Wednesday, December 28, 2016

Top 10 Posts of 2016

2016 proved to be a fantastic year for Emergency Medicine PharmD. We have shared a lot of great content with you, and we hope to maintain our trajectory within the world of #FOAMed.

Below are the top 10 posts in view count published this year on the blog:

Trick of the Trade: Diphenhydramine for Local Anesthesia
Author: Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)
No More Epinephrine Ratios!
Author: Craig Cocchio, PharmD, BCPS (@iEMPharmD)
Managing Rate Control in the Face of Borderline Hypotension
Author: Craig Cocchio, PharmD, BCPS (@iEMPharmD)
Gabapentin Misuse: A Growing Challenge
Author: Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

Euglycemic DKA from SLGT2 Inhibitors: Don't Worry, I Can't Pronounce Them Either
Author: Craig Cocchio, PharmD, BCPS  (@iEMPharmD)

8 Points Worth Noting From New Guideline for Convulsive Status Epilepticus
Author: Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

Weighing in on Alteplase Dosing: Is Estimating Weight Harming Our Patients?
Author: Laura Johnson, PharmD

Idarucizumab: An Imperfect Reversal Agent for Dabigatran
Author: Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

Mirror Mirror on the Wall, Who's the Most Fragile of Them All? Assessing the Fragility Index of ECASS III
Author: Kyle DeWitt, PharmD, BCPS (@EmergPharm)

Debates in the Management of Hyperkalemia
Authors: Bryan D. Hayes, PharmD, DABAT, FAACT (@PharmERToxGuy) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

As always, should you have any ideas for submission as potential blog posts on Emergency Medicine PharmD, please do not hesitate to contact Craig and me.

We thank you all for your continued support of our endeavors in providing views and perspectives of emergency medicine practice from the eyes of the emergency medicine pharmacist. Here is to a happy and healthy 2017.

Wednesday, December 14, 2016

Early Pharmacotherapy Management for the Potential Organ Donor in the Trauma Bay

Thinking ahead is something most EM pharmacists are excellent at and we are – amongst other things – in the business of saving lives. On the (hopefully) rare occasion that the 30-something-year-old trauma patient rolls in with a blatantly obvious and observable poor prognosis, being steps ahead may be doing just that. In the back of your mind, you think this otherwise healthy patient could potentially be an organ donor. In the immediate, sense you are struggling to keep the mean arterial pressure (MAP) above 60 mmHg, and fluids alone are not cutting it. Oftentimes, you might reach for that norepinephrine drip after fluids and transfusions of blood products have failed, but this time you have other thoughts.
Donor management generally starts in the intensive care unit, but in certain situations, interventions may be justified as early as in the trauma bay. To be able to recognize these times, we must first understand some pathophysiology.
The pathways associated underlying the progression of brain death are complex. Increased intracranial pressure leads to cerebral herniation and brainstem ischemia. Initially, parasympathetic activation resulting in sinus bradycardia and hypotension may be seen due to mesencephalic ischemia. Pontine ischemia follows, resulting in sympathetic stimulation, causing hypertension and bradycardia (often described as a characteristic Cushing’s response). An autonomic storm ensues, causing massive catecholamine release due to medullary ischemia, leading to tachycardia and increased systemic vascular resistance. This phenomenon  is typically short-lived, with depletion of catecholamine stores resulting in autonomic collapse, causing diminished sympathetic activity, reduced vascular tone, decreased peripheral arterial and venous resistance, and impaired cardiac output.1 The severe vasodilation and cardiovascular collapse occurs is arguably most crucial in preventing and has been cited as the stage when medical failure often occurs in the management of a potential organ donor.2
Most donor management protocols are implemented after there is determination of brain death and consent is obtained – which inevitably takes time. Brain death is usually determined several hours after initial injury, and some states require two separate examinations, which can delay determination of brain death.3 While the complex pathophysiology above would seemingly provide time to initiate therapies in most patients, delays in the potential donor presenting with hemodynamic instability  initially can significantly impact the number of organs procured.4 It is in these situations that initiating the right therapies for hemodynamic stability prior to declared brain death in a potential donor can be justified.
Back to Our Trauma Patient

Because you read the recent AJHP article regarding organ donor management,5 maybe you are hesitating with norepinephrine as your next choice after volume resuscitation attempts. If you have encountered this patient scenario before, you know that maintaining organ perfusion while avoiding excessive vasopressor use is a United Network for Organ Sharing (UNOS)-defined donor management goal to increase the number of organs procured.6 With that being said, what approaches are reasonable?

