by the Pediatric Channel of the medical community, which analyzes the cases layer by layer with rigorous medical logic thinking, and takes you closer to the "real culprit" behind the disease. Each layer of analysis reaches a turning point, asking the reader an answer by asking a question, and then moving on to the next level of reasoning and speculation. Through this "problem-oriented model" case study, readers can get close to clinical examples at zero distance and let readers develop "academic" clinical thinking, which is believed to be of great benefit to the clinic.
Tips: The full text is about 5300 words, and it takes 10 to 15 minutes to read.
Le Le was a poor child, diagnosed with acute lymphoblastic leukemia more than 2 years ago, after multiple chemotherapy remissions, 4 days ago re-examination of bone puncture found a recurrence. In order to assess whether the brain tissue is invaded by leukemia, after admission to the hospital, the brain magnetic resonance imaging (MRI) examination of the skull occurred, and a thrilling and strange scene occurred, which really scared the family and doctors out of a cold sweat.
The author believes that after reading this case, you will have a new understanding of the analysis method of cyanosis and the interpretation of blood gas analysis.
1
Before, it was okay to be calm, why is there something now?
After oral sedation of chloral hydrate in the outpatient resuscitation room, Lele developed cyanosis of the lips and progressive exacerbation, and the blood oxygen saturation decreased as low as 60% for about ten minutes, when the heart rhythm was 50-66 bpm, 22 breaths per minute, the symptoms recovered slowly after giving oxygen to the mid-flow mask, and the pulse oxygen fluctuations under oxygen inhalation were 96% to 97%.
The doctor thought it was very strange, Lele had also taken sedatives many times before, and even often used intravenous sedatives, there was no problem, why did this problem occur this time?
Cyanosis after sedation, the doctor can easily think of cardiopulmonary disease, but this kind of disease is generally aggravated after exercise, rather than aggravated after sedation, and the doctor further gave Lele lung CT, cardiac color ultrasound and electrocardiogram, and did not find much problem.
Cyanosis associated with sedation is also reminiscent of the effects of sedation on the nervous system, resulting in a lack of oxygen after sedation. However, MRI only suggests a delay in myelination and does not find too severe lesions.
What's even more strange is that there has been no cyanosis in many times before, but this time, where is the problem? Could it be that cyanosis has nothing to do with sedation, but other causes?
Due to the needs of the disease, Lele once again underwent bone marrow aspiration, gave sedation and analgesia before surgery, and once again appeared the above cyanosis, which was another wave of rescue. Therefore, the doctor judged that Lele's cyanosis was related to sedation.
But even if sedation and cyanosis are related, why not before, and now? It's puzzling.
2
Will there be an unexpected discovery in the medical history?
Further questioning of the medical history, it was learned that Lele had been active as usual during this time, and that cyanosis would not appear or worsen after the activity. However, carefully examining Lele's face, quietly without inhaling oxygen, her face was slightly cyanosis, and if it were not for two severe cyanosis attacks, this slight change would not really be visible.
The doctor measured Lele's finger pulse oxygen with an instrument, and in the case of quiet oxygen inhalation, her blood oxygen saturation was 92% to 94%, and the value of normal people was usually above 94%, and most of them were in 98% to 100%.
However, the doctor gave Lele blood gas, but strangely found that her blood gas analysis showed that it was basically normal, the oxygen partial pressure was slightly higher by 15.26%, and the oxygen saturation was normal. The oxygen saturation of blood gas is normal, but the finger pulse oxygen is slightly lower, what is the reason?
From this abnormal phenomenon, combined with sedation, cyanosis, can the cause be clear? If you've done a good job of physiology, the diagnosis may already be obvious here.
In order to better combine the two and let everyone have a better grasp of the strategy of case analysis, we may wish to analyze the causes of the disease in two lines. One line is based on cyanosis, and the other line is based on the angle of blood gas analysis.
3
Complete information, do you know where the root cause of the disease is?
