Prevention of hypokalemia-induced adverse cardiovascular effects in diabetic ketoacidosis: a novel role of the pH-adjusted potassium level
CC BY-NC-SA 4.0
Prevention of hypokalemia-induced adverse cardiovascular effects in diabetic ketoacidosis: a novel role of the pH-adjusted potassium level
CC BY-NC-SA 4.0
Introduction
Hypokalemia is a common observation in diabetic ketoacidosis (DKA) and it is usually associated with insulin deficiency.1 At first, it hinders the inflow of serum potassium (SK) from extra- to intracellular compartments, which triggers hyperkalemia.2 In the course of progressive DKA, hyperglycemia and ketosis‑induced osmotic diuresis increases potassium excretion, contributing to potassium depletion in intracellular compartments. Insulin deficiency–mediated increased catecholamine levels have a relative effect on potassium concentration via β-adrenoceptors.3,4 Moreover, potassium loss is increased, as the degree of acidosis worsens.5 Acidosis has also been associated with changes on electrocardiography similar to those typical of hypokalemia.3,6 However, despite a significant potassium loss, patients with DKA present with various degrees of potassium disturbance on admission, which range from normal kalemia to hyperkalemia.
During DKA treatment, insulin forces SK to shift to intracellular compartments, and the remaining SK is diluted as a result of intravenous fluid reconstitution1,7; this causes clinical hypokalemia in patients with DKA. In emergency departments (EDs), this type of hypokalemia is promptly monitored using electrocardiography.4,8 However, as this modality mainly does not reflect potassium loss in extracellular compartments, the ratio of potassium concentrations in extra- and intercellular compartments is crucial to determine hypokalemic electrocardiographic changes.9 Therefore, much time is required to obtain a stable electrocardiogram and avoid cardiovascular risk. Considering the significance of SK concentration, DKA treatment guidelines still recommend physicians to initiate potassium replacement if its level falls below 5.5 mmol/l1,7,10; such a measure puts patients at risk of hypokalemia. Contrarily, following the guidelines may put the DKA patient at risk of hyperkalemia.11 To address the issue of timely yet safe potassium supplementation in DKA, we aimed to adjust SK levels to the degree of acidosis (pH‑adjusted potassium [pHK] levels) as well as to evaluate the association of hypokalemic electrocardiographic changes with pHK and other clinical parameters in DKA.
Patients and methods
The data of the patients with DKA from Universiti Kebangsaan Malaysia Medical Centre, collected during 3 years (between January 2015 and December 2017) were retrospectively analyzed. Code E1X.1 (X ranging between 0 to 4) of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision was used to identify DKA cases.
Data acquisition
Primary data included blood gas analysis, renal profile, complete blood count, electrocardiographic findings, and ED treatment. Secondary data provided information on demographics, physical presentation, and medical history. An electrocardiogram was considered indicative of hypokalemia when purely hypokalemic changes were reported4,8; multiple abnormalities on electrocardiography were regarded as unrelated to hypokalemia. With each 0.1‑decrease in pH, 0.6 mmol/l was subtracted from the SK level to obtain the pHK level.5
Inclusion criteria
All adult DKA patients with hyperglycemia, ketone bodies in either blood or urine, and acidosis were included in the study. Euglycemic DKA episodes were also recorded.1 A bicarbonate level ≤18 mmol/l with pH ranging between 7.3 and 7.35 rendered the patient acidotic. Venous blood samples were adjusted by 0.3 for pH and 0.52 mmol/l for bicarbonate to consider them as arterial blood gas values.12
Exclusion criteria
We excluded patients with incomplete ED records in primary data, younger than 18 years of age, managed by a pediatric team, treated for gestational diabetes–induced DKA, pregnant during DKA, with a history of cardiovascular disease, admitted due to cardiovascular disease, or taking medication known to influence hypokalemic changes on electrocardiography.8
Statistical analysis
Statistical analysis was performed using the SPSS package for social sciences, version 23 (IBM Corp., Armonk, New York,United States). Univariable logistic regression was used to determine the effect of an independent variable on the outcome, ie, hypokalemic electrocardiographic changes, with 95% CI. Variables with P value ≤0.2 were entered in the multivariable regression model to ascertain their strength against confounding variables. The performance of the model was recorded using a receiver operating characteristic curve, based on probabilities derived from the multiple regression model. A P value less than 0.05 was considered significant. Data were expressed as median and interquartile range (IQR).
