CICU Pharmacotherapy MythBusters Jaclyn Sawyer Pharm D Clinical

CICU Pharmacotherapy Myth-Busters Jaclyn Sawyer, Pharm. D Clinical Pharmacy Specialist, Cardiology Division of Pharmacy Cincinnati Children's Hospital Medical Center David Nelson, MD, Ph. D Medical Director, Cardiovascular Intensive Care Unit Division of Cardiology Cincinnati Children's Hospital Medical Center

MYTHS • CALCIUM INFUSIONS ARE NOT AN EFFECTIVE INOTROPE • INTRAVENOUS POTASSIUM REPLACEMENT IS MORE EFFECTIVE THAN ENTERAL POTASSIUM REPLACEMENT • ECONOMIC MYTHS – OLDER DRUGS ARE CHEAPER – COST REALITY CHECK

MYTH: CALCIUM INFUSIONS ARE NOT AN EFFECTIVE INOTROPE

Cardiomyocyte Calcium Concentration Contractility and Relaxation • Mature mammalian myocytes => Sarcoplasmic reticulum • Sarcoplasmic reticulum is immature in neonatal hearts Na/Ca Exchanger – Structurally and functionally under-developed Neonatal Hearts Demonstrate Markedly Increased Ca+2 Sensitivity L-type Ca Channel

Calcium Chloride • Unique inotrope – Improves myocardial function with minimal change in heart rate minimizing myocardial oxygen demand => Improved cardiac output in patients with myocardial dysfunction with no increase in heart rate • Small incidence of non-cardiac side effects • Ongoing studies – Prospective – Safety

Calcium Chloride Infusions, Used as an Inotrope, Improve the Hemodynamics of Critically Ill Children • Calcium Chloride – Retrospective – Ca. Cl for hemodynamic instability • 2. 5 -15 mg/kg/hr – May 2011 -May 2012 – Efficacy at 2 hrs and 6 hrs • • Heart Rate Blood Pressure Systemic arterial O 2 and mixed venous O 2 – AVO 2 difference NIRS Lactate Urine Output Other inotropes – Safety Averin K. CCHMC data awaiting publication

Calcium Chloride Infusions Improve Cardiac Output: Baseline Characteristics Table 1. Characteristics Total Population (N = 116) Newborn (0 -30 days) (N = 65) Infant (1 -6 months) (N = 21) Children (>6 months) (N = 30) 0. 87 ± 2. 67 68 (59%) 5. 93 ± 6. 75 0. 02 ± 0. 02 36 (55%) 2. 98 ± 0. 76 0. 26 ± 0. 11 17 (81%) 4. 57 ± 0. 84 3. 15 ± 4. 58 15 (50%) 13. 28 ± 10. 1 67. 25 (IQR 37. 33, 130. 44) 70. 10 (IQR 44. 93, 138. 98) 71. 40 (IQR 54. 88, 177. 37) 52. 82 (IQR 27. 68, 83. 35) 8 (7%) 88 (76%) 20 (17%) 6 76 17 1 10 2 1 Ionized Calcium Level at Initiation (mmol/L) 1. 22 (IQR 1. 09, 1. 30) 1. 17 (IQR 1. 03, 1. 30) 1. 27 (IQR 1. 22, 1. 35) 1. 23 (IQR 1. 12, 1. 26) Ionized Calcium Level at Initiation (mmol/L) <1 1 -1. 45 >1. 45 16 (16%) 79 (80%) 4 (4%) 12 (21%) 45 (79%) 0 2 (12%) 13 (76%) 2 (12%) 2 (8%) 21 (84%) 2 (8%) Inotropes at Baseline None 1 Inotropes 2 Inotropes 3 Inotropes 16 (14%) 51 (44%) 36 (31%) 13 (11%) 14 (22%) 30 (46%) 16 (25%) 5 (8%) 1 (5%) 10 (48%) 6 (29%) 4 (19%) 1 (3%) 11 (37%) 14 (47%) 4 (13%) Demographics Age (y) Male Weight (kg) Calcium Infusion Duration (hours) Duration of calcium infusion <24 hours 1 -7 days >7 days Averin K. CCHMC data awaiting publication LCO etiology: • Nonsurgical: 46% • Surgical: 53% (CHD)