Option 1: Start dopamine and/or vasopressin and titrate to effect
  • Traditionally, dopamine has been utilized as a first-line agent for inotropic support. However, current guidelines acknowledge there is no evidence that its use is superior over vasopressin. Up to 80% of brain dead donors will experience diabetes insipidus, which may be a compelling reason to take advantage of  vasopressin initially and gain multiple benefits from one drug.7
  • In patients with low systemic vascular resistance, norepinephrine and/or phenylephrine are recommended.7

Option 2: Start Hormone Replacement Therapy (HRT)
(Commonly some form of dextrose + methylprednisolone + thyroid hormone + insulin + vasopressin)
There has been controversy in the use of HRT as part of donor protocols. Randomized controlled trials – largely conducted in hemodynamically stable donors – have not shown the use of HRT to be beneficial. Subgroups of donors identified as hemodynamically unstable have been too small to detect a difference.8 Retrospective studies, however, have found significant benefit with regards to the number of organs procured and decreased vasopressor use, specifically in hemodynamically unstable donors.8–13 The premise of initiating these therapies has traditionally been based on presumed anterior pituitary hormone deficits causing hypocortisolism and hypothyroidism, although reports of decreased ACTH, TSH, and T4 have been widely variable. It has been proposed that a “sick euthyroid syndrome” may occur in brain death, with the body preferentially converting T4 to reverse T3 (rT3) instead of T3 as a physiological response. However, reports of increased rT3 have also been variable.14 There is recent evidence thyroid hormones have anti-inflammatory properties, which has been suggested as having an additional contributory benefit in organ donor management.15
Previous guidelines had strong recommendations in the use of hormone replacement therapy for all potential donors, which may entail the use of a multi-drug cocktail of T3, vasopressin, methylprednisolone, and insulin titrated to goal blood glucose of 140-180 mg/dL.16 In the past, retrospective data indicated higher organ procurement rates with this regimen.17 However, more recent data, though limited, has indicated hemodynamically unstable patients are the most likely to gain benefit from HRT, specifically the use of thyroid hormones.

  • Improves vasodilatory shock, counteracts diabetes insipidus, and reduces catecholamine use.
  • Dose: Initiate at 0.01-0.04 IU/min
Thyroid Hormone
  • Mechanism still not well understood – benefits may be due to sick euthyroid syndrome in the donor; improves hemodynamic stability, decreases need for vasopressor use, and increases the probability of successful organ recovery. Recommended for hemodynamically unstable patients or those with a LVEF <45% (predisposed to having existing sick euthyroid syndrome).7,18
  • T3 vs. T4: Liothyronine (T3) was previously preferred over T4 due to more rapid onset, but no obvious differences in efficacy have been noted in retrospective reviews, thus no preference is indicated in current guidelines. As UNOS will not reimburse until they have taken over donor management, T4 would appear to be the more reasonable option cost-wise ($100/day vs. $2700/day).
  • IV versus PO: Although serum concentrations in one small trial of brain dead donors (n = 32) indicated oral T4 to be 93% that of intravenous at 6 hours (2 mcg/kg given once), bioavailability of levothyroxine has historically been reported as 60-80% in euvolemic patients.19,20  Larger studies would be necessary to more fully evaluate the use of oral T4, especially in the setting of hypoperfusion and concern for GI ischemia.
  • Dose:
    • Levothyroxine (T4): 20 mcg bolus followed by 10 mcg/hr infusion
    • Liothyronine (T3): 4.0 mcg bolus, followed by 3 mcg/hr infusion

  • Still recommended for all potential donors to reduce the negative effects of the inflammatory cascade on donor organ function. The incidence of adrenal suppression in brain death has been inconsistent.7
  • Dose: A bolus dose of 250-1000 mg IV or 15 mg/kg IV followed by continuous infusion of 100 mg/hr have been recommended
    • May suppress leukocyte antigen expression and should be administered after blood collection for tissue typing.7
Dextrose + Insulin
  • Most institutional protocols will often have this combination. Current guidelines support the use of insulin to target blood glucose levels < 180 mg/dL.7 A recent UNOS evaluation of glucose control in organ donors found that blood glucose levels < 180 mg/dL to be an independent predictor of at least four organs transplanted per donor. Kidney graft survival at 10 months was also found to be associated with blood glucose levels maintained at  < 200 mg/dL.21
  • Recently, Novitzky et al. conducted a follow-up analysis of their previous retrospective study in 63,593 organ donors,11 reporting the use of insulin may have been negatively associated with pancreas procurement and graft survival. This has not been previously reported, and as authors state, may be due to pathophysiological response of pancreatic islet cells in brain death or potentially a reflection of poor hemodynamic status of the donor. Despite being able to consistently evaluate glucose levels and insulin dosing regimens, they suggest high levels of insulin may indicate marginal pancreatic donor quality.15
  • Dose: Routine use of IV dextrose is not recommended.7 However, 1 ampule of 50% IV dextrose has traditionally been used and given first in the HRT regimen, followed by methylprednisolone, and then 20 units of regular insulin.22

It is an unfortunate reality in trauma that we are not always going to be able to save the immediate life brought to us. As responding pharmacists, having familiarity with the HRT regimen – as well as the ability to identify when it should be considered sooner rather than later – may be the lifesaving difference for another patient not in our direct care.
Christine Tafoya, PharmD (@ChrissieTPharmD)
Pharmacy Practice Resident (PGY-1)
Banner –  University Medical Center
Phoenix, Arizona

