Hrev_master [page 6] [Emergency Care Journal 2016; 12:5458] Lactate levels as a marker of tissue hypoperfusion in acute heart failure patients seen in the emergency department: a pilot study Kori Sauser,1 Lora Alkhawam,2 Linda Pierchala,3 Peter S. Pang4 1Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA; 2Department of Emergency Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL; 3Loyola University Medical Center, Chicago, IL; 4Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Abstract Acute heart failure (AHF) may lead to sub- clinical tissue ischemia due to hypoperfusion from inadequate forward flow or congestion. The aim of the present study is to test whether lactate levels are elevated in emergency department (ED) patients with AHF. A prospec- tive pilot study of ED AHF patients was con- ducted. Venous lactate level was measured at baseline and 6-12 hours after initial draw. Of the 50 patients enrolled, mean age was 65.3 years, 68% were male. Only 7 (14%) had an elevated lactate on either draw, with no differ- ences in baseline characteristics between patients with and without elevated lactate. Patients with an elevated lactate had a higher mean heart rate (99 vs 81, P=0.03) and trend- ed toward an increased rate of abnormal initial temperature (57 vs 23%, P=0.06). In this pilot study, only a minority of acute HF patients had an elevated lactate on presentation. Introduction Heart failure occurs with any impairment in the heart’s ability to fill with or eject blood.1 During acute heart failure (AHF), further dele- terious hemodynamic and neurohormonal changes occur, which may lead to tissue hypoperfusion.1,2 As myocardial, renal, and liver injury has been observed in AHF, signifi- cant tissue injury and organ hypoperfusion may result in elevated lactate levels.2 As a marker of poor perfusion, lactate rises with tis- sue hypoxia. Elevated lactate is used clinically, and serves as a prognostic marker in trauma and sepsis.3 In a small study of AHF patients with reduced ejection fraction (<30%), 22 of 29 patients had elevated lactate levels ≥2 mmol/L; this suggests AHF patients may suffer from occult tissue hypoperfusion despite no overt clinical shock.4 However, this study was conducted prior to the era of natriuretic pep- tide testing, only included patients with reduced ejection fraction (EF), and did not per- form a detailed characterization of patients at baseline, though central venous catheteriza- tion was performed.4 In this small pilot study, our primary objec- tive was to evaluate whether AHF is associated with subclinical organ hypoperfusion, as demonstrated by elevations in serum lactate, and if so, the magnitude and duration of the elevation. Materials and Methods Study design This was a prospective cohort study of a con- venience sample of patients presenting with AHF to a single urban emergency department (ED) during the study period of August 2010 through April 2012. The study was funded through an Investigator Initiated Grant from Abbott Point of Care and approved by the Institutional Review Board. The study design, database, data analysis, and final manuscript were independent of the sponsor. Study population Acute heart failure patients were identified within 8 hours of ED presentation. In order to qualify, patients had to have signs and symptom of HF resulting in a primary diagnosis of AHF, were >18 years of age, and had an initial B-type natriuretic peptide (BNP)>200 pg/mL. Patients with ongoing acute coronary syndrome or tro- ponin elevation greater than three times the upper limit of normal, dialysis dependent, new devices or surgery within the last 30 days, enrolled in an investigational agent or therapy in the last 30 days, unable to provide informed consent, and currently pregnant or up to 60 days post-partum, were excluded. Study protocol