Emergency. 2018; 6 (1): e52 OR I G I N A L RE S E A RC H Correlation of Hyperchloremic Metabolic Acidosis and Re- nal Function in Critically ill Patients of Emergency De- partment: an Observational Study Mauro Giordano1∗, Tiziana Ciarambino1, Pietro Castellino2, Lorenzo Malatino2, Giuseppe Signoriello1, Giuseppe Paolisso1, Luigi Elio Adinolfi1 1. Department of Medical, Surgical, Neurological, Metabolic and Geriatrics Sciences, University of Campania “L. Vanvitelli”, Italy. 2. Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy. Received: May 2018; Accepted: August 2018; Published online: 25 August 2018 Abstract: Introduction: Early detection is crucial for prompt management of acute kidney injury (AKI) patients in emer- gency department (ED). This study aimed to investigate the usefulness of hyperchloremic metabolic acidosis (HCMA) levels in this regard. Methods: In this retrospective observational study, > 18 years old critically ill pa- tients presenting to ED of Marcianise Hospital, Italy, were divided into non-AKI and AKI group according to KDIGO guideline. The level of HCMA ((arterial pH x bicarbonate)/chloride) was compared between groups and correlation of HCMA with estimated glomerular filtration rate (e-GFR) in ARF patients was evaluated. Results: 134 patients with the mean age of 76.5 ± 3.1 years were enrolled (64 non-AKI and 70 AKI; 64% female). Two groups were similar regarding mean age (p = 0.251), sex (p = 0.091), APACHII score (p = 0.215), Charlson Comor- bidity Index (p= 0.187), and body mass index (p = 0.129). The mean HCMA level was 1.98 ± 0.09 in the non-AKI group and 1.56 ± 0.07 in the AKI group (p=0.039). There was a positive correlation between HCMA and e-GFR levels in AKI group (r: 0.467, p=0.0092). Conclusion: If confirmed and validated in a future study, ABG derived formula for HCMA may be a useful tool for early detection of AKI patients in emergency department. Keywords: Acute kidney injury; hyperchloremic metabolic acidosis; emergency department; renal function © Copyright (2018) Shahid Beheshti University of Medical Sciences Cite this article as: Giordano M, Ciarambino T, Castellino P, Malatino L, Signoriello G, Paolisso G, Elio Adinolfi L. Correlation of Hyper- chloremic Metabolic Acidosis and Renal Function in Critically ill Patients of Emergency Department: an Observational Study. Emergency. 2018; 6(1): e52. 1. Introduction A cute kidney injury (AKI) is a frequent and potentially life-threatening syndrome, with high costs for pa- tients and the healthcare systems (1). Overall, 5.5% of all emergency department patients had acute kidney in- jury in one study (2). AKI is defined as a rise in creatinine, 50% from its baseline value, and/or a fall in the glomerular fil- tration rate (GFR) by 25%, and/or a decrease in urine output reaching less than 0.5 ml/kg/h for 6 h or more (3). AKI in pa- tients is associated with higher mortality. Patients with severe sepsis and septic shock exhibit a complex metabolic acidosis ∗Corresponding Author: Mauro Giordano; Department of Medical, Surgical, Neurological, Metabolic and Geriatrics Sciences, University of Campania, L. Vanvitelli, Italy. Email: mauro.giordano@unicampania.it upon intensive care unit admission, caused predominantly by hyperchloremic acidosis, which is more pronounced in non-survivors (4). Normally, the major renal defense against metabolic acidosis is the net urinary excretion of strong an- ions, such as chloride, and the retention of strong cations (5). This mechanism becomes impaired in AKI patients. An early diagnosis is crucial for prompt management of AKI to an- ticipate acute renal dysfunction. The purpose of this study was to investigate the usefulness of hypercloremic metabolic acidosis (HCMA) levels evaluated, using an arterial blood gas (ABG) analysis derived formula, for early suspicion of AKI in emergency department (ED). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com M. Giordano et al. 2 2. Methods 2.1. Study design and setting In the present retrospective observational study, eligible pa- tients who were admitted to University Hospital of Mar- cianise, Italy, from January 2017 to March 2017, were eval- uated regarding HCMA level and its’ correlation with renal function. Ethical Committee of North Campania approved the protocol of the present study and all researchers adhered to the principles of the Helsinki declaration during the study period. Additionally, a consent form was obtained from pa- tients. 