Reviewed by: 
Mark Culver, PharmD, BCPS (@EMdruggist);
Craig Cocchio, PharmD, BCPS (@iEMPharmD); and
Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

  1. King R, Hinkle J, Werman H. Organ procurement in trauma. Trauma Reports. Atlanta, GA: AHC Media; 2010.
  2. Kwon Y, Baldisseri M. Care of the organ donor. In: O’Donnell J, Nacul F, eds. Surgical Intensive Care Medicine. 2nd ed. New York, NY: Springer Science; 2010:591-597.
  3. Wijdicks EF,  Varelas PN, Gronseth GS, Greer DM. Evidence-based guideline update: Determining brain death in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010;74(23):1911-1918.
  4. Lustbader D, O’Hara D, Wijdicks EFM, et al. Second brain death examination may negatively affect organ donation. Neurology. 2011;76(2):119-124.
  5. Korte C, Garber JL, Descourouez JL, Richards KR, Hardinger K. Pharmacists’ guide to the management of organ donors after brain death. Am J Health Syst Pharm. 2016;73:e592-e602.
  6. Patel MS, Zatarain J, De La Cruz S, et al. The impact of meeting donor management goals on the number of organs transplanted per expanded criteria donor: A prospective study from the UNOS Region 5 Donor Management Goals Workgroup. JAMA Surg. 2014;149(9):969-975.
  7. Kotloff RM, Blosser S, Fulda GJ, et al. Management of the potential organ donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement. Crit Care Med. 2015;43(6):1291-1325.
  8. Macdonald PS, Aneman A, Bhonagiri D, et al. A systematic review and meta-analysis of clinical trials of thyroid hormone administration to brain dead potential organ donors. Crit Care Med. 2012;40(5):1635-1644.
  9. Salim A, Vassiliu P, Velmahos GC, et al. The role of thyroid hormone administration in potential organ donors. Arch Surg. 2001;136(12):1377-1380.
  10. Salim A, Martin M, Brown C, et al. Using thyroid hormone in brain-dead donors to maximize the number of organs available for transplantation. Clin Transplant. 2007;21(3):405-409.
  11. Novitzky D, Mi Z, Sun Q, Collins JF, Cooper DKC. Thyroid hormone therapy in the management of 63,593 brain-dead organ donors. Transplantation. 2014;98(10):1119-1127.
  12. Joseph B, Aziz H, Pandit V, et al. Levothyroxine therapy before brain death declaration increases the number of solid organ donations. J Trauma Acute Care Surg. 2014;76(5):1301-1305.
  13. Lam L, Inaba K, Branco BC, et al. The impact of early hormonal therapy in catastrophic brain-injured patients and its effect on organ procurement. Am Surg. 2012;78(3):318-324.
  14. Novitzky D, Ekser B, Cooper D. Early clinical experience of hormonal therapy in the brain-dead potential organ donor. In: Novitzky D, Cooper D, eds. The Brain-Dead Organ Donor: Pathophysiology and Management. New York, NY: Springer Science; 2013:191-207.
  15. Novitzky D, Mi Z, Videla LA, Collins JF, Cooper DKC. Hormone resuscitation therapy for brain-dead donors - is insulin beneficial or detrimental? Clin Transpl. 2016;30(7):754-759.
  16. Zaroff J, Rosengard B, Armstrong W, et al. Consensus conference report: Maximizing use of organs recovered from the cadaver donor: cardiac recommendations. Circulation. 2002;106(7):836-841.
  17. Rosendale JD, Kauffman HM, McBride M a, et al. Aggressive pharmacologic donor management results in more transplanted organs. Transplantation. 2003;75(4):482-487.
  18. Novitzky D, Cooper DKC. Thyroid hormone therapy to the recipient of a heart from a brain-dead donor. In: Novitzky D, Cooper D, eds. The Brain-Dead Organ Donor: Pathophysiology and Management. New York, NY: Springer Science; 2012:321-331.
  19. Sharpe MD, van Rassel B, Haddarra W. Oral and intravenous thyroxine (T4) achieve comparable serum levels for hormonal resuscitation protocol in organ donors: A randomized double-blinded study. Can J Anesth. 2013;60:998–1002.
  20. Colucci P, Seng Yue C, Ducharme M, Benvenga S. A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. European Endocrinology. 2013;9(1):40–7.
  21. Sally MB, Ewing T, Crutchfield M, et al. Determining optimal threshold for glucose control in organ donors after neurologic determination of death: A United Network for Organ Sharing Region 5 Donor Management Goals Workgroup prospective analysis. J Trauma Acute Care Surg. 2014;76(1):62-69.  
  22. Salim A, Martin M, Brown C, Rhee P, Demetriades D, Belzberg H. The effect of a protocol of aggressive donor management: Implications for the national organ donor shortage. J Trauma. 2006;61(2):429-433.

Wednesday, December 7, 2016

Debates in the Management of Hyperkalemia

At the 2016 Midyear Clinical Meeting of the American Society of Health-Systems Pharmacists (ASHP), my colleague Bryan Hayes (@PharmERToxGuy) and I presented a continuing education program on debates in the management of hyperkalemia.

