6.2.1. Drugs that increase blood volume

← PREVIOUS: [[6.2. Pharmacological interventions]] | NEXT: [[6.2.2. Drugs that lower heart rate]] → -------- ##### Summary >[!Summary] > Many POTS patients are hypovolemic and increasing fluid and blood volume is a useful target for ameliorating POTS symptoms[[#^1]] > >------------ >**Salt supplementation** >- recommended intake of 10–12 g of sodium daily[[#^2]] >- salt supplements are available, for patients who have trouble increasing sodium through diet alone[[#^2]] ; should be taken in 250–1000 mg doses in buffered tablets or capsules, due to poor toleration (GI discomfort)[[#^3]] > >**Oral Rehydration Salts (ORS)** >- powder mixture of sodium, potassium, and glucose that is meant to be mixed with 1 L of water to create a low osmolality solution that optimizes sodium absorption by the small intestines[[#^4]] >- study found that ORS was similar to IV saline at increasing orthostatic tolerance in POTS[[#^5]] >- optimal dosing is 1–2L of ORS daily or less on an as needed basis[[#^6]] >- main side effects of ORS are hypernatremia, hyperkalemia, and vomiting[[#^6]] > >**Fludrocortisone** >- used empirically to address the potential contribution of hypovolemia to orthostatic symptoms. >- synthetic corticosteroid[[#^9]] (aldosterone[[#^10]]) whose main action is on the Na+/K+ transporter in the kidney where it enhances reabsorption of sodium ions from the tubular fluid into the plasma, and increases the urinary excretion of potassium and hydrogen ions. This leads to increased sodium retention and increase in plasma volume. it may also sensitize the alpha-adrenergic receptor, further helping to support blood pressure[[#^10]] >- must be careful to watch for hypokalemia since fludrocortisone increases potassium excretion at the expense of sodium preservation[[#^9]][[#^11]] (recommended to check the serum potassium levels 1 week after any dose change (to allow the drug to reach steady-state) and every 3 to 4 months at a stable dose. If the potassium level is low, patients should be advised to increase intake of potassium-rich foods and to possibly take potassium supplements)[[#^11]] >- promotes fluid retention, if it is effective, it should acutely cause a small weight gain (from the fluids) although some patients have significant weight gain[[#^11]] >- prescribed for POTS as 0.1 to 0.2 mg daily[[#^12]][[#^13]] >- At low doses (up to 0.2 mg/day), it does not seem to cause suppression of the hypothalamic-pituitary axis[[#^10]] >- dose can be taken all at once or in divided doses. Given the long effective half-life of the medication, the dosing interval does not much matter[[#^12]] >- may exacerbate headache and vertigo, particularly in patients with migraine[[#^8]] >- may also improve IBS symptoms[[#^14]] > >**Desmopressin** >- can be prescribed as 0.1 to 0.2 mg daily for POTS[[#^19]] >- an acute 0.2 mg dose of DDAVP compared to placebo attenuated orthostatic tachycardia and improved symptoms in POTS[[#^16]][[#^18]][[#^20]] >- treatment with DDAVP for one year improved symptoms and decreased orthostatic tachycardia in half of the patients who tolerated the drug[[#^18]] >- antidiuretic hormone that limits the amount of water that is eliminated in the urine, and promotes free water retention.[[#^17]] >- can lead to hyponatremia, so it's to be used with caution for regular use. as "occasional use" medication it has been used successfully and with this approach there has been no hyponatremia[[#^16]][[#^18]] >- Electrolyte levels (especially the blood sodium levels) must be monitored to ensure patient safety[[#^19]] >- Patients taking DDAVP should also take salt supplements to decrease the risk of hyponatremia[[#^19]] > >**Erythropoietin** >- increases red cell mass and may also stimulate vasoconstriction[[#^21]] >- Potential adverse effects include vascular complications (myocardial infarction, stroke, venous thromboembolism[[#^23]]). This, combined with its high cost and the need for injection, makes it a less attractive option[[#^21]] >- EPO has been given in POTS intravenously 10,000–20,000 IU per week and 50 IU/kg 2 to 3 times a week[[#^22]] >- Hemoglobin and hematocrit levels should be monitored every 3–4 weeks to ensure that hematocrit remains < 50%[[#^23]] >- can also be injected subcutaneously[[#^23]] >- improved orthostatic symptoms in the 24/39 patients who took EPO after other treatments failed[[#^24]] >- rationale for its use in POTS patients who are hypovolemic and refractory to other treatments[[#^24]] > >**Intravenous saline** >- pharmacologic intervention most commonly reported to improve brain fog[[#^25]] (given that 86 % of subjects reported dehydration as a trigger of their brain fog, it seems likely that it would help[[#^26]]) > >**Intravenous saline - acute** >- normal saline 1L infused intravenously over 1 