Calcium Chloride – HD Response 64% to 69% P<0. 001 69 to 77 P<0. 001 3. 4 to 2. 5 P<0. 0001 Not significant 33% to 26% P<0. 001 UOP increased by 29% in 8 hr period after Ca initiation Averin K. CCHMC data awaiting publication

Calcium Chloride Infusions Improve Cardiac Output: Results • Baseline i. Ca does not change effect to Ca infusion • HD improvements did not correlate with higher i. Ca • All age groups had improvements CO measures – Neonates most robust • Single and Bi – ventricular groups both had improvements in CO • Surgical and non-surgical groups both had improvements in CO Averin K. CCHMC data awaiting publication

Calcium Infusion Considerations • Calcium Chloride vs Calcium Gluconate – calcium gluconate: 4. 65 m. Eq Ca++/gram – calcium chloride: 13. 6 m. Eq Ca++/gram • Safety monitoring – Pancreatic enzymes – Nephrolithiasis and nephrocalcinosis • Compatibility considerations – TPN

MYTH: INTRAVENOUS POTASSIUM REPLACEMENT IS MORE EFFECTIVE THAN ENTERAL POTASSIUM REPLACEMENT

Institute for Safe Medication Practices classifies Intravenous Potassium as a “High-alert” medication

ISMP - IV Potassium classified as “high alert medication” • Inappropriate administration can lead to serious adverse events such as cardiac arrest or death • 1980 s-1990 s - Concentrated KCl products removed from patient care areas • Commercially mixed solutions used when at all possible • Other safety measures – Standard concentrations – Double checks, infusion pump guardrails, storage precautions

• • Texas Children’s Hospital Practice change: Enteral potassium supplementation preferred over IV unless severe GI disease (NEC, surgical abdomen) • IV: 1 m. Eq/kg/dose (max 40 m. Eq/dose); 0. 3 m. Eq/m. L over 1 hr • Enteral: 1 m. Eq/kg/dose (max 40 m. Eq/dose) oral or NG; 2. 67 m. Eq/m. L with SW eq vol for flush • Definitions: – Hypokalemia: <3. 5 mmol/L – Hyperkalemia: >5. 5 mmol/L Moffett B. et al. Ped Crit Care Med 2011 Vol 12, No 5

Enteral Potassium Supplementation Patient Demographics IV Potassium (n=15) Enteral Potassium (n=25) Intravenous and Enteral Potassium (n=36) 7. 8 (0. 1 -108. 2) 6. 1 (0. 1 -72) 2. 4 (0. 1 -143. 5) 7. 6 ± 4. 6 7. 2 ± 4. 2 5. 5 ± 4. 7 Surgery prior to KCl (%) 14 (93. 3%) 25 (100%) 36 (100%) Mechanical Support (%) 1 (6. 7%) 0 (0%) 5 (13. 8%) Urine Output (m. L/kg/day) 3. 9 ± 1. 5 3. 1 ± 1. 7 3. 9 ± 1. 2 Inotropic medication (%) 11 (78. 6%) 21 (84%) 34 (94. 4%) Vasopressin (%) 4 (26. 7%) 2 (7. 4%) 17 (47. 2%) Diarrhea (%) 1 (6. 7%) 1 (3. 7%) 5 (13. 8%) Age in Months (median and range) Weight (kg) • Treatment Bias − Preference of IV in patients on vasopressin Moffett B. et al. Ped Crit Care Med 2011 Vol 12, No 5

Enteral Potassium Supplementation Change in Serum Potassium Concentrations Intravenous Enteral Bolus Intravenous (n=15) 0. 89 ± 65 − Enteral (n=25) − 0. 65 ± 0. 33 IV and Enteral (n=36) 0. 85 ± 0. 39 0. 72 ± 0. 36 Totals (n=76) 0. 86 ± 0. 48 0. 69 ± 0. 34 • Treatment Bias’ − Preference of IV in patients on vasopressin − Preference of IV in patients with lower potassium levels Moffett B. et al. Ped Crit Care Med 2011 Vol 12, No 5

