Acute Chest Syndrome in Sickle Cell Disease

1. Sickle cell anemia is also known as sickle cell disease, but is different from sickle cell trait. It is an autosomal recessive hemoglobinopathy where amino acid 6 on beta globin gene changes from glutamic acid to valine (missense mutation). This results in hemoglobin S, which sickles and causes hemolysis under hypoxic conditions.
2. HbSS, HbSC, and HbSBeta thalassemia can all cause sickle cell disease (SCD)
3. Sickle cell disease can affect every organ, and treatment begins in childhood and is multidisciplinary. Clinical manifestations include vaso-occlusive syndromes (e.g. dactylitis, acute pain syndrome, acute chest syndrome, priapism), visceral complications such as stroke, infections due to immunosuppresion from a functional asplenia, osteomyelitis, avascular necrosis of the femoral/humeral head, renal dysfunction, retinopathy, pulmonary arterial hypertension, skin ulcers, etc. Please refer to the review article below as a reference. 
4. Acute chest syndrome (ACS) is a respiratory complication of sickle cell disease that can be life-threatening. It is caused by vaso-occlusive disease in the pulmonary vasculature or is triggered by vaso-occlusive disease elsewhere in the body (e.g. fatty embolism from infarcted bone marrow)
5. ACS is more common in children than adults but more severe when in occurs in adults. It is also more common with HbSS disease than HbSC or HbSBeta thalassemia disease. The case mortality rate is usually between 1-10%. 
6. As per the Cooperative Study in Sickle Cell Disease (CSSCD), ACS will occur in roughly 50% of SCD patients. 
7. The diagnosis of ACS requires radiologic evidence of a pulmonary infiltrate as well as a fever or respiratory symptoms (e.g.. cough, increased work of breathing, hypoxia, tachypnea, PaO2<60mmHg) so it cannot diagnostically be distinguished from pneumonia. 
8. Triggers include pulmonary fatty embolism from infarcted bone marrow (45-75% of cases; a bronchoalveolar lavage can be performed to confirm this etiology but is invasive and usually not done), infection (mostly Chlamydiae pneumonia, Mycoplasma pneumonia, RSV, Streptococcus pneumonia), asthma, pain crisis (e.g. vaso-occlusive crisis in long bones), and hypoventilation.
9. Treatment is divided into acute and preventive therapies. Acute therapies include the following 5 pillars of management:

• Pain control (opioids usually effective, but must balance analgesic effects with risk of respiratory depression; NSAIDS should be avoided as they worsen vaso-occlusive disease)
• IV hydration to keep the patient euvolemic as dehydration increases sickling of RBCs
• Antibiotics: Should cover expected organisms above so usually a 3rd generation cephalosporin + a macrolide is chosen, or a 3rd/4th generation fluoroquinolone. 
• Supplemental oxygen, bronchodilators, and incentive spirometry (e.g. 10 deep breaths every 2 hours while awake)
• Blood transfusions to keep Hb between 90-100g/L. A Hb >100g/L can lead to increased viscosity which worsens vaso-occlusion. There have not been any RCTs to compare simple versus exchange tranfusions, but generally exchange transfusions are used in "severe" cases.

    10. Preventive measures include the following:

• Hydroxyurea: Indicated with 1 or more episodes of ACS and acts by increasing the level of HbF (fetal hemoglobin, composed of 2 alpha and 2 gamma chains). Increased HbF reduces the likelihood of HbS polymerization. There is an inverse correlation between HbF levels and the incidence of ACS, and in the MSH study the incidence of ACS decreased by 50% with the use of hydroxyurea. The dose is 30mg/kg per day divided BID. 
• Chronic transfusion if 2 or more episodes of ACS in the last 12 months. NB hyperhemolytic syndrome can occur 5-7 days post transfusion in SCD patients and can lead to an acute drop in hemoglobin. 
• HSCT (hematopoietic stem cell transplant) can be a curative therapy.
• Incentive spirometry. 

Reference Articles:

1. Management of sickle cell disease in the community by Valentine Brousse, Julie Makani, and David Rees

• BMJ 2014;348:g1765  

2. Acute chest syndrome: sickle cell disease by Rabindra Paul, Oswaldo Castro, Anita Aggarwal, and Patricia Oneal

• European Journal of Haematology 87 (191-207)