After providing written informed consent, a venous blood draw and serum lactate level were determined using whole blood by i-STAT (Abbott Point-of-Care, Inc., Abbott Park, IL, USA) lactate analyzer. The reportable range is 0.30-20.00 mmol/L, reference range of 0.36- 1.25 mmol/L arterial and 0.90-1.70 mmol/L venous. Per the package insert, lactate is measured amperometrically. The enzyme lac- tate oxidase, immobilized in the lactate biosensor, selectively converts lactate to pyru- vate and hydrogen peroxide (H2O2). The liber- ated hydrogen peroxide is oxidized at a plat- inum electrode to produce a current which is proportional to the sample lactate concentra- tion. While venous or arterial blood may be sampled, for our study, capillary whole blood was used. Initial lactate level was determined within 8 hours of ED presentation, and a fol- low-up level was measured at 6-12 hours from first measurement. Demographic, clinical, and physical exam characteristics were also col- lected either primarily or through review of the medical record. Objectives Our primary outcome was lactate elevation at time of initial assessment. Lactate level <2 mmol/L was defined as normal a priori, based on literature where lactate level of 2 or higher was associated with worse outcomes.5 Our sec- ondary objective was to examine lactate clear- ance in the subset of patients with an initial elevated lactate. Emergency Care Journal 2016; volume 12:5458 Correspondence: Peter S. Pang, Department of Emergency Medicine, Indiana University School of Medicine, 720 Eskenazi Avenue, FOB 3rd Floor, 46202 Indianapolis, IN, USA. Tel. +1.317.880.3900 - Fax: +1.317.880.0545. E-mail: ppang@iu.edu Key words: Acute heart failure; Lactate; Emergency department; Hypoperfusion. Contributions: KS, drafted the initial manuscript; LA and PSP, extensively edited the initial manu- script and all subsequent revisions; KS and LP were the primary research personnel collecting primary data; KS performed the primary analysis; KS, LA, LP, and PSP all reviewed the final manu- script. Conflict of interest: KS, LA, and LP declare no potential conflict of interest; PSP reports that in the last 12 months, he is or has been or received consultant for Intersection Medical, INSYS, Janssen, Medtronic, Novartis, Trevena, scPharmaceuticals, Cardioxyl, Roche Diagnostics. Acknowledgments: an Investigator Initiated Grant from Abbott Point of Care supported this work; the study design, database, data analysis, and final manuscript were independent from the sponsor. Received for publication: 25 July 2015. Revision received: 26 October 2015. Accepted for publication: 26 October 2015. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright K. Sauser et al., 2016 Licensee PAGEPress, Italy Emergency Care Journal 2016; 12:5458 doi:10.4081/ecj.2016.5458 Non co mmerc ial us e o nly [Emergency Care Journal 2016; 12:5458] [page 7] Article Table 1. Baseline patient characteristics. Demographics All patients (n=50) Elevated lactate (n=7) Normal lactate (n=43) P Mean age, years (SD) 65.3 (15.7) 65.6 (10.0) 65.2 (16.6) 0.96 Male gender, % (n) 68 (34) 71 (5) 67 (29) 0.83 Race, % (n) White 58 (29) 43 (3) 60 (26) 0.85 aT Asian 0 0 0 Hispanic 2 (1) 0 2 (1) Other 2 (1) 0 2 (1) Cardiovascular history Coronary artery disease, % (n) 38 (19) 14 (1) 42 (18) 0.16 Valvular disease, % (n) 17 (8) 14 (1) 18 (7) 0.84 Prior myocardial infarction, % (n) 19 (8) 0 22 (8) 0.17 History of cardiomyopathy, % (n) 46 (21) 57 (4) 44 (17) 0.51 Prior PCI, % (n) 23 (11) 0 28 (11) 0.11 Prior CABG, % (n) 14 (6) 0 16 (6) 0.29 Prior CVA, % (n) 16 (7) 0 18 (7) 0.22 Ejection fraction mean, % (%range, n) 45 (10-76, 38) 38 (15-70, 4) 46 (10-76, 34) 0.38 Non-cardiovascular history, % (n) Obesity 38 (17) 0 44% (17) 0.04 Peripheral vascular disease 4 (2) 0 5 (2) 0.54 Asthma/COPD 33 (16) 43 (3) 32 (13) 