Before the analysis? We supplement the complete information, we first analyze it according to these data, and then follow the author's thinking again. Details are as follows:
■ (1) Medical history
Preschool girls, acute onset:
Main complaint: Acute lymphoblastic leukemia was diagnosed for more than 2 years, and bone marrow recurrence was 4 days.
Current medical history: About 2 years ago, he was diagnosed with acute lymphoblastic leukemia in our hospital due to "repeated fever for more than 10 days", glucose-6-phosphate dehydrogenase (G6PD) deficiency. On 2018-11-08, chemotherapy was started according to the Acute Lymphatic Multicenter Collaborative Group Protocol (CCCG-ALL-2015) of the Chinese Children's Oncology Professional Committee, and the chemotherapy drugs involved are detailed in the figure below.
Figure 1: Drugs and schedules for chemotherapy in children
At the same time, pediatric compound sulfamethoxazole and dapsone were successively given to prevent Pneumocystis carinii pneumonia. During chemotherapy, the child had three lung infections, but improved after anti-infection treatments such as imipenamcistatin sodium, vancomycin hydrochloride, posaconazole, voriconazole, cefoperazone sodium sulbactam sodium, azithromycin, and caspofungin. Admitted to hospital 4 days ago due to a bone marrow recurrence.
Admission date: 2020-9-14.
Family history: The child's mother and sister have darker lips, which are unknown.
Initial diagnosis: acute lymphoblastic leukemia (early recurrence).
■ (2) Physical examination
Body temperature (T): 36.6 °C, pulse (P): 104 beats/min, breathing (R): 24 beats/min, blood pressure (BP): 86/50 mmHg, unspired oxygen saturation 92% to 95% at rest.
Clear-headed, mental, reactive, lively expression, lips, nail bed slightly darker skin tone, right lower extremity can be seen in the old rash, neck lymph nodes are not touched and enlarged.
Thick breath sounds in both lungs, no dry and wet rales, strong heart sounds, rhythmic, no murmurs, slightly bulging abdomen, 4 cm under the liver ribs, soft texture, 3 cm under the spleen ribs, normal limb activity, no abnormalities on neurological examination. CRT less than 2s.
■ (3) Auxiliary inspection
Blood count: white blood cells (WBCs) 1.6×109/L, bone marrow nucleated cells (ANCs) 0.88×109/L, hemoglobin (HGB) 109 g/L, platelets (PLT) 220×109/L;
Arterial blood gas analysis: PH 7.397, PCO24.76 kPa, PO215.26 kPa, alkali residual (BE-) 2.8 mmol/L. (without oxygen)
Organ function: Alanine aminotransferase (ALT) 13U/L, aspartate aminotransferase (AST) 23U/L, albumin (ALB) 43.9g/L, total bilirubin (TBIL) 3.4 μmmol/L, blood uric acid (UA) 223 μmmol/L, creatinine (Cr) 18 μmmol/L, creatine kinase (CK) 92 U/L, creatine kinase isoenzyme (CKMB) 28 U/L;
Coagulation function: no abnormalities are seen;
Electrocardiogram: approximately normal ECG;
CT of the lungs: the basal segment of the posterior lower lobe of the left lung is scattered in the patch blurred shadow is reduced compared with the previous one;
Cranial MRI: bilateral ventricular posterior corner of the small patchy shadow range is reduced compared to the front, consider the area of delayed maturation of the myelin sheath, please follow up for follow-up review.
4
Can a summary of the medical history find flaws?
Let's summarize the medical history together:
Preschool girls, acute onset.
Changes in condition after admission, manifested by multiple cyanosis after sedation, have not been detected using the same sedation method previously.
Previously, the chemotherapy process used a variety of chemotherapy and anti-infective drugs, and the child had three lung infections, and the pediatric compound sulfamethoxazole and dapsone were given to prevent Pneumocystis carinii pneumonia.
There is nothing special about personal history. Family history: The child's mother and sister have darker lips.
Examination: Lips, nail beds slightly darker complexion. There were no abnormalities in the partial pressure of arterial blood gas oxygen and carbon dioxide. CT of the lungs: the left lung patch is reduced compared with before; in the state of quiet daily activities and no oxygen inhalation, the face is mildly cyanosis, and the blood oxygen saturation is 92% to 94%.