The learning objectives from our session are below:
  1. Evaluate recommendations for dosing and administration of parenteral calcium in the treatment of hyperkalemia. 
  2. Apply practical methods for co-administration of insulin and dextrose in the management of hyperkalemia.
  3. Discuss evidence-based literature surrounding administration of sodium bicarbonate and sodium polystyrene sulfonate in the treatment of hyperkalemia. 
  4. Appraise literature related to clinical trials evaluating novel and newly approved agents for hyperkalemia.
This blog post serves as a summary of the key points of the presentation, and we created this resource as an active and living reference of the educational material shared in the session that can be shared at any point following the session.



An elevated calcium concentration decreases the depolarization effect of an elevated K+ concentration. IV calcium antagonizes the cardiac membrane excitability thereby protecting the heart against dysrhythmias. (Hoffman BF, et al. Am J Physiol 1956;186:317-24) (Treatment of Acute Hyperkalemia in Adults - Clinical Practice Guideline. UK Renal Association 2014)

  • Life-threatening ECG changes, dysrhythmias, & cardiac arrest - YES 
  • Peaked T waves - PROBABLY 
    • ECG can be normal, but in some cases is an insensitive marker for assessing severity in hyperkalemia (Parham WA. Tex Heart Inst J 2006;33:40-7) (Szerlip HM, et al. Am J Kidney Dis 1986;7:461-5) (Bandyopadhyay S, et al. Int J Clin Pract 2001;55:486-7) 
  • Optimal dose unclear. Start with at least 1 gm CaCl2 or 2 gm calcium gluconate IV 
  • Starts to work in about 3 minutes 
  • Redose in 5-10 minutes if no effect seen from first dose 
  • Effects last 30-60 minutes (may need to redose if further treatment needed while awaiting emergent hemodialysis) 
  • Does calcium gluconate act slower than calcium chloride because it needs hepatic activation? No! 
    • Serum ionized calcium levels were measured in 15 hypocalcemic patients during the anhepatic stage of liver transplantation. Half received CaCl 10 mg/kg, the other half received calcium gluconate 30 mg/kg. Serum concentrations of ionized calcium were determined before and up to 10 min after calcium therapy. Equally rapid increases in calcium concentration after administration of CaCl and gluconate were observed, suggesting that calcium gluconate does not require hepatic metabolism for the release of calcium and is as effective as CaCl in treating ionic hypocalcemia in the absence of hepatic function. (Martin TJ, et al. Anesthesiology 1990;73:62-5) 
    • A weird randomized prospective study in both children and dogs compared ionization of CaCl and calcium gluconate. The authors conclude that equal elemental calcium doses of calcium gluconate (10%) and CaCl (10%) (approximately 3:1), injected over the same period of time:
      • Are equivalent in their ability to raise calcium concentration during normocalcemic states in children and dogs 
      • The changes in calcium concentration following calcium administration are short-lived (minutes)  
      • The rapidity of ionization seems to exclude hepatic metabolism as an important factor in the dissociation of calcium gluconate (Cote CJ, et al. Anesthesiology 1987;66:465-70) 
    • In ferrets and in vitro human blood, equimolar quantities of CaCl and calcium gluconate produced similar changes in plasma ionised calcium concentration when injected IV into anaesthetised ferrets or when added to human blood in vitro. In vivo changes were followed with a calcium electrode positioned in the animal’s aorta, and this showed that the ionisation of calcium gluconate on its first pass through the circulation is as great as that of CaCl. This does not support the common suggestion that CaCl is preferable to calcium gluconate because of its greater ionisation. (Heining MP, et al. Anaesthesia 1984;39:1079-82)
Calcium in Digoxin Overdose
  • There are only 5 case reports suggesting a temporal relationship between calcium administration and death in the setting of digoxin toxicity (primarily from the 1930s and 1950s); symptoms of digoxin toxicity are not described, no digoxin levels were taken and only 2 cases had a strong temporal relationship (which does not imply causation).There are also case reports of calcium use in patients with digoxin toxicity without any ill effects. 
  • Original animal models flawed - toxic effects only occurred when animals were made severely hypercalcemic prior to digoxin administration. Subsequent animal models mimicking digoxin toxicity failed to demonstrate adverse effects. 
  • The most recent study retrospectively reviewed 159 dig toxicity cases, 23 of which received calcium (Levine M, et al. J Emerg Med 2011; 40:41-46). Death rate was same in both groups and no dysrhythmias were noted. The problem is all except 1 were chronic digoxin overdose. Hyperkalemia is more problematic in the acute overdose.
  • Stone heart theory is probably false. Calcium appears safe, but we don’t even know if it would work the same as in hyperK from other causes. Little evidence in acute overdose where hyperkalemia may be more problematic. If known digoxin-induced hyperkalemia, give antidote. Otherwise give calcium.
Insulin and Dextrose