hour normalized the orthostatic tachycardia[[#^27]] ; (1-2L) can quickly expand blood volume and lessen tachycardia in POTS patients[[#^28]] ; decreases orthostatic symptoms in POTS acutely and for several hours to two days following infusion[[#^29]] >- acutely, this treatment is more effective at heart rate control than other medications[[#^27]] >- while this can be a very effective “emergency” therapy, it is not a practical “day to day” approach[[#^27]] ; recommend that this be used during an acute clinical decompensation[[#^30]] > >**Intravenous saline - chronic** >- very controversial[[#^31]] >- reported that chronic administration of intravenous saline in POTS patient improves symptoms in patients whose POTS was refractory to several other treatments[[#^31]] >- chronic regular saline infusions are not recommended due to concerns about complications related to long-term venous access[[#^28]] ; chronic use discouraged because this usually requires a central venous catheter, which carries the risk of infection and blood clots[[#^32]] -------- >*“Many POTS patients are hypovolemic and increasing fluid and blood volume is a useful target for ameliorating POTS symptoms (Fouad et al., 1986;Jacob et al., 1997 ;Raj et al., 2005 ). While blood volume is not often measured in POTS patients clinically, the plasma volume is lower than normal in most patients (Raj and Robertson, 2007). There are several ways to attempt to increase blood volume, although this can be a difficult task.”* ([[Miller-2018]], [p. 2](zotero://open-pdf/library/items/A3CIPE3G?page=2&annotation=Q43YFCR6))^1 ##### 1. Sodium ###### 1.1. Salt supplementation >*“The Heart Rhythm Society Expert Consensus Statement recommends that POTS patients consume 10–12 g of sodium daily (Sheldon et al., 2015). For patients who have trouble increasing sodium through diet alone, salt supplements are available.”* ([[Miller-2018]], [p. 2](zotero://open-pdf/library/items/A3CIPE3G?page=2&annotation=CPJC5H55))^2 >*“Salt supplements should be taken in 250–1000 mg doses. Higher doses are often poorly tolerated and can cause GI discomfort. Taking this with food may minimize gastrointestinal upset. Buffered tablets or capsules may be better tolerated.”* ([[Miller-2018]], [p. 2](zotero://open-pdf/library/items/A3CIPE3G?page=2&annotation=K3VQFBYV))^3 ###### 1.2. Oral Rehydration Salts (ORS) >*“Oral rehydration salts (ORS) is a therapy used to prevent and treat dehydration. ORS is a powder mixture of sodium, potassium, and glucose that is meant to be mixed with 1 L of water to create a low osmolality solution that optimizes sodium absorption by the small intestines.”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=4CZRIC3R))^4 >*“One pilot study found that ORS was similar to IV saline at increasing orthostatic tolerance in POTS (Medow et al., 2012). In this study, ingesting 1 L of ORS increased the time patients were able to tolerate lower-body negative pressure and improved blood pressure and cardiac output responses to this orthostatic stress (Medow et al., 2012).”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=BZI7XKDP))^5 >*“Since 1 L of ORS is equivalent to 1 L of IV saline, optimal dosing is 1–2L of ORS daily or less on an as needed basis. The main side effects of ORS are hypernatremia, hyperkalemia, and vomiting.”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=2C732QSN))^6 ##### 2. Fludrocortisone >*“mineralocorticoid fludrocortisone to promote intravascular volume expansion”* ([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=AVITDGBK))^7 >*“Fludrocortisone may exacerbate headache and vertigo, particularly in patients with migraine.”* ([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=U2U9ZZGQ))^8 >*“Another approach that can be combined with vasoactive medication is administration of medications to expand blood volume. Fludrocortisone is a synthetic corticosteroid that preferentially binds to the mineralocorticoid receptor and acutely increases sodium reabsorption in the distal tubules of the kidney. Fludrocortisone also stimulates potassium excretion, making it necessary to watch for hypokalemia, and it can also worsen migraine headaches” *([[Garland-2015]], [p. 10](zotero://open-pdf/library/items/CAWTWYLR?page=10&annotation=ISHWCHRF))^9 >*“Fludrocortisone is a synthetic form of aldosterone that is used to increase plasma volume in POTS. Some patients with POTS have been found to have low levels of aldosterone (Raj et al., 2005). Fludrocortisone is a glucocorticoid that has been modified to increase its affinity for the mineralocorticoid receptor compared to the glucocorticoid receptor. At low doses (up to 0.2 mg/day), it does not seem to cause suppression of the hypothalamic-pituitary axis. The main action ([p. 2](zotero://open-pdf/library/items/A3CIPE3G?page=2&annotation=NDIQSTZP)) of fludrocortisone is on the Na+/K+ transporter in the kidney where it enhances reabsorption of sodium ions from the tubular fluid into the plasma, and increases the urinary excretion of potassium and hydrogen ions. This leads to increased sodium retention and increase in plasma volume. Fludrocortisone may also sensitize the alpha-adrenergic receptor, further helping to support blood pressure.”