3. How I treat acute chest syndrome in children with sickle cell disease by Scott Miller

• Blood, 19 May 2011. Volume 117, Number 20

Metabolic Acidosis

1. Metabolic Acidosis (MA) is defined by a decreased serum bicarbonate and an arterial blood gas (ABG) indicating acidemia.
2. Metabolic acidoses are separated into those with a wide anion gap (WAGMA) and normal anion gap (NAGMA, aka hyperchloremic metabolic acidosis)
3. The anion gap (AG) is artificial in the sense that it is a lab artifact. In theory all the positive charges in the serum should equal the negative charges to achieve electrical neutrality. The serum anion gap is calculated as AG= Na - (Cl + HCO3). In other words, it is the measured cations minus the measured anions. Another way to think of it is the unmeasured anions minus the unmeasured cations. 
4. Albumin is the major unmeasured anion in the serum. One must correct for the albumin level. Generally, for every 10g/L below the normal value of 40g/L, one should add a correction factor of 2.5 for the corrected anion gap. 
5. The normal anion gap range depends on whether K (potassium) is used in the equation to calculate it. Generally, it is not. It also depends on the lab's way of measuring chloride. At LHSC a normal AG is 12-14. 
6. Causes of a low anion gap include anything that causes a high level of unmeasured cations (e.g. paraproteinemias, hypermagnesemia, hypercalcemia) or low level of unmeasured anions (e.g. hypoalbuminemia)
7. WAGMA is usually due to unmeasured organic acids. It is usually due to ketoacidosis, lactic acidosis, acute kidney injury/chronic kidney disease, or ingestions.

• Ketoacidosis: The ketoacids are beta-hydroxybutyrate and acetoacetic acid. Acetone is a ketone body but not a ketoacid. Ketoacidosis can result from diabetic ketoacidosis, starvation, or alcohol consumption. 
• Lactic Acidosis: Type A is due to impairment in tissue oxygenation (e.g. circulatory or respiratory failure, sepsis, ischemic bowel). Type B is due to impaired lactate clearance (e.g. liver disease), metastatic disease, or certain drugs (e.g. metformin when renal function is impaired, salicylates, NRTIs). D-Lactate (NB L-Lactate is measured routinely in the serum) can be due to short-gut syndrome in which bacteria in the colon metabolize glucose to D-Lactate. 
• AKI or CKD: Impaired clearance of organic acids, phosphates, sulfates, and urates. 
• Ingestions
• Salicylates (e.g. acetylsalicylic acid, methyl salicylate from oil of wintergreen, bismuth subsalicylate): Lactic acidosis can result from impaired oxidative phosphorylation since salicylate overdose can poison the mitochondria involved in the Kreb's cycle. 
• Acetaminophen: 5-oxoproline (aka pyroglutamic acid) can result from chronic acetaminophen use, usually in older, typically malnourished females. 
• Ethylene glycol: Metabolized into oxalic/glycolic acid. Used in antifreeze solution. 
• Propylene glycol: Can result in lactic acidosis. Used as diluent in IV lorazepam/diazepam infusions as well as IV nitroglycerin. 
• Methanol: Metabolized into formic acid. Used in engine coolants. 
• Iron: Can result in a lactic acidosis since excess iron can be toxic to mitochondria.
• Toluene: Can result in hippuric acidosis. Used as solvent for dyes, paints, rubbers. 

   8. NAGMA (hyperchloremic metabolic acidosis) are usually a result of a loss of bicarbonate, gain of chloride, or impaired excretion of acids. Causes include:

• Loss of HCO3 (e.g. for the GI tract from diarrhea, from the kidneys in type 2 RTA (renal tubule acidosis when HCO3 reabsorption in the proximal tubules is impaired)
• Impaired acid excretion (e.g. type 1 or type 4 RTA)
• Infusing HCO3-free fluid (e.g. IV normal saline infusions)
• Total parenteral nutrition (amino acids are broken into ammonium chloride which is an acid)
• Ureteral-ileal/colonic conduits or diversions. Urine makes contact with the GI tract and HCO3/Chloride exchange can occur, resulting in hyperchloremia. 
• Pancreatic fistulas
• Drugs (e.g. acetazolamide, cholestyramine, toluene)

   9. Remember that acid base disturbances are often mixed. For example, a WAGMA can coexist with a NAGMA or a metabolic acidosis can be combined with a respiratory acidosis. It is diagnostically convenient when a single acid-base imbalance occurs, but this is seldom the case. 

   10. Because of the above, the delta/delta gap, or the ratio of the extent of the anion gap divided by the extent of the metabolic acidosis (i.e. anion gap -12/24-HCO3, where 12 is considered a "normal" anion gap and 24 a "normal" HCO3 level), can be used to help evaluate a mixed versus pure NAGMA/WAGMA or the presence of a concurrent metabolic alkalosis. 

Reference Article:

Kraut, J.A. and Madias, N.E. Metabolic acidosis: pathophysiology, diagnosis and management. Nat. Rev. Nephrol. 6, 274-285 (2010).