Treating Hyperkalemia with Insulin

  • Insulin remains one of the cornerstones of early severe hyperkalemia management. Insulin works via a complex process to temporarily shift potassium intracellularly. 
  • Insulin lowers serum potassium by activating Na+-K+ ATPase and by recruitment of intracellular pump components into the plasma membrane. Insulin binding to specific membrane receptors results in extrusion of Na+ and cellular uptake of K+. (Hundal HS, et al. J Biol Chem 1992;267:5040-3)
  • Doses of 5 units boluses up to 20 unit/hr infusions have been used. The most common dose studies is 10 units IV regular insulin as a bolus. This lowers the potassium level by about 1 mEq/L. Neither of these regimens provides sustained effect.
  • Based on what is known of physiology and drug kinetics, one group suggests the most logical regimen for a 70-kg subject (with weight adjustment of dosages for others) would be an infusion of short-acting insulin at 20 U/h after a 6-U loading dose, given with 60 g of glucose per hour (Sterns, Kidney Int 2016). This needs to be studied before it can be recommended.
Preventing Hypoglycemia
  • Though insulin certainly lowers plasma potassium concentrations, we often underestimate the hypoglycemic potential of a 10 unit IV insulin dose in this setting.
  • Incidence of Hypoglycemia
    • A 10 unit dose of IV regular insulin has an onset of action of about 5-10 minutes, peaks at 25-30 minutes, and lasts 2-3 hours. Herein lies the problem in that IV dextrose only lasts about an hour (at most). Allon et al reported up to 75% of hemodialysis patients with hyperkalemia developed hypoglycemia at 60 minutes after insulin administration (Kidney Int 1990;38:869-72). A retrospective review of 219 hyperkalemic patients reported an 8.7% incidence of hypoglycemia after insulin treatment (Schafers S, et al. J Hosp Med 2012;7:239-42). More than half of the hypoglycemic episodes occurred with the commonly used regimen of 10 units of IV insulin with 25 gm of dextrose. A more recent study of 221 end-stage renal disease patients who received insulin for treatment of hyperkalemia reported a 13% incidence of hypoglycemia (Apel J, et al. Clin Kidney J 2014;0:1-3) 
    • The overall incidence of hypoglycemia appears to be ~10%, but could be higher. 
  • Risk Factors for Developing Hypoglycemia
    • The study by Apel et al identified three factors associated with a higher risk of developing hypoglycemia:
      1. No prior diagnosis of diabetes [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.0–5.1, P = 0.05]
      2. No use of diabetes medication prior to admission [OR 3.6, 95% CI 1.2–10.7, P = 0.02]
      3. A lower pretreatment glucose level
        • In mg/dL: mean 104 ± 12 mg/dL vs 162 ± 11 mg/dL, P = 0.04
        • In mmol/L: mean 5.8 ± 0.7 mmol/L vs 9.0 ± 0.6 mmol/L, P = 0.04
    • Renal dysfunction in and of itself may also be a risk factor for developing hypoglycemia. Some evidence suggests that insulin is metabolized by the kidneys to some extent. Furthermore, patients with acute kidney injury (AKI) have clinically relevant changes in insulin metabolism, as evidenced by increased hypoglycemic events and lower insulin requirements upon developing AKI (Dickerson RN, et al. Nutrition 2011;27:766-72).
  • Strategies for Avoiding Hypoglycemia
    • Preventing hypoglycemia is important. Some clinicians use up to 20 units of IV regular insulin as the hypokalemic effect is dose dependent (Blumberg A, et al. Am J Med 1988;85:507-12). Here is a suggested strategy for administering enough dextrose to counter the initial insulin bolus of 10 or 20 units: It is loosely based on the Rush University protocol (Apel 2014).
Sodium Bicarbonate