2.2. Participants Adult (>18 years old) critically ill patients (Acute Physiol- ogy and Chronic Health Evaluation (APACHE II) index >18) in emergency department were subdivided in the non-AKI (with normal creatinine levels and GFR > 90 ml/min/1.73 m2) and the AKI group according to KDIGO guideline. AKI pa- tients were defined as patients whose serum creatinine had increased to ≥ 0.3 mg/dl (26.5 micrmol/L) within 48 hours or 1.5-fold from the baseline, which was known or presumed to have occurred in the preceding 7 days, with decrease in urine output, according KDIGO guidelines (3,8). Adults with chronic kidney disease or need for renal replacement ther- apy, those not giving consent, less than 18 years of age, history of acute gastrointestinal and post-operative patients were excluded. The Acute Physiology and Chronic Health Evaluation (APACHE II) score and Charlson Comorbidity In- dex (CCI) (6, 7) were calculated from the patient charts. 2.3. Data gathering and measurements Demographic and clinical characteristics, patient diagnoses, procedures (e.g. laboratory tests), treatments/interventions and patient outcomes were extracted from patients’ profiles by an emergency medicine specialist who was responsible for data gathering and patients were enrolled using random sampling method. Glomerular filtration rate (GFR) was evaluated via CKD- EPIdemiology Collaboration (CKD-EPI) equation (8). Serum levels of albumin, creatinine and various electrolytes, includ- ing Na, K, Ca, Mg, Cl and HPO4, were recorded for each pa- tient. Blood pH and the partial pressures of oxygen and car- bon dioxide in the blood (PaO2 and PaCO2) were measured using a RapidLab Blood Gas Analyzer (GEMr Premiertm 4000 plus). HCMA was evaluated in emergency department, using the following formula: ((pH x HCO3-) / Cl −), where pH is the arterial pH, HCO3- is the arterial bicarbonate concentration and Cl− is the arterial chloride concentration, as reported by ABG analysis, on admission to the Emergency Department. Figure 1: Linear positive correlation between hyperchloremic metabolic acidosis (HCMA) and estimated glomerular filtration rate (e-GFR) levels in AKI group (r: 0.467, p=0.0092). 2.4. Statistical Analysis Data analyses were performed using SPSS, Version 19.0 (IBM Corp, Armonk, NY). Statistical significance was set at p<0.05 for all procedures. Analyses of ABG were made using a non- parametric U-test by Mann-Whitney for independent sam- ple. Data are presented as percentage and mean ± standard error (SE). 3. Results 134 patients with the mean age of 76.5 ± 3.1 (68-85) years were enrolled (64 non-AKI and 70 AKI; 64% female). Base- line characteristics of studied patients are reported in table 1. Two groups were similar regarding mean age (p = 0.251), sex (p = 0.091), APACHII score (p = 0.215), Charlson Comorbid- ity Index (p= 0.187), and body mass index (p = 0.129). Table 2 summarizes the ABG, electrolyte findings of studied patients. The mean HCMA level was 1.98 ± 0.09 in the non-AKI group and 1.56 ± 0.07 in the AKI group (p=0.039). Figure 1 shows the correlation of HCMA and e-GFR levels in AKI patients. There was a positive correlation between HCMA and e-GFR levels in AKI group (r: 0.467, p=0.0092). 4. Discussion In this paper we reported the differences of HCMA levels in non-AKI and AKI patients in the emergency department. In AKI patients a significant association between ABG de- rived hyperchloremic metabolic acidosis state and e-GFR was found. AKI is associated with higher mortality in emer- gency patients (9, 10). It has been reported that hyper- chloremic acidosis due to the intraoperative chloride load also has an important role in deterioration of renal func- tion (11). Thus, early identification of AKI patients is cru- cial for their prompt management. Acute kidney injury can lead to hyperchloremic metabolic acidosis especially when the glomerular filtration rate is between 30 to 59 mL/min (stage III) (12, 13). HCMA has been reported in AKI patients This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com 3 Emergency. 