The prognostic value of lactate albumin ratio and prob natriuretic peptide for predicting 28 days mortality in burn patients presenting to the burn intensive care unit: a prospective study

BACKGROUND AND RATIONALE

In spite of major advances in therapeutic strategies for the management of patients with severe burns, including improved resuscitation, enhanced wound coverage, infection control, and management of inhalation injuries, the consequences of a severe burn are profound and result in complex metabolic changes that can adversely affect every organ system.1-3 Management of a patient with a severe burn injury is a long-term process that addresses the local burn wound as well as the systemic, psychologic, and social consequences of the injury.

A severe burn is one that is complicated by major trauma or inhalation injury, a chemical burn, high-voltage electrical burn, and, in general for adults, any burn encompassing >20 percent of the total body surface area (TBSA), excluding superficial burns (epidermal; first-degree burns). For older adults and young children, a burn encompassing less than 20 percent of the TBSA may be considered severe. The prevalence of burns complicated by major trauma ranges from 0.4 to 5.8 percent.4 Severe burns usually require initial care in a specialized intensive careunitofaburncenter.Althoughburnsinvolvingtheeyes,ears, face, hands, feet, or perineum that are likely to result in cosmetic or functional impairment should be cared for in a burn center, not all will require management in an intensive care unit. Severeburns occur in approximately 5 to 20 percent of survivors of conventionalconflictsandfromcivilianmassdisastersorterrorist events. Emergency care of the burn patient and triage criteria for referral to a burn center are discussed in detail separately.

Severe burns are associated with high morbidity and mortality justifying admission in Intensive Care Unit (ICU).1 Pathophysiology of the shock developed in the first hours followingsevereburninjuryremainsincompletelyunderstoodbut could mainly be based on severe hypovolemia, due to capillary leak, secondarily associated with a major systemic inflammatory response responsible for decreased systemicresistances.

Based on this pathophysiology, fluid therapy and vasopressorsare considered as the cornerstone of the early hemodynamic resuscitation of severe burn injury to improve impaired hemodynamics.7 However, in this context, strong and powerful markers as well as targets to reach during initial hemodynamic resuscitationtohelpphysicianinthemanagementofsevereburned patients are lacking. Blood lactate level is frequently used by critical care physicians for diagnosis, prognosis and stratification risk of all-cause shockstates.4,5

The predictive value of lactate to predict outcome is currently discussed in ICU patients. As a matter of fact, plasmatic lactate is influenced by several factors namely tissue hypoxia, adrenergic stimulation, liver failure and hyperglycemia. In addition, several factors can affect lactate clearance (like sepsis e.g.) affecting its ability to predict bad outcomes in ICU patients. Therefore, resuscitation algorithm based on lactate decrease did not improve outcome in septic shock patients. 6,7

Recent studies in severe burned patients demonstrated a negative association between hypoalbuminemia with mortality and/or multiple organ dysfunction. In the same manner, plasmatic albumin level has been proposed as a therapeutic target to reach during the initial resuscitation of critically ill burned patients. However, several conditions secondary to severe burns including inflammation, sepsis or capillary leakage [4] could potentially affectthealbumin’splasmaticlevelmakingitanunusabletoolfor prediction of patient outcome. Lactate albumin ratio (LAR, corresponding to the ratio of plasmatic lactate on plasmatic albuminemia) has been previously proposed in septic patient’s management as a simple, quick, prognostic biomarker that can be reproduced, associated with multiple organ failure and mortality in ICU.5,6

Natriuretic peptides are produced primarily within the heart and released into the circulation in response to increased wall tension.10Brainnatriureticpeptide(BNP),incontrasttoatrial natriuretic peptide (ANP), is not only secreted from the atria but also from the ventricles, especially in patients with heart failure.11 Circulating concentrations of several cardiac natriuretic peptides—including ANP, BNP, and their N-terminal pro- hormones (N-terminal pro-atrial natriuretic peptide (NT-proANP) and N-terminal pro-brain natriuretic peptide (NT-proBNP))—are raised in both symptomatic and asymptomatic patients with left ventricular dysfunction.8,9,12 Recent smaller studies suggest that BNP and NT-proBNP may be superior to ANP and NT-proANP in the detection of left ventricular dysfunction.12,13 Recently a reliable and less time consuming enzyme linked immunosorbent assay (ELISA) method for the analysis of NT-proBNP has been developedandNT-proBNPmaythereforebeasuitablepeptidefor a diagnostic assay.14Majority of burn mortality prognostic scores were developed and validated in Asianpopulations.