5
The first clue: to start with the cause of cyanosis
Cyanosis is a common pediatric symptom and is more common in mucous membranes, thin skin, and capillary abundance, such as the lips, tip of the nose, cheeks, and nails.
Is it really cyanosis?
Taking cyanosis as the starting point, the essence of cyanosis is the increase of reduced hemoglobin in the blood, resulting in a bluish-purple appearance of the skin mucosa. After sedation, the blood sample saturation decreases, which is really cyanosis.
Is cyanosis persistent or episodic?
In the state of quiet and non-oxygen inhalation, the face is mildly cyanosis, and the blood oxygen saturation is 92% to 94%; the cyanosis is aggravated after sedation. Therefore, consider persistent cyanosis, which is aggravated after sedation.
Which lesion organ is located? Central nervous
Heart or lungs?
>>>> 1. Cyanosis caused by central nervous system abnormalities
Multiple cyanosis occurs after sedation, and attention should be paid to cyanosis caused by sympathetic and vagus nerve excitatory changes caused by sedation. Combined with the child's history of leukemia, chemotherapy and recurrence, it is necessary to be vigilant against nerve compression caused by secondary solid tumors, but the patient's head MR examination does not see abnormalities, and the cyanosis caused by abnormal nervous system regulation is not considered.
>>>> 2. Cardiogenic cyanosis
Cardiogenic cyanosis is divided into three main conditions, namely structural abnormalities, abnormal pumping function and ecglyctic abnormalities.
The first is a structural abnormality (shunting) that causes an elevation of reducing hemoglobin in the blood, leading to cyanosis. In this case, the percutaneous oxygen saturation is often decreased during non-seizures, and the blood gases may be abnormal, mostly persistent with intermittent exacerbations. For example, right-to-left shunts such as Tetralogy of Fallot or cyanosis such as complete pulmonary venous ectopic drainage (TAPVC).
Structural abnormalities of the heart, often with heart murmurs on physical examination, do not seem to support cyanosis caused by structural abnormalities. Moreover, this kind of congenital, the child's previous sedation will not appear cyanosis, only recently appeared, so this type of disease is not supported.
The second type of cardiogenic cyanosis is cyanosis caused by decreased blood pumping function of the heart, which is seen in patients with decreased EF values in heart failure, and the case data does not provide any manifestations of heart failure in children and does not seem to support it. However, daunorubicin and daunorubicin used in chemotherapy in children are cardiotoxic, and it is necessary to be vigilant against drug-induced myocardial damage leading to abnormal pumping function.
However, the child did not have any manifestations of heart failure, and his usual activities were not affected, so he did not consider the heart failure caused by drugs, resulting in impaired blood pumping function and cyanosis.
The third type of ecglyctic abnormality caused by cyanosis, this cyanosis is episodic, such as III ° atrioventricular block, sick sinus syndrome, etc., resulting in a slower episodic heartbeat, insufficient blood pumped into the lungs through the heart, resulting in cyanosis. The child's heart rate drops to 50 to 66 beats per minute after sedation, and it is necessary to be vigilant for episodes of pre-existing arrhythmias induced by sedation.
The child's ECG failed to support this arrhythmia. Myocardial enzyme profile and, if necessary, 24-hour ECG, atropine test, or six-minute walk test are recommended to rule out cardiogenic cyanosis in the above three conditions. This cyanosis is random, and the child has cyanosis after sedation every time, which generally never occurs, and does not support cyanosis caused by ECG abnormalities.
>>>> 3. Pulmonary cyanosis
Common mechanisms of cyanosis in the lungs include two types, namely ventilation disorders and ventilation disorders.
In the case of ventilation disorders, abnormal intrapulmonary arteriovenous exchanges are common, such as abnormal vascular malformations of arteriovenous arteries and veins in the lungs, hepatopulmonary syndrome, and pulmonary interstitial fibrosis, and cyanosis of this etiology is usually persistent or progressively worse, with congenital vascular abnormalities or progressive exacerbations of underlying disease.