  • History has not been on our side when it comes to understanding and appreciating the role of sodium bicarbonate in the management of hyperkalemia.
  • In one survey of directors of nephrology training programs, respondents indicated that sodium bicarbonate was among their top choices as an agent for treating hyperkalemia, with over 30% indicating that this agent should be used either alone or in conjunction with calcium gluconate. (N Engl J Med 1989; 320:60-61)
  • This attitude has been perpetuated across decades of training, but it is essential to understand the mechanism that sodium bicarbonate holds in the management of hyperkalemia.
  • It has often been said that sodium bicarbonate is effective in hyperkalemia due to its effects on enhancing the excretion of potassium, shifting potassium into the intracellular space, and/or decreasing the amount of hydrogen ions in the extracellular fluids.
  • However, one little known fact related to the role of sodium bicarbonate is its influence on the sodium-bicarbonate co-transport system as well as the exchange system for sodium and hydrogen within the skeletal muscles in promoting uptake of potassium. (Clin J Am Soc Nephrol 2015; 10:1050-1060)
  • By increasing sodium in the intracellular space, the activity of the enzyme sodium-potassium adenosine triphosphatase also increases.
  • One of the key influences of promoting the activity of the sodium-hydrogen exchange system is the presence of intracellular acidosis, which is thought to account for the purported efficacy of sodium bicarbonate in the treatment of hyperkalemia. (Kamel et al. Nephrol Dial Transplant 2003; 18:2215-2218)
  • One of the earliest evaluations of sodium bicarbonate in the management of hyperkalemia occurred in the setting of chronic kidney disease and severe acidosis with administration as a continuous infusion. (Circulation 1959; 19:215-220) For every 10 mmol/L increase in serum sodium bicarbonate, serum potassium levels decreased by 2 mmol/L.
  • A few caveats:
    • This evaluation was conducted in was conducted in four patients.
    • In addition, this is not generally the way we typically administer sodium bicarbonate in the emergency department; oftentimes, we administer it as a one-time IV bolus dose of 50 mEq.
Myths Debunked
  • One thing that we do know that within the literature, there are several controlled studies that have indicated that sodium bicarbonate will not work within the first 60 minutes of administration for the treatment of hyerpkalemia. (Am J Med 1988; 85:507-512) (Nephron 1996; 72:476-482) (Am J Kidney Dis 1996; 28:508-514) (Korean Med Sci 1997; 12:111-116)
    • Its onset is within 4 to 6 hours, with a duration of activity of the same time frame. The effects have reportedly been “variable” at best.
  • Even in the stetting of worsening metabolic acidosis and concomitant hyperkalemia, sodium bicarbonate has not been shown to be more effective that other common therapies used for this condition.
  • Some have said that perhaps the effect is more of dilutional in nature, simply because of the volume of sodium bicarbonate that is infused when administered as a continuous infusion as opposed to a bolus dose. (Miner Electrolyte Metab 1991; 17:297-302) (Kidney Int 1992; 41:369-374)
Concomitant Agents
  • Most of us who manage hyperkalemia in the health-system setting will often see orders for several agents to be administered simultaneously, with common agents being calcium gluconate or chloride, insulin with dextrose, sodium bicarbonate, and potentially other medications.
  • This is the origin of the hyperkalemia cocktail as we know it today:
    • Not surprisingly, this was described in 1954, and it was used in the military, specifically on the battlefield in soldiers who experienced traumatic acute kidney injury. (J Am Med Assoc 1954; 155:877-883)
    • The cocktail consisted of 400 mL of D25, 50 units of regular insulin, 50 mmol of sodium bicarbonate, and boluses of calcium administered as an as needed basis, but generally incorporating 100 mL of 10% solution of calcium gluconate.
    • When all the agents were compounded in an isotonic solution of sodium chloride at a rate of 25 mL/hr, this was a means to control hyperkalemia in soldiers on the battlefield for several days. 
  • However, there is little to suggest that the use of sodium bicarbonate within so-called hyperkalemia treatment cocktails actually effectively enhances the effects of other agents used to decrease serum concentrations of potassium. (Am J Kidney Dis 1996; 28:508-513) (East Afr Med J 1997; 74:503-509)

More to the Story: Thinking Beyond All About That Base

Utility of Hypertonic Saline
  • Case series of four patients who received a 5% solution of hypertonic saline for managing hyperkalemia in the setting of profound hyponatremia. (Am Heart J 1962; 64:483-488)
  • The study has been replicated a few times, but mostly in animal models, not in clinical practice with humans. (Am J Med 1953; 14:504) (Acad Emerg Med 1997; 4:93-99) (Acad Emerg Med 2000; 7:965-973)
Sodium-Loading Agent?
  • Activity at a specific voltage-gated sodium channel known as Nav1.5. (Am J Physiol 1975; 229:935-940)
    • It has been suggested that this sodium channel is antagonized in the setting of hyperkalemia, preventing the entry of sodium across the ventricular myocytes, which leads to a subsequent stalling of Phase 0 of the action potential, and may manifest in cardiac arrhythmias. The sodium load with sodium bicarbonate may allow for entry of sodium at the level of ventricular myocytes, which can normalize any manifestations in abnormalities in cardiac conduction. (Kidney Int 2016; 90:450-451)
Other Potential Mechanisms
  • Improved cellular perfusion in cardiac pacemaker cells
  • Decrease in systemic vascular resistance leading to reduction in afterload and induction of reflex tachycardia
  • Dilutional effect of extracellular potassium with rapid expansion of the volume of the plasma. (Acad Emerg Med 2000; 7:965-973)
Sodium Polystyrene Sulfonate (SPS)