0.57 Diabetes, insulin-dependent 13 (6) 0 15 (6) 0.28 Diabetes, non-insulin dependent 10 (5) 14 (1) 10 (4) 0.70 Renal insufficiency 54 (25) 67 (4) 53 (21) 0.52 Liver disease 2 (1) 17 (1) 0 0.008 Anemia (hgb<12) 34 (16) 14 (1) 38 (15) 0.23 Cancer history 20 (10) 0 24 (10) 0.15 Hypertension 83 (40) 67 (4) 86 (36) 0.24 Baseline medications Beta blocker 68 (34) 57 (4) 70 (30) 0.51 ACE inhibitor 48 (24) 57 (4) 47 (20) 0.60 ARB 10 (5) 14 (1) 9 (4) 0.68 Aldosterone antagonist 10 (5) 0 12 (5) 0.34 Diuretic 66 (33) 71 (5) 65 (28) 0.74 Cardiac glycoside 4 (2) 14 (1) 2 (1) 0.13 Pacemaker 14 (7) 0 16 (7) 0.25 ICD 10 (5) 0 12 (5) 0.34 Presentation Abnormal temperature 28 (14) 57 (4) 23 (10) 0.06 (>38°C, or <36°C), % (n) Systolic BP ,% (n) >140 48 (24) 43 (3) 49 (21) 0.61 100-140 44 (22) 43 (3) 44 (19) <100 8 (4) 14 (1) 7 (3) Heart rate, mean, % (%range, SD) 84 (37-138, 21) 99 (75-138, 22) 81 (37-118, 20) 0.03 Respiratory rate mean, % (%range, SD) 19 (16-28, 2) 20 (16-24, 3) 19 (16-28, 2) 0.88 SpO2 mean, % (%range, SD) 97 (90-100, 2) 96% (90-100, 4) 98 (91-100, 2) 0.06 Supplemental O2 source % (n) None 56 (28) 43 (3) 58 (25) 0.45 Nasal cannula 44 (22) 57 (4) 42 (18) Facemask 0 0 0 Non-rebreather 0 0 0 Positive pressure ventilation 0 0 0 Physical exam findings, % (n) JVD 54 (27) 71 (5) 51 (22) 0.382 Rales 44 (22) 29 (2) 47 (20) 0.553 Peripheral edema 78 (39) 71 (5) 79 (34) 0.155 Lab values, median (IQR) Creatinine, mg/dL 1.21 (1.04-1.57) 1.35 (1.00-1.55) 1.19 (1.04-1.64) 0.675 BUN, mg/dL 21 (15-26) 24 (22-30) 20 (13-26) 0.218 BNP, pg/mL 1103 (647-1936) 2213 (1225-4941) 991 (564-1586) 0.009 CXR findings, % (n) Interstitial edema 50 (25) 43 (3) 51 (22) 0.684 Pulmonary edema 42 (21) 57 (4) 40 (17) 0.381 Pleural effusion 44 (22) 43 (3) 44 (19) 0.948 SD, standard deviation; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; CVA, cerebrovascular accident; COPD, chronic obstructive pulmonary disease; hgb, hemoglobin; ACE, angiotensin-converting-enzyme; ARB, angiotensin receptor blocker; ICD, implantable cardioverter defibrillator; BP, blood pressure; JVD, jugular venous pressure; IQR, interquartile range; BUN, blood urea nitrogen; BNP, B-type natriuretic peptide; CXR, chest x-ray. Non co mmerc ial us e o nly [page 8] [Emergency Care Journal 2016; 12:5458] Article Table 2. Characteristics of patients with elevated lactate levels. Patients Characteristics Age (years) Gender Brief history Exam Lactate levels Hospital course 1 69 M History of HF, T=97.6 F, BP=124/95, 2.05, 2.46 In the ED, diuresed with lasix 40 mg IV. afib, s/p MVR, HR=91 in afib, 98%, Admitted to the general medicine presented with signs of congestion (JVD) floor for heart failure exacerbation, fatigue and dyspnea no additional HF therapies initiated on exertion, EF=30% aside from resumption of patient’s home meds, discharged on HD #2 2 73 M History of COPD, T=95.1 F, BP=93/68, 98%, 2.49, 1.84 In the ED, diuresed with bumex 1 mg IV, alcoholic cirrhosis, HR=138, signs also empirically treated for community hypothyroidism of congestion acquired pneumonia with antibiotics, (no history of HF), (crackles, LEE) and given a therapeutic dose of LMWH presented with SOB for suspected PE. Admitted to the CCU and dyspnea on exertion after developing hypotension in the ED. Echography performed on HD#2 demonstrated EF 20% and Grade II-III diastolic dysfunction. Underwent LHC given new HF, no obstructive CAD. Determined to have likely alcohol induced vs tachycardia induced ca diomyopathy. Patient had a hospital course complicated by hypotension, atrial fibrillation with RVR, delirium, thrombocytopenia, and urinary retention. Discharged on HD#20 3 70 M History of DM2, HTN T=96.6 F, BP=127/79, 1.79, 2.08 In ED, diuresed with lasix 20 mg IV, (no history of HF), HR=114 in afib, 95%,x hypokinesia with EF<25%, presented with cough signs of congestion (LEE) Grade III diastolic dysfunction. and leg swelling Admitted to general medicine floor for evaluation and management of new heart failure and afib with RVR. Started on lasix gtt for diuresis, and bridged with heparin to oral anticoagulant for new afib. Underwent RHC and LHC demonstrating significant CAD w 75% lesion in left main coronary artery, CABG recommended. Underwent extensive pre-operational evaluation as an inpatient, discharged home with LifeVest on HD# 12. Readmitted for planned CABG and Maze procedure 9 days later 4 60 F History of HTN, COPD T=97.1 F, BP=186/108, 1.08, 2.20 In ED, diuresed with lasix 20 mg IV, had (no history of HF), HR=121, 99%, been given sublingual nitro presented with SOB, signs of congestion 400 mcg by EMS prior to arrival. cough and leg swelling (crackles, LEE) Also received 1 duoneb for cough/SOB. Echography performed in ED demonstrated dilated cardiomyopathy with EF=10-15%. Admitted to cardiology initiated on lasix 40 mg IV BID. Hospital course complicated by DVT, stayed inpatient to titrate oral anticoagulant dose, threatened to leave AMA on multiple occasions. Discharged on HD#14, stated to her team upon dicharge that she planned to be non-compliant with her medications Continued on next page Non co mmerc ial us e o nly [Emergency Care Journal 2016; 12:5458] [page 9] Article Table 2. Continued from previous page Patients Characteristics Age (years)Gender Brief history Exam Lactate levels Hospital course 5 78 F History of CHF, HTN, T=94.6 F, BP=152/122, 1.84, 2.83 In ED, diuresed with lasix 40 mg IV and presented with SOB. HR=105, 100%, given home dose of PO antihypertensives, EF=30-35% signs of congestion but persistently hypertensive so given (hepatomegaly, LEE) nitropaste. Admitted to general medicine floor, underwent diuresis with bumex IV BID and bumex gtt. Had HF and HTN meds titrated as an inpatient. Discharged on HD# 7 6 61 F History of CHF, T=97.2 F, BP=131/74, 1.06, 3.13 In ED, diuresed with lasix 80 mg IV, sarcoidosis, pulmonary HR=83, 87%, placed on 40% FiO2 via face mask for HTN, presented with signs of congestion low O2 saturations. CTA in ED negative leg swelling and cough. (JVD, LEE) for PE. MICU consulted given EF>70% supplemental O2 requirement, determined patient stable for admission to general medicine floor. Admitted to general medicine floor for lasix gtt and titration of HF and pulmonary HTN medications, with pulmonary service following. Echography obtained as inpatient demonstrated severe, worsened pulmonary HTN. On HD#4, transferred to the MICU for tachypnea, increasing O2 requirement, increased WOB and fever. Upon transfer to MICU was placed on BiPAP, treated for HCAP with antibiotics, and continued on treatment for HF and pulmonary HTN. Respiratory status failed to improve in the MICU, but patient decided she did not want to be on BiPAP at home. Transitioned back to 5L nasal cannula and seen by palliative care. Patient elected to go home from the MICU and at the time of discharge on HD#10 was considering hospice care 7 48 M History of nonischemic T=95.8 F, BP=150/107, 1.87, 2.83 In the ED, given diltiazem 10 mg cardiomyopathy, CHF, HR=121 in afib, 98%, IV for afib with RVR, no diuretics atrial flutter, presented signs of or nitrates administered. to EP clinic with vomiting congestion (LEE) Digoxin level obtained and was and epigastric pain, sent to within normal limits (1.9). Patient ED by EP medical doctor admitted to the inpatient due to concern for digoxin cardiology service for management toxicity. EF=15% of heart failure exacerbation and afib w RVR. Daily diuresis with IV lasix, bumex; initially on IV anticoagulant therapy for afib while cardiology service considered cardioversion, but TTE demonstrated thrombus, so patient bridged to oral anticoagulant as an inpatient and discharged on HD#5 with plan to