Thecomplexandvariableclinicalpathofcriticallyillpatientswith large burn injuries motivated further assessment of the dynamics of the BNP system. We hypothesized that the amount of excess wateraccumulatedduringacutecare,theextentofthephysiologic trauma response, and the extent to which organ dysfunction appearedwouldrelatetochangesintheBNPsystem.Wetherefore measured NT-proBNP and related this to burn characteristics, hydration state, physiologic trauma response, and organ dysfunction.NT-proBNP was chosen over Pro-BNPbecauseithas a longer half-life.

Kistorp C et al (2005) conducted a population-based prospective study of 764 participants aged 50 to 89 years from a community in Copenhagen, Denmark, in which 658 participants provided blood and urinary samples and were examined between September 1, 1998, and January 24, 2000. Of these participants, 626 without heart or renal failure were enrolled. A subgroup of 537 had no history of cardiovasculardiseaseatbaseline.During5yearsoffollow-up(toDecember31, 2003), 94 participants died and 65 developed a first major  cardiovascular  event.Riskofmortalityandfirstmajorcardiovasculareventbybaselinelevelsof NT-proBNP, CRP, and urinary albumin/creatinine ratio levels. After adjustment for the cardiovascular risk factors of age, sex, smoking, diabetes mellitus, hypertension or ischemic heart disease, total cholesterol, and serum creatinine, the hazard ratio (HR) of mortality for values above the 80th percentile of NT- proBNPwas1.96(95%confidenceinterval[CI],1.21-3.19);forCRP,1.46(95% CI,0.89-2.24);andforurinaryalbumin/creatinineratio,1.88(95%CI,1.18-2.98). Additional adjustment for left ventricular systolic dysfunction did not markedly attenuatethepredictivevalue of NT-proBNP(HR,1.82;95%CI,1.11-2.98).The absolute unadjusted increase in mortality risk for participants with values above the 80th percentile vs equal to or below the 80th percentile was 24.5% for NT- proBNP,7.8%forCRP,and19.5%forurinaryalbumin/creatinineratio.TheNT- proBNP levels were associated with first major cardiovascular events (nonfatal myocardialinfarction,fatalcoronaryheartdisease,unstableangina,heartfailure, stroke,andtransientischemicattack)withanadjustedHRof3.24(95%CI,1.80- 5.79)vs1.02(95%CI,0.56-1.85)forCRPand2.32(95%CI,1.33-4.05)for urinary albumin/creatinine ratio when comparing participants with values above the 80th percentile with those with values equal to or below the 80th percentile. Measurements of NT-proBNP provide prognostic information of mortality and firstmajorcardiovasculareventsbeyondtraditionalriskfactors.NT-proBNPwas  stronger risk biomarker for cardiovascular disease and death than CRP was in nonhospitalized individuals aged 50 to 89 years.

 Lindahl AE et al (2013) conducted a study that total Fifty patients with a burn size greater than 10% were studied for the first 2 weeks. P-NT-proBNP changes were analyzed in relation to burn size, age, changes in body weight, C-reactive protein in plasma, and organ function assessed as Sequential Organ Failure Assessment (SOFA) scores. P-NT-proBNP showed large day-to-day and between patient variations. Daily change in body weight correlated with P-NT- proBNP only on Day 2, when maximum mobilization of edema occurred. Thereafter,P-NT-proBNPcorrelatedwithC-reactiveproteininplasmaaswell as with SOFA scores. Burn size correlated with maximal weight change, which in turn correlated with both time for and value of maximum P-NT-proBNP. MaximalP-NT-proBNPwasrelatedtomortalityandcorrelatedbetterwithSOFA scoreonDay14comparedwithageandburnsize.Inlinearregressions,together with age at injury and total body surface area, P-NT-proBNP assessed on Days3 to 8 was an independent predictor for every subsequent SOFA score measured one or more days later up to Day 14. P-NT-proBNP exhibited considerable interindividual and day-to-day variations. Values were related to mortality, burn size,wateraccumulation,posttraumaticresponse,andorganfunction.Maximum P-NT-proBNPcorrelatedstrongerwithlengthofstayandwithorganfunctionon Day 14, compared with age and burn size. High values in Days 3 through 8were also independent predictors of subsequent organ function up to 2 weeks after injury.