  • SPS made its way onto the market in 1958, nearly four years before the passage of the Kefauver-Harris amendments requiring proof of both effectiveness and safety prior to medications being potentially approved by the Food and Drug Administration.
  • SPS has the claim to fame of serving as an ion-exchange resin. By design, it exchanges sodium for ammonium, calcium, and magnesium in addition to potassium as a means to facilitate fecal elimination of potassium. It generally works in the lower portion of the gastrointestinal tract, specifically in the distal colon, which contains the greatest proportion of potassium. At acidic pH, SPS cannot function as hydrogen ions occupy the sulfonate groups with the general structure of the compound. (Lancet 1953; 265:791-795) (Gastroenterology 1994; 107:548-571)
  • In the “pivotal” studies of SPS, 33 patients were evaluated and were deemed to be successfully treated with SPS for hyperkalemia.
  • One evaluation was a case report (N Engl J Med 1961; 264:111-115.), and the other study included the remaining 32 patients. (N Engl J Med 1961; 264:115-119.)
    • The latter reflected a decrease in serum potassium of 0.9 mEq/L in the first 24 hours with effects noted at 1 to 5 days post-administration.
    • There was no control for concomitant agents that could potentially be administered, and so it is difficult to attribute that this effect occurred due to the influence of the resin or the presence of other cathartic agents such as hypertonic glucose.
Controversies of SPS
  • SPS possesses many other properties that deem several questions related to its use in treating hyperkalemia: (J Am Soc Nephrol 2010; 21:733-735.)
    1. Sodium Load: 100 mg of sodium is contained per gram of SPS, which is equivalent to 4 mEq of sodium. The Heart Failure Society of America recommends exercising the use of caution of SPS in patients with congestive heart failure. 
    2. Many times, SPS is used in patient with chronic, end-stage renal disease (ESRD). However, for those with ESRD, colonic excretion is actually enhanced due to the actions of aldosterone. So whether SPS is truly beneficial in patients with ESRD is questionable.
    3. Fatal colonic perforation associated with SPS formulated with and without sorbitol.
    4. Based on a Cochrane review of studies evaluating the role of SPS in hyperkalemia, SPS has never been found to be effective within the first few hours of treatment, and fecal elimination of potassium has never been found to be significantly enhanced with use as well as no demonstrated benefit in reduction of serum potassium. (Coch Data Syst Rev 2005 Issue 2. CD 003235)

This agent is a non-absorbable synthetic polymer that acts as a “me-too” resin, in that similar to SPS, it facilitates fecal potassium excretion in the distal colon in exchange for calcium. It has been evaluated primarily in patients with chronic kidney disease with concomitant cardiovascular disease (N Engl J Med 2015; 372:211-221.) (JAMA 2015; 314:151-161.)(Eur Heart J 2011; 32:820-828.). It has a black box warning for separation from other orally administered medications by at least six hours due to demonstration of in vitro binding. One of its major adverse drug event is hypomagnesemia, which was observed in over 8% of patients in clinical trials; however, no neuromuscular abnormalities nor cardiac arrhythmias have been reported as manifestations.

Sodium zirconium cyclosilicate (ZS-9)

This agent is a crystal structure with high selectivity for potassium and ammonium ions. Hydration shells of these ion shells must be shed to induce thermodynamic stability, which requires energy (PLoS One 2014;9(12):e114686.) A binding pore within its structure traps potassium due to the size of pocket, which prevents binding of other smaller and larger cations. It is highly specific in that it entraps more than nine times the amount of potassium than SPS. Upon binding, sodium zirconium cyclosilicate facilitates excretion of potassium in exchange with sodium and hydrogen through the entire GI tract (not restricted to distal colon). It has been suggested to be effective in the long-term maintenance of normokalemia (Kidney Int 2015; 88:404-411.) (N Engl J Med 2015; 372:222-231.)

  • The publication of a subgroup analysis of two phase 3 trials that led to its approval is somewhat controversial (N Engl J Med 2015; 372:1577-1578.) This article was published as a correspondence to the journal and it described 45 patients with baseline serum potassium concentrations ranging between 6.1 and 7.2 mmol/L, demonstrating a somewhat rapid reduction in potassium at 1, 2, and 4 hours post-administration. 
  • Taking a closer look at patient populations, namely, among those excluded consisted of:
    • Hemodialysis
    • Outpatient treatment with phosphate binders (ergo end-stage renal disease)
    • Outpatient treatment for hyperammonemia (ergo end-stage liver disease)
    • Diabetic ketoacidosis
    • Life-threatening cardiac arrhythmias
  • These excluded patient populations consists of the majority of the patients that we encounter in the acute care setting such as the emergency department with hyperkalemia. We cannot confidently state that sodium zirconium cyclosilicate has a role in managing hyperkalemia acutely due to exclusion of these patient populations. (Hypertension 2015; 66:731-738) (Pharmacotherapy 2016; 36:922-923)

Monday, November 28, 2016

How the NEJM and Star Wars May Just Have Predicted My Future in #FOAMed

It sometimes is a bit wondrous how our past actions can influence how our future pursuits.

I have discussed how #FOAMed has made an impact on research, discovery, and my professional pursuits here and here. To be quite frank, I can't imagine how my life would be if I was not engaged in social media.

But obviously, at one point, I did, and I may have predicted my own engagement in #FOAMed without even realizing it. In addition, I think I have the New England Journal of Medicine (NEJM) and the Star Wars franchise to thank for this foretelling of my future.

This week, five years ago, as I was in the midst of applying and interview at programs to pursue post-graduate training in emergency medicine pharmacy, I was also putting the final touches of an essay for a contest that I will confess that I entered as a sort of joke that I had with one of my co-residents.