Enteral Potassium Supplementation • Enteral and intravenous potassium supplementation are equivalent • Other advantages beyond safety – Reduced fluid administration – Cost $ – Decreased resource utilization – Decrease frequency of IV line access • Too small to assess safety – No difference in potassium related ADE Moffett B. et al. Ped Crit Care Med 2011 Vol 12, No 5

Enteral Potassium Supplementation • Enteral and intravenous potassium supplementation are essentially equivalent • Other advantages beyond safety – Reduced fluid administration • Example: 3 Kg infant, K Replacement 1 m. Eq/Kg – Central IV Potassium: 15 m. L » 0. 2 m. Eq/m. L (CCHMC standard concentration) – Peripheral IV Potassium: 75 m. L » 0. 04 m. Eq/m. L (CCHMC standard concentration) – Enteral Potassium: 1. 1 m. L » 2. 67 m. Eq/m. L Moffett B. et al. Ped Crit Care Med 2011 Vol 12, No 5

Enteral Potassium Supplementation • Enteral and intravenous potassium supplementation are essentially equivalent • Other advantages beyond safety – Reduced fluid administration – Cost $ – Decreased resource utilization – Decrease frequency of IV line access • Too small to assess safety – No difference in potassium related ADE Moffett B. et al. Ped Crit Care Med 2011 Vol 12, No 5

MYTH: ECONOMIC MYTHS - OLDER DRUGS COST LESS MONEY $ COST REALITY CHECK $

Older drugs cost less? Diuretics FDA Approval Dosage Form Dose Cost/dose for 10 kg patient (AWP) Furosemide (Lasix) 1966 PO – tablet 1 mg/kg $0. 07 1987 PO – solution 1 mg/kg $0. 17 1982 IV 1 mg/kg $1. 64 Chlorothiazide (Diuril) – Initial FDA approval 1973 PO – tablet 10 -15 mg/kg $0. 28 -0. 42 1962 PO – solution 10 -15 mg/kg $0. 53 -0. 79 1958 IV 2 -5 mg/kg $14. 30 -35. 72 1967 PO – tablet 1 mg/kg $6. 45 1967 IV 1 mg/kg $601. 61 Ethacrynic Acid (Edecrin)

Cost Reality Check ACE Inhibitors Captopril Enalapril Lisinopril Dosage Form Dose Cost for 5 kg patient x 30 DAYs (AWP) PO – tablet 0. 5 mg/kg/dose TID $27. 90 PO – compound* 0. 5 mg/kg/dose TID $47. 90* PO – tablet 0. 1 mg/kg/dose BID $10. 50 PO – Epaned suspension 0. 1 mg/kg/dose BID $68. 40 PO - tablet 0. 1 mg/kg/dose Qday $1. 49 PO - compound* 0. 1 mg/kg/dose Qday $21. 49* *Includes average compounding fee: $20

Cost Reality Check Dexmedetomidine vs. Midazolam Dose Cost for 10 kg patient (AWP) X 24 hrs Midazolam (Versed) 0. 1 mg/kg/hr $6. 77 Dexmedetomidine (Precedex) 0. 5 mcg/kg/hr $39. 99

Cost Reality Check • The Affordable Care Act and Accountable Care Organizations Ø Reduce expenditures and preserve or improve the quality of care

Summary – Myths-Busted!? • Calcium chloride infusions are effective in improving hemodynamics in patients with LCOS, with a low incidence of non-cardiac side effects and a trend towards a decrease in heart rate • Efficacy of enteral potassium is equivalent to that of intravenous potassium for potassium replacement in pediatric patients in the CICU • Due to the Affordable Care Act, costs of medications will become much more relevant to clinicians and Health Care Administrators

Thank you! Are there other Pharmacy-related myths to bust at your institution? Jaclyn Sawyer, Pharm. D Clinical Pharmacy Specialist, Cardiology Division of Pharmacy Cincinnati Children's Hospital Medical Center David Nelson, MD, Ph. D Medical Director, Cardiovascular Intensive Care Unit Division of Cardiology Cincinnati Children's Hospital Medical Center

FINAL MYTH: PHYSICIANS AND NURSE PRACTITIONERS HAVE ADEQUATE TRAINING IN PHARMACOLOGY AND DO NOT NEED CLINICAL PHARMACISTS (PHARM. D. ) TO PROVIDE OPTIMAL CARE.