Introduction: Hypokalemia secondary to diuretic therapy and cardiopulmonary bypass in children following cardiac surgery occurs frequently, placing them at risk for life threatening arrhythmias. However, the risk of renal insufficiency after cardiopulmonary bypass warrants careful administration of potassium. There are no prior published reports about the efficacy and safety of potassium repletion protocols in pediatric patients after cardiac surgery nor in critical care settings. The Cardiothoracic Intensive Care Unit (CTICU) at Children’s Hospital Los Angeles historically utilized an intravenous potassium chloride (KCl) replacement protocol based on monitoring serum potassium (K+) concentrations every 8 hours with 0.5 mEq/kg replacement doses as necessary. However, low-dose replacements (LD) were often insufficient to correct serum K+ levels, resulting in frequent supplemental doses. Thus, two different protocols (high dose [HD] of 1 mEq/kg for K+ ≤ 3.2 mEq/L, and a tiered dosing [TD] of 0.5 mEq/kg for K+ 2.9–3.2 mEq/L and 1 mEq/kg for K+ ≤ 2.8 mEq/L) were implemented to identify an optimal replacement regimen. Methods: Charts of patients admitted to the CTICU placed on potassium replacement protocols from June 1, 2008 to May 31, 2009 were retrospectively reviewed to determine the efficacy and safety of the protocols. Efficacy was defined as a higher protocol to total doses ratio per patient (i.e., fewer supplemental doses per patient). Safety was defined as a lower percentage of serum K+ levels ≥ 4.8 mEq/L after a protocol dose of KCl. Between group differences were assessed by non-parametric analysis since the data was not normally distributed. Results: The collected data included 138 patients: a total of 141 KCl doses in the LD protocol, 404 KCl doses in the HD protocol, and 689 KCl doses in the TD protocol. The median age and weight were 3.0 (0.23–10.0) months and 4.1 (3.0–7.9) kg, respectively. The incidence of potassium levels ≥ 4.8 mEq/L after a protocol dose was higher in the HD protocol versus the TD protocol (2.2% vs 0.5%, p=0.05), but not different between the LD and TD protocols (1.6% vs 0.5%, p=ns). The ratio of protocol doses to total doses per patient was significantly lower in the LD protocol compared to the TD protocol (0.54 vs 1.0, p<0.01), but not different in the HD protocol versus the TD protocol (1.0 vs 1.0, p=ns). Conclusions: The tiered KCl replacement protocol (TD) was associated with a decreased need for supplemental replacement doses compared to the LD protocol without the increased risk of high serum K levels in the HD protocol, making it both effective and safe in the treatment of hypokalemia in pediatric patients after cardiac surgery. Such multidisciplinary protocols may safely and effectively treat electrolyte defects while saving provider time and preventing delays in treatment.