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=MI92J7UZ))^10 >*“One must be careful to watch for hypokalemia since fludrocortisone increases potassium excretion at the expense of sodium preservation. We recommend checking the serum potassium levels 1 week after any dose change (to allow the drug to reach steady-state) and every 3 to 4 months at a stable dose. If the potassium level is low, patients should be advised to increase intake of potassium-rich foods and to possibly take potassium supplements. Since fludrocortisone promotes fluid retention, if it is effective, it should acutely cause a small weight gain (from the fluids) although some patients have significant weight gain while taking fludrocortisone. Fludrocortisone can worsen migraine headaches in some patients who are predisposed to migraines”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=IMHU7NAQ))^11 >*“Fludrocortisone is prescribed for POTS as 0.1 to 0.2 mg daily. The dose can be taken all at once or in divided doses. Given the long effective half-life of the medication, the dosing interval does not much matter (unlike most other medications used to treat POTS).”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=HS9PE4GX))^12 >*“Fludrocortisone (0.1–0.2 mg daily) is a synthetic version of aldosterone that promotes renal sodium absorption and secondary blood volume expansion; hypokalemia is a potential adverse effect. Although data from a 2016 RCT suggest fludrocortisone suppresses vasovagal syncope,52 the data for POTS are not as strong and controlled studies are lacking.”* ([[Raj-2022]], [p. 6](zotero://open-pdf/library/items/YN8BG2FZ?page=6&annotation=6L23RGWN))^13 >*“Interestingly, the treatment of POTS may improve IBS symptoms, as seen in a cohort of children treated with fludrocortisone.”* ([[Wells-2017]], [p. 2](zotero://open-pdf/library/items/HLELIN7I?page=2&annotation=G2J8VI9H))^14 >*“Fludrocortisone, a synthetic aldosterone analog, is often used empirically to address the potential contribution of hypovolemia to orthostatic symptoms.”* ([[Wells-2017]], [p. 6](zotero://open-pdf/library/items/HLELIN7I?page=6&annotation=7V2NTFXT))^15 ##### 3. Desmopressin >*“Two other agents used to increase blood volume are the vasopressin analog, desmopressin (DDAVP), and erythropoietin. Although DDAVP reduces tachycardia and symptoms [72;71], it can lead to hyponatremia. We have been cautious about the regular use of DDAVP, but we have successfully used this as an “occasional use” medication. With this approach, we have not seen hyponatremia.” *([[Garland-2015]], [p. 10](zotero://open-pdf/library/items/CAWTWYLR?page=10&annotation=W9WS7SCG))^16 >*“The anti-diuretic desmopressin (DDAVP) is commonly used for diabetes insipidus and bedwetting in children. DDAVP is an antidiuretic hormone that limits the amount of water that is eliminated in the urine, and promotes free water retention.”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=4JUN6UV5))^17 >*“DDAVP can also be used to increase fluid retention in POTS patients. One study found that an acute 0.2 mg dose of DDAVP compared to placebo attenuates orthostatic tachycardia and improves symptoms in POTS (Coffin et al., 2012). A retrospective analysis found that treatment with DDAVP for one year improved symptoms and decreased orthostatic tachycardia in half of the patients who tolerated the drug (Coffin et al., 2012). DDAVP can be used as a “special event drug” to help expand the blood volume before a specific event that the patient really wishes not to miss. Alternatively, it can be used at a low dose on a daily basis.”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=4QRC3F8Y))^18 >*“DDAVP can be prescribed as 0.1 to 0.2 mg daily for POTS (Coffin et al., 2012). Electrolyte levels (especially the blood sodium levels) must be monitored to ensure patient safety. Patients taking DDAVP should also take salt supplements to decrease the risk of hyponatremia”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=3SBW4YAL))^19 >*“Desmopressin is a synthetic vasopressin that promotes renal retention of free water. It has been shown to acutely reduce orthostatic tachycardia in patients with POTS,53 but careful monitoring for hyponatremia is required.”