In this case, arterial blood gases usually indicate that the alveolar-arterial partial pressure difference will be elevated; if it is drug or chemotherapy-related, there are many interstitial changes in the lungs, and the child's lung CT only indicates a slight abnormality. Therefore, from the current clinical data, the child does not meet the cyanosis caused by ventilation dysfunction.
Another type of cyanosis of lung origin is caused by ventilation disorders. The child's first (first appearance is important) cyanosis attacks occur after MR test sedation, followed by multiple subsequent cyanosis episodes after "sedation". Sedation can lead to downregulation of the excitability of the respiratory muscles, which leads to respiratory muscle weakness, known as "pump failure", which further leads to cyanosis.
Combined with the child's leukemia chemotherapy and multiple pneumonia history, the possibility of copernicsis should be considered, but from the ct examination of the lungs, the lung lesions do not have obvious airway structures caused by the lung ventilation changes.
>>>> 4. Family history
In addition, it is particularly worth mentioning that the case data suggests that "the mother and sister of the child have darker lips". I think of a group of rare diseases—hereditary hemoglobin oxygen affinity abnormalities. These include genetic disorders with increased and decreased hemoglobin affinity. The former such as erythrocyte defects, activation mutations in erythropoietin receptors, idiopathic familial polycythemia, and the latter such as Kansas hemoglobinosis (Hb Kansas, Kansas).
Cyanosis in this condition can be asymptomatic, with only occasionally a decrease in blood oxygen saturation detected. The disease can be determined by high performance liquid chromatography (HPLC) by isolating hemoglobin and measuring whole blood P50, or by genetic testing. However, in general, there is and will not be this process of change that "did not come before, only recently" and therefore does not support it.
>>>> 5. So, what problems can cause cyanosis?
Back to the definition of cyanosis, cyanosis is divided into two categories, one is the reduction of Hb in the blood (true cyanosis), when the child's blood circulation of reduced hemoglobin > 50g / L can appear cyanosis, such as the above heart, lungs and neurogenic cyanosis, all belong to this type of disease.
The other is the presence of abnormal hemoglobin derivatives in the blood (also known as pseudo-cyanosis), when the child's blood circulation of methemoglobin > 30 g /L, or sulfide hemoglobin is greater than >5 g / L cyanosis. Methemoglobin is more common in foodborne cyanosis, such as eating spoiled foods and pickled foods leading to nitrite poisoning. This type of disease usually begins abruptly, progresses rapidly, and mostly develops into severe illness in a short period of time, asking for medical history, the child did not eat such food, and the pathogenesis process is not consistent.
We have noticed that in order to prevent Pneumocystis carinii pneumonia, children take dapsone for a long time. Dapsone is an oxidizing drug that can cause methemoglobinemia or sulfide hemoglobinemia in children, which can lead to cyanosis.
The children's examination of methemoglobin was significantly increased; 30 hours after stopping dapsone, the symptoms of cyanosis disappeared and the met-Hgb quantitative decreased to the normal range; and the amount of met-Hgb was mildly increased when taking small doses of dapsone again.
The above three pieces of evidence are sufficient to support the diagnosis of "methemoglobinemia (Met-Hgb)".
6
The second clue: oxygen dissociation curve and blood gas analysis method
The case came from the Department of Hematology and Oncology of our hospital, and after the answer was revealed, the host believed that the diagnosis was not perfect. Why?
The host said that the oxygen saturation of Met-Hgb should be normal, but the blood oxygen saturation in this case is reduced, and after the deactivation of dapsone, the blood oxygen saturation gradually rises to normal, is there any other problem in the child? Does dapsone cause damage to organs other than methemoglobinemia?
This is precisely what we want to say is the second line: oxygen dissociation curve and blood gas analysis.