2018; 6 (1): e52 Table 1: Baseline characteristics of studied patients Variables non-AKI (n=64) AKI (n=70) P value Sex Male 22 (34.3) 26 (37.1) 0.091 Female 42 (65.7) 44 (62.9) Age (years) Mean± SE 75±4 77±3 0.251 APACHE II score Mean± SE 22±3 24±4 0.215 Charlson Comorbidity Index Mean± SE 4.0 ±1.8 4.0 ±1.3 0.187 BMI (Kg/m2 ) Mean± SE 21.2 ± 6.0 22.3 ± 5.0 0.129 Serum Creatinine (mg/dl) Mean± SE 0.79 ± 0.02 2.06 ± 0.01 0.0091 e-GFR (ml/min/1.73 m2 ) Mean± SE 91.3 ± 0.45 33.4 ± 0.25 0.0087 Comorbid disease Diabetes 22 (31) 33 (47) 0.041 Hypertension 44 (59) 35 (50) 0.101 Cirrhosis 2 (3) 5 (10) 0.037 COPD 6 (10) 8 (11) 0.180 Heart Failure 11 (17) 15 (21) 0.140 Data are presented as mean ± standard error (SE) or number (%). APACHE: Acute Physiology and Chronic Health Evaluation; BMI: Body Mass Index; COPD: Chronic Obstructive Pulmonary Disease. Table 2: Laboratory findings of studied patients Variables non-AKI (n=64) AKI (n=70) P value Arterial blood gas parameters pH 7.44 (7.43-7.46) 7.35 (7.35-7.41) 0.131 PCO2 43 (41-44) 45 (42-44) 0.110 PO2 65 (61-70) 60 (62-71) 0.197 HCO3 - 25.4 (24.5-26.3) 22.5 (21.3-23.7) 0.021 Serum electrolyte Na+ 136 (135-139) 137 (135-140) 0.199 K+ 4.5 (4.1-5.1) 5.0 (4.5-5.3) 0.213 Cl− 95.3 (90.6-102.1) 106.4 (104.2-108.8) 0.046 (pH x HCO3 -) / Cl- HCMA 1.98 (1.73-2.08) 1.56 (1.48-1.65) 0.039 Data are presented with 95% confidence interval. HCMA: hyperchloremic metabolic acidosis level. (4). In fact, to maintain normal pH, the kidneys have to per- form two physiological functions. The first is to reabsorb all the filtered HCO3-. The second is to excrete the daily H + load (14). In particular, during the early phases of AKI, progres- sive hyperammonemia results in hyperchloremic metabolic acidosis because of impairment in renal ammonia excretion (15). In the course of AKI there are no classic physical signs and symptoms in the early stage to alert the clinician of on- going injury. Identifying individuals with suspicion for de- veloping AKI in the ED is of increasing interest. In fact, the present data suggest that the ABG derived formula, for eval- uation of HCMA state, may have a potential to be used as a screening test, for early diagnosis of AKI in emergency pa- tients. These data are crucial, because actually the diagnosis of AKI is usually based on changes in serum creatinine. In this regard, serum creatinine is a less rapid indicator of acute renal dysfunction and it may lead to a delay in the diagno- sis of AKI. On this note, we found a linear positive correlation between the levels of HCMA, as evaluated by the ABG derived formula, and the impairment of renal function (e-GFR). This is the first study that shows such an association in AKI pa- tients in ED. If confirmed and validated in a future study, the use of ABG derived formula for HCMA may represent a useful tool for early detection of AKI in the emergency department. It seems that HCMA level may be a useful tool for the early detection of AKI within the first few hours of admission. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com M. Giordano et al. 4 5. Limitation Limitations of the present study are mainly represented by the retrospective study design. In this regard, a future large prospective study may be needed to confirm the present findings. 6. Conclusion This is the first report that shows an association between HCMA level and AKI in emergency department patients. If confirmed and validated in a future study, the use of ABG de- rived formula for HCMA may represent a useful tool for early detection of AKI patients in emergency department. 7. Appendix 7.1. Acknowledgements None. 7.2. Author contribution Mauro Giordano and Tiziana Ciarambino designed the study. Pietro Castellino, Lorenzo Malatino, Giuseppe Signoriello, Giuseppe Paolisso, Luigi Elio Adinolfi participated in acqui- sition and management of data. All authors approved final version of the manuscript to be published and are account- able for all aspects of the work. 7.3. Funding/Support This research has not been supported. 7.4. Conflict of interest The authors declare no conflicts of interest. References 1. Li PKT, Burdmann EA, Mehta RL. Acute kidney injury: global health alert. Arab journal of nephrology and trans- plantation. 2013;6(2):75-81. 2. Scheuermeyer FX, Grafstein E, Rowe B, Cheyne J, Grunau B, Bradford A, et al. The clinical epidemiology and 30-day outcomes of emergency department patients with acute kidney injury. Canadian journal of kidney health and dis- ease. 2017;4:2054358117703985. 3. 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