* ([[Raj-2022]], [p. 6](zotero://open-pdf/library/items/YN8BG2FZ?page=6&annotation=4H3XWUTM))^20 ##### 4. Erythropoietin >*“Erythropoietin increases red cell mass and may also stimulate vasoconstriction [7]. Potential adverse effects include vascular complications (myocardial infarction and stroke). This, combined with its high cost and the need for injection, makes it a less attractive option” *([[Garland-2015]], [p. 10](zotero://open-pdf/library/items/CAWTWYLR?page=10&annotation=EZAMAUGD))^21 >*“Erythropoietin (EPO) therapy can be used to increase blood volume in POTS by increasing erythropoiesis. EPO has been given in POTS intravenously 10,000–20,000 IU per week and 50 IU/kg 2 to 3 times a week”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=N6QXFXLA))^22 >*“EPO can also be injected subcutaneously. It is important to realize that EPO has serious ([p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=86E5J3ZG)) side effects including increased risk of myocardial infarction, stroke, and venous thromboembolism. Hemoglobin and hematocrit levels should be monitored every 3–4 weeks to ensure that hematocrit remains < 50%”* ([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=5BNE7X9F))^23 >*“One small prospective study found that EPO did not improve orthostatic tachycardia but improved orthostatic symptoms in 3/8 subjects (Hoeldtke et al., 1995). The other was a retrospective analysis that showed improved orthostatic symptoms in the 24/39 patients who took EPO after other treatments failed (Kanjwal et al., 2012). There is a rationale for its use in POTS patients who are hypovolemic and refractory to other treatments. However, safety concerns and drug insurance coverage can limit its use.”* ([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=3GTBDBAM))^24 ##### 5. Intravenous saline >*“IV saline was the pharmacologic intervention most commonly reported (51/66 subjects) to improve brain fog”* ([[Ross-2013]], [p. 5](zotero://open-pdf/library/items/5NBCV5L2?page=5&annotation=G4BDRGP4))^25 >*“Given that 86 % of subjects reported dehydration as a trigger of their brain fog, it seems likely that IV saline treatment would improve brain fog”* ([[Ross-2013]], [p. 5](zotero://open-pdf/library/items/5NBCV5L2?page=5&annotation=MPG2U5SH))^26 ###### 5.1. Intravenous saline - acute >*“Acute blood volume expansion will over the short-term improve symptoms and control the heart rate. Jacob et al. 16 found that normal saline 1L infused intravenously over 1 hour normalized the orthostatic tachycardia (PRE: 33±5 bpm; POST:15±3 bpm). Acutely, this treatment is more effective at heart rate control than other medications. While this can be a very effective “emergency” therapy, it is not a practical “day to day” approach.” *([[Raj-2013]], [p. 6](zotero://open-pdf/library/items/CCJLQKRB?page=6&annotation=EHJD7C7I))^27 >*“Intravenous saline (1-2L) can quickly expand blood volume and lessen tachycardia in POTS patients [58]. IV saline for an acute clinical decompensation in POTS is a HRS Class IIa recommendation, but chronic regular saline infusions are not recommended (HRS Class III) due to concerns about complications related to long-term venous access” *([[Garland-2015]], [p. 9](zotero://open-pdf/library/items/CAWTWYLR?page=9&annotation=Q8ZSCPR2))^28 >*“Intravenous saline can increase blood volume in POTS. Several studies have shown that an acute infusion of intravenous saline decreases orthostatic symptoms in POTS acutely and for several hours to two days following infusion”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=UXRZTY79))^29 >*“We often recommend that this be used during an acute clinical decompensation. For example, when a patient feels poorly enough to go to the emergency department we advocate a trial infusion of 2 L of normal saline before making a decision about hospital admission.”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=J7ZLMXBQ))^30 ###### 5.2. Intravenous saline - chronic >*“The regular and chronic use of intravenous saline infusions for POTS is very controversial. Two retrospective case-series have recently reported that chronic administration of intravenous saline in POTS patient improves symptoms in patients whose POTS was refractory to several other treatments”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=XIAF2RJR))^31 >*“These data suggest that short-term intravenous saline delivered through a peripheral intravenous catheter might be safe, as the majority of the risks relate the central line insertions and access. The challenge is to avoid the “slippery slope” leading to longterm saline infusions. Currently, the Heart Rhythm Society Expert Consensus Statement recommends occasional acute intravenous saline therapy to prevent hospitalization (Class 2B recommendation), but discourages the chronic use of intravenous fluids because this usually requires a central venous catheter, which carries the risk of infection and blood clots”* ([[Miller-2018]], [p. 3](zotero://open-pdf/library/items/A3CIPE3G?page=3&annotation=M4G9523Y))^32