return to EP clinic for scheduled outpatient cardioversion HF, heart failure; afib, atrial fibrillation; MVR, mitral valve replacement; EF, ejection fraction; T, temperature; BP, blood pressure; HR, heart rate; ED, emergency department; JVD, jugular venous pressure; IV, intra- venous; HD, hospital day; COPD, chronic obstructive pulmonary disease; SOB, shortness of breath; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; CCU, coronary care unit; LHC, left heart catheteri- zation; CAD, coronary artery disease; RVR, rapid ventricular rate or response; DM2, type 2 diabetes; HTN, hypertension; RHC, right heart catheterization; CABG, coronary artery bypass graft surgery; EMS, emergency medical system; BID, twice a day; DVT, deep vein thrombosis; AMA, against medical advice; CHF, chronic heart failure; CTA, computed tomography angiography; MICU, medical intensive care unit; WOB, work of breathing; BiPAP, bi-level positive airways pressure; HCAP, healthcare-associated pneumonia; EP, electrophysiology; TTE, transthoracic echocardiogram. Non co mmerc ial us e o nly [page 10] [Emergency Care Journal 2016; 12:5458] Data analysis Our sample size of 50 patients was deter- mined based on logistical and budgetary con- straints. Using a one-tailed estimate, 80% power, and an alpha of 0.05, this sample size was powered to show an effect size of 33% comparing the proportion of patients with and without elevated lactate. Patients were divided into elevated (≥2 mmol/L) or normal lactate groups. Due to small number of patients with elevated lactate levels, patients were included in the elevated group if they had an elevated lactate on either of the two blood draws. Comparisons between groups were done with student’s t-test, chi-square test, and ANOVA as appropriate. Given the small number of patients with elevated lactate levels, repeated measures analysis was not performed. Results Of the 50 patients enrolled, 68% were male, 58% white, with a mean age of 65.3 years (standard deviation=15.7 years) (Table 1). Mean ejection fraction was 45% (range 10- 76%), and the majority of patients were on a beta-blocker or a diuretic (68 and 66% respec- tively). Seven patients had an elevated lactate level on either blood draw. Two patients had elevat- ed lactate on the first blood draw, within 8 hours of ED presentation. One of those patients had a persistently elevated lactate on second blood draw 6-12 hours later, and 5 other patients had a newly elevated lactate on sec- ond draw. Patients were similar in cardiovas- cular and non-cardiovascular medical history, and in historical heart failure medications. Characteristics of patients in the elevated lactate group are presented in Table 2, with brief summaries of history and hospital course. Of the 7 patients with elevated lactate, 4 were male, and ages ranged from 48-78 years. Three of the 7 patients had no previous- ly documented diagnosis of heart failure. None of the patients had systolic blood pressure less than 90mmHg on ED arrival. Patients with an elevated lactate had a higher mean heart rate (99 vs 81, P=0.03) and trended toward an increased rate of hypothermia (57 vs 23% with either hyper or hypothermia, P=0.06). Six patients were admitted to the floor, and one to the coronary care unit; one patient was admit- ted to the floor and later transferred to the medical intensive care unit for respiratory dis- tress. With the exception of one patient who developed pneumonia on hospital day four (Table 2), no patients were diagnosed with infection during the course of hospitalization. Hospital length of stay ranged 2-20 days (medi- an 10 days). All patients survived hospitaliza- tion. Discussion The burden of acute heart failure has been well described.1,6 Hospitalization consumes the largest portion of financial resources spent on heart failure every year, and are independently associated with a worse outcome.6 EDs are the primary gateway for these admissions, yet the role of the ED in the management of AHF and its impact on downstream care or outcomes has not been well studied.7 Small studies or retrospective analyses highlight the impor- tance of timely intervention, suggesting a time-dependent pathogenic mechanism. As such, we sought to better understand the early pathophysiology of AHF through a pilot study of lactate levels over time to explore whether hypoperfusion might inform our understand- ing of AHF in the ED. Only a minority of patients presenting to the ED with AHF had elevated lactate levels. Although the study is limited by small sample size, overall our results suggest that the hemodynamic and neurohormonal derangements present in acute heart failure do not consistently lead to hypoperfusion sufficient to elevate lactate lev- els. This is in marked contrast to Ander and colleagues’ study where the majority of patients enrolled, although also a convenience sample, had elevated lactate levels.4 This may be due to differences in the patient popula- tions. Most of our patients had an EF>40%, whereas in the Ander and colleagues’ study, the mean EF was 16%. Elevated lactate levels are most commonly associated with shock states, given their rise due to ischemia from hypoperfusion. However, we focused on a more general AHF population to determine whether sub-clinical hypoperfu- sion might be a pathologic finding. This hypothesis was informed by data suggesting that organ injury or dysfunction occurs in AHF outside of cardiogenic shock or clear hypoper- fusion states.2 Although great caution is war- ranted regarding conclusions from a limited sample, the fact that 5 patients had elevated lactate levels despite normal levels at baseline suggests that either patients worsened, required more aggressive management initial- ly or during hospitalization, or reflects a unique pathophysiology of worsening perfu- sion despite appropriate treatment. The small number of enrolled patients and utilization of a convenience sample from a sin- gle center are major limitations with a strong risk for Type II error. Also, samples were drawn within 8 hours of presentation. Thus, treat- ment may have impacted lactate levels. Conclusions In this pilot study, elevated lactate levels were rarely seen at baseline or soon after hos- pitalization. In those patients with elevated lactate, the elevation was more likely to occur after initial treatment. While this may be a chance finding, it was unexpected given that AHF patients presumably would be at greatest risk at the time of presentation. Given the small sample size, any conclusion should be interpreted with caution; still, this may repre- sent an avenue for further investigation. References 1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:147-239. 2. Metra M, Cotter G, Davison BA, et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development pro- gram: correlation with outcomes. J Am Coll Cardiol 2013;61:196-206. 3. Jansen TC, van Bommel J, Bakker J. Blood lactate monitoring in critically ill patients: a systematic health technology assess- ment. Crit Care Med 2009;37:2827-39. 4. Ander DS, Jaggi M, Rivers E, et al. Undetected cardiogenic shock in patients with congestive heart failure presenting to the emergency department. Am J Cardiol 1998;8:888-91. 5. Mikkelsen ME, Miltiades AN, Gaieski DF, et al. Serum lactate is associated with mor- tality in severe sepsis independent of organ failure and shock. Crit Care Med 2009;37:1670-7. 6. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation 2014;129:2-267. 7. Pang PS, Schuur JD. Emergency depart- ments, acute heart failure, and admis- sions: one size does not fit all. J Am Coll Cardiol 2014;2:278-80. Article Non co mmerc ial us e o nly