At the time, the NEJM put forth a call for student and residents to enter an essay contest in commemoration of the 200th anniversary of the journal. The question surrounding the essay was as follows:

In the last twenty years, the internet and social networking have brought profound changes in how information is communicated. How can we harness this technology to improve health?

The editors of the journal would select 150 winners of the essay contest, and those student and trainees who won would be invited to a full-day symposium of the 200th anniversary of the journal at Harvard Medical School in Boston. In addition, all of the winning essays would be featured on the NEJM 200th anniversary website.

When I received the email, I was on my drug information learning experience, and there was some opportunity for me to write during downtime. I showed the email to my co-resident, who stated that I was lucky that she was not entering the contest as her essay would "blow all the others out of the water. " I took this as a challenge and said to her that I would enter, and that I may very well prove to her that I could win. We both laughed, and I proceeded to write, not thinking much of it, but I did have a tiny glimmer of hope of being one of the lucky 150. Once I submitted the essay, I forgot about it in the haze of everything else that was occurring at the time.

A short few months later, on a spring day in March, as I was checking my email,  one subject heading that caught my eye in my inbox was "Results of the NEJM Essay Contest." Once I clicked it open, I read congratulatory notes on having won the essay contest with further details related to registration and traveling to the Boston to attend the 200th anniversary symposium. I was shocked and gleefully laughed as I showed my co-resident the email, and she commended me on my efforts.

After being granted full permission to do so from the editors of the NEJM, I have reproduced my essay below. For all I know, the title may have pushed this essay over the edge for the judges.

"Electronic Information Technologies in Healthcare: May the Source Be With You

It is difficult to imagine the world without the existence of smartphones, personal computer tablets, and other devices that we currently utilize as a means to obtain and communicate information.

Social networking websites such as Facebook and Twitter are tools we use every day to receive the most up-to-date information on a minute-to-minute basis. With these resources, we can literally carry the world at our fingertips.

The advancements in the availability of information via electronic means have changed the way healthcare professionals practice. Many medical journals utilize an electronic table of contents (eTOC) for subscribers to receive information regarding newly completed and ongoing clinical trials, the latest review articles and treatment guidelines, and interesting case reports that can be applied to our clinical practice. If we have questions or need clarification regarding indications, appropriate dosing, or adverse effects of medications, various mobile applications that contain a wealth of drug information are available to us to research the information and are only a touchscreen away.

Social networking has allowed for communication between healthcare professionals who share the same field of practice that would not have been otherwise possible. This has established a foundation for the exchange of ideas through the development of workshops and conferences regarding the latest therapeutic updates, which has fostered an environment for collaborative practice amongst healthcare professionals. In the setting of natural disasters and other types of emergency crises, social networking websites can serve as a means of sharing information with the public regarding preparedness and response to these types of situations, especially when determining the status of local hospital operations and emergency room access. Governmental agencies such as the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) provide the general public with information regarding the latest news in the media regarding healthcare on a regular basis.

With the growing interest in the promotion of health literacy, both the Internet and social networking websites can serve as useful vehicles for healthcare professionals and patients alike to make appropriate health decisions. As health literacy initiatives continue to grow and progress, patient safety and health outcomes will improve, which can eventually lead to a reduction in medication errors and decreased healthcare costs.

Through these instances, we can see that the Internet and social networking websites have become an essential component of the healthcare setting. As healthcare organizations continue develop innovative means to utilize this technology, stakeholders will be able to influence the means  in  which both patients and healthcare professionals can acquire and gain access to health information. With the evolution of these technologies, healthcare providers have the responsibility to evaluate the accuracy and clarity of these resources for use by the general public, which is a huge challenge that will need to be addressed and overcome in the future. In doing so, we can ensure that the practical application of information obtained through these technologies will ultimately improve the quality of life for our patients."


Here is what still surprises me: I wrote this essay prior to my engagement in #FOAMed - nearly a full year prior, to be exact. That is to say that at the time that I wrote this essay, I had never even heard of #FOAMed. In addition, at the time of writing the essay, I was not yet on Twitter - I thought it was only for celebrities - and I was on the brink of closing my Facebook page for good, which I did later on that year. Much of what I knew about social media at the time of writing the essay came from my own research on the topic from other disciplines. The way that I kept up with the latest in the medical and pharmacy literature came from my own subscriptions through electronic tables of contents of various journals - that was it. Admittedly, all that I knew back then was that people used blogs as live journals to record the occurrences of daily life and to share recipes, and podcasts were for listening to books on tape and for folks to discuss the latest in pop culture. This was the limited scope of knowledge that I had about social media, and yet, there was something that made me push forward in writing about its role in medicine.

I also find it ironic that it may have very well been a journal - a traditional, 200-year-young print publication - that sparked my initial interest in social media and medicine.

Reading this now, there are certain themes in the essay that emerge that are #FOAMed-like in nature, if not, fall within the very realms of #FOAMed. In reflecting upon this, maybe I had some sort of gut feeling that in time, social media could be leveraged for some good.

Funny how things turn out.

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