The host said that the oxygen saturation of the disease should be "normal". However, she was only half right, and her conclusion was probably obtained from checking the literature. Why? Let's first look at a case reported in the literature:
An 18-year-old girl with a 7-day history of shortness of breath for worsening. There is no history of fever, chest pain, hemoptysis, sitting upright, or palpitations. The patient had a background of recurrent mouth ulcers (secondary to an unclassified autoimmune disease), for which she had been taking dapsone and prednisolone for the past 5 years.
Ambulance doctors found her hypoxic (pulse oximeter) and oxygen saturation of 84%. She started taking oxygen and was sent to the emergency department. Normal systemic examination. Her arterial blood gas specimens were "chocolate" colored, and the analysis (6 L/min oxygen) showed PCO227.2 kPa (normal 11 to 14 kPa), PCO 23.6 kPa (normal 4.6 to 6.4 kPa), sodium bicarbonate 23.9 mmol/L (normal 22 to 29 mmol/L), and blood gas oxygen saturation of 95%.
She was short of breath, called the intensive care team urgently, and planned to intubate her; when the medical team reviewed her, they noticed that her arterial blood gas results showed that her methemoglobin level was 14.4 percent (usually less than 1.5 percent). Thought her symptoms were secondary to dapsone-secondary methemoglobinemia, intubation was postponed, and methylene blue was given. Regular monitoring of arterial blood gases shows a gradual decrease in methemoglobin levels.
This is also a case of methemoglobinemia caused by long-term use of dapsone. When the host said that the oxygen saturation is normal, does it mean that the blood sample saturation is normal after inhalation, or the oxygen saturation in the arterial blood gas is normal?
In fact, the characteristic of this disease, when the oxygen saturation of the finger pulse is low, the oxygen saturation in the blood gas analysis can be completely normal. This is because the oxygen saturation detection in blood gases is usually done indirectly, that is, calculated indirectly based on the partial pressure of oxygen, rather than the measured value.
Oxygen in the blood is divided into physically dissolved oxygen and chemically bound oxygen, the partial pressure of oxygen in blood gas reflects the inability to dissolve oxygen tension, and oxygen saturation reflects the oxygen content of chemical combination. The following paragraph focuses on learning!
The detection of oxygen saturation in blood gas analysis is divided into direct measurement method and indirect measurement method! Most laboratories use indirect measurements, i.e., by measuring the partial pressure of oxygen, the oxygen saturation is calculated from the oxygen dissociation curve, which is a calculated value rather than an actual measurement. A more accurate method, using spectrophotometry (Co-Oximetry), is the measured value, which can accurately reflect the blood oxygen saturation value, and can measure abnormal hemoglobin in the blood, such as methemoglobin and sulfide hemoglobin.
How to distinguish it? If the method is not marked in the blood gas list, it may not be known, the specification label is that if it is written as "SaO2%" then it is the measured value; if it is written as "SaO2c%" it is the calculated value, and there is a small "c". This small "c" means "comparison with a standard curve", i.e. the blood gas analysis here simply measures the partial pressure of oxygen in the arterial blood and then calculates the oxygen saturation according to the normal oxygen dissociation curve.
Figure 2: Labeled "c", an indirect measurement, is an indirect measurement of the relative value measured according to the partial pressure of oxygen.
Figure 3: Co-Oximetry is labeled as spectrophotometry and measured.
Of course, due to the irregular labeling, many blood gas analyses, even if written as "SaO2%", may be measured indirectly. Usually, the measured blood gas analysis will also label the content of methemoglobin. If you don't label it, you're playing hooligans.
Figure 4: Oxygen dissociation curve, i.e. the relationship between oxygen partial pressure and oxygen saturation.
【Acknowledgements】
This case is from the wonderful case provided by the Department of Hematology and Oncology of Guangzhou Women and Children's Medical Center in November 2020, and I thank the doctors who participated in the case report and spoke. Most of the above content is based on the author's abbreviated speech before the case discussion, although he did not attend the meeting in person, and gave the above content to Dr. Guipei to speak on behalf of the department.
This article was first published: Pediatrics Channel of the Medical Professions
The author of this article: Guangzhou Women and Children's Medical Center Pediatrics Crayon Xiaoxin
Editor-in-Charge: CiCi