 Thapa S et al (2017) conducted a hospital based cross sectional study done at Tribhuvan University Teaching Hospital, Kathmandu from November 2015 to October 2016. The consent was taken from patients. Acute Physiology and Chronic Health Evaluation II score, serum lactate and serum albumin levels on first day of arrival in emergency room were calculated. patients were classified as severe sepsis and septic shock and treated according to Surviving Sepsis Campaign2012guideline.Thepatientwerefollowupat28day,Theassociations of 28-day outcome with Acute Physiology and Chronic Health Evaluation II score, serum lactate value, serum albumin value and serum lactate albumin ratio value were derived. Out of total 240 severe sepsis and septic shock patients it is foundthatincreasedserumlactate/albuminratiowasanindependentpredictor of the mortality with cut off value of 0.07. Furthermore serum lactate albumin ratio shows strong correlation with APACHE 2 score in predicting mortality insevere sepsis and septic shock. Increased lactate/albumin ratio predicts mortality in patients with severe sepsis and septicshock.

RafiezadehShahiHetal(2018)conductedaprospectiveobservationalstudywas performed at an academic burn unit. Aged between 16 and 65, patients who presentedwithburnsonmorethan20%oftotalbodysurfacearea(%TBSA)were included. Patients with severe comorbidities, concomitant trauma or referred fromothercenterswereexcludedfromthestudy.Themainvariablesinthestudy were Alb0h, Alb24h and Abbreviated Burn Severity Index (ABSI) scores. The primary outcome was in-hospital mortality.   In a population  of 105 patients, %TBSA, being female, inhalational injury, Alb0h, Alb24h and ABSI score (p<0.001) and the presence of a full thickness injury (p=0.008) were associated with mortality. In the multivariable analysis, ABSI scores and Alb24h remained in the model (OR, 2.32 and 0.06, respectively). The area under curves (AUCs) were 0.94, 0.97 and 0.97 for ABSI, ABSI+Alb0h and ABSI+Alb24h, respectively. No significant difference among the AUCs was seen, but adding Alb0h and Alb24h improved the mortality predictions of ABSI by 5 (4.7%) and 4 (3.8%) patients, respectively. Alb0h (at 3.5g/dL) and Alb24h (at 2.4g/dL) showed84-85%and88-85%sensitivity-specificityformortality,respectively.         Measuring serum albumin levels in clinical assessments slightly increases the accuracyofmortalitypredictions;however,differentcut-offpointsforAlbumin at 0 hourand Albumin at 24 hours needs to be considered to avoid interpretationerrors.

  Herrero De Lucas E et al (2020) conducted a prospective, unicentric, observational study of a cohort of 214 burn patients admitted in the Burn Intensive Care Unit. We collected demographic and laboratory data, complications, absolute lactate levels and lactate clearance every 8 h since admission to 72 h. In critical patients we monitored hemodynamic parameters with transpulmonary thermodilution. We used Student’s t-test or nonparametric tests, mixed models and Pearson and Spearman methods, Fisher’s exact and chi- squared test. Total 214 patients, 76.6% were male, mean age were 46 ± 15 years and 23.0 ± 19.5% of Total Basal Surface Area (TBSA) burned. Initial mean absolute levels of lactate were 2.02 ± 1.62 mmol/L in survivors vs. 4.05 ± 3.90 mmol/Linnonsurvivors.Initialelevatedlactatelevelsincreasedmortality(p<