Ethics
The study was approved by Monash University (MUHREC‑2 018‑13 643), Universiti Kebangsaan Malaysia (NF‑RES‑2018‑15), and Universiti Kebangsaan Malaysia Medical Centre (JEP‑2018‑145). No patient consent was required in this study.
Results
Objective observations
Eighty‑five patients fulfilled the inclusion criteria (Supplementary material, figure S1). Median (IQR) blood glucose and ketone levels on admission were 30.9 (23.6–38.5) mmol/l and 4.3 (3–5.9) mmol/l, respectively. The study patients were moderately acidotic with median (IQR) pH at 7.22 (7–7.28) and a median (IQR) bicarbonate level of 10.7 (8.3–14.4) mmol/l. Median (IQR) white blood count and pulse rate were higher than normal, ie, 14.6 × 103/µl (10.3–18 × 103/µl) and 108 (98–126) bpm, respectively. The remaining biochemical and physical profiles of the study patients were unremarkable.
Treatment and potassium‑associated parameters
The median (IQR) levels of SK and pHK were 4.8 (4.1–5.5) mmol/l and 3.8 (3.1–4.4) mmol/l, respectively. The study patients developed hypokalemia within a median (IQR) time of 9 (5–17) hours from admission, with a median (IQR) SK level of 3.2 (3–3.5) mmol/l. A total of 37.6% of the patients experienced hypokalemia during pH normalization. The median (IQR) length of stay in the ED was 8 (5–14) hours, during which most patients (98.8%) received continuous intravenous insulin infusion at a median (IQR) rate of 6 (3–6) units per hour. More than 1/3 of the patients (38.8%) received potassium supplementation during their stay in the ED, according to the DKA treatment guidelines.1,7,10
Hypokalemic changes on electrocardiography
The multivariable regression model indicated 3 variables significantly affecting hypokalemic changes on an electrocardiogram: pHK (odds ratio [OR], 0.42; 95% CI, 0.18–0.98), units of insulin per hour (OR, 0.58; 95% CI, 0.36–0.94), and age (OR, 1.04; 95% CI, 1–1.09) (table 1).
OR | 95% CI | P value | OR | 95% CI | P value | |
Baseline characteristics | ||||||
Therapeutic indicators | ||||||
Model summary | ||||||
- Kitabchi AE, Umpierrez GE, Murphy MB. Diabetic ketoacidosis and hyperosmolar state. In: DeFronzo RA, Ferrannini E, Zimmet P, Alberti G, eds. International Textbook Of Diabetes Mellitus, 4th Edition. New Sussex, United Kingdom: John Wiley & Sons; 2015: 799‑814.
- Palmer BF, Clegg DJ. Physiology and pathophysiology of potassium homeostasis: core curriculum 2019. Am J Kidney Dis. 2019; 74: 682‑695. | Crossref
- Long B, Warix JR, Koyfman A. Controversies in management of hyperkalemia. J Emerg Med. 2018; 55: 192‑205. | Crossref
- Sheehan L, Calfas D. Cardiovascular complications of ketoacidosis. US Pharm. 2016; 41: 39‑42.
- May DB. Clinical laboratory tests. In: Shargel L, Mutnick AH, Souney PF, Swanson L, eds. Comprehensive Pharmacy Review for NAPLEX. Baltimore, Maryland, United States: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013: 542‑559.
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