.001), length of ICU stay, mechanical ventilation and shock. In the subgroup of burned TBSA < 20%, lowering the lactate cut-off point from 2.0 to 1.8 mmol/L improved the mortality prediction (OR:9.3). We found no relationship between lactate clearance in the first 24 h and mortality. In more severe patients (> 20% TBSAburnedandinitiallactatelevels>2),agoodcorrelationwasfoundbetween lactateandcardiacindex;butnotwithintrathoracicbloodvolumeindex(ITBVI). Patients with low ITBVI preload (< 600 mL/m2) did not show significant differences in lactate clearance compared with those with ITBVI > 600. Initial elevatedlactatelevelsareafactorofpoorprognosisandthecut-offpointthatbest predicts mortality should be adjusted in the patients with TBSA burned < 20%. The global clearance of lactate in the first 24 h, unlike what occurs in other injuries,doesnotcorrelatewithmortality.Monitoringlactatecanensureadequate peripheral perfusion during resuscitation with lower than normal fluid preload values.

Bou Chebl R et al (2020) conducted a single-center retrospective cohort study thatalladultpatientsabovetheage of 18withadiagnosisofsepsiswhopresented betweenJanuary1,2014andJune30,2019wereincluded.Theprimaryoutcome was in-hospital mortality. A total of 1,381 patients were included, 44% were female.Overallin-hospitalmortalitywas58.4%withthemortalitiesofsepsisand septic shock being 45.8 and 67%, respectively. 55.5% of patients were admitted to the intensive care unit. The area under the curve value for lactate was 0.61 (95%CI0.57–0.65,p<0.001)andfortheL/Aratiowas0.67(95%CI0.63–0.70, p < 0.001). The cutoff generated was 1.22 (sensitivity 59%, specificity 62%) for the L/A ratio in all septic patients and 1.47 (sensitivity 60%, specificity 67%) in patients with septic shock. The L/A ratio was a predictor of in-hospital mortality (OR 1.53, CI 1.32–1.78, p < 0.001). The L/A ratio has better prognostic performance than initial serum lactate for in-hospital mortality in adult septic patients.

  Wang, G., et al (2022) conducted a a single-center retrospective study clinical data of 8,832 critical patients aged between 28 days and 18 years were collected from the pediatric intensive care (PIC) database from 2010 to 2018. Theprimary outcome was the in-hospital mortality rate. There was a higher level of L/A ratio innon-survivorsthansurvivors(P<0.001).Logisticregressionindicatedthatthe association between the L/A ratio and in-hospital mortality was statistically significant (OR 1.44, 95% CI 1.31–1.59, P < 0.001). The AUROC of the L/A ratioforpredictingin-hospitalmortalitywashigherthanlactatelevelalone(0.74 vs 0.70, P < 0.001). Stratification analysis showed a significant association between the L/A ratio and in-hospital mortality in the age and primary disease groups (P < 0.05). This study suggested that the L/A ratio was a clinical tool to predictin-hospitalmortalityincriticallyillchildrenbetterthanlactatelevelalone. However,giventhatthestudywasretrospective,moreprospectivestudiesshould be conducted to test the predictive value of the L/A ratio in criticalillness.

  Dudoignon E et al (2022) conducted a retrospective cohort study including all burn patients hospitalized in intensive care unit. The primary endpoint was the 28-daymortality.Onethousandthreehundredthirtyfourpatientswerescreened, and 471 were included between June 2012 and December 2018. Briefly, the population study was mainly composed by men (249, 59.1%), the median age, TBSA burned, full thickness, ABSI and IGS2 were 52 [34-68], 20 [10-40], 8[1-23], 7 [5-9] and 25 [15-40] respectively. Fifty-two patients (12.4%) died at day 28 after admission. At admission, the LAR level was lower in 28-day survivors compared non-survivors (0.05 [0.04, 0.08] vs 0.12 [0.07, 0.26], p < 0.001 respectively). In multivariate analysis accounting for ABSI, LAR levels at admission> 0.13 was independently associated with 28-day mortality (adjusted OR = 3.98 (IC95 1.88-8.35)). The ability of LAR at admission to discriminate 28-day mortality showed an AUC identical when compared to SOFA and ABSI scores(0.81(IC950.74-0.88),0.80(IC950.72-0.85)and(0.85(IC950.80-0.90), p < 0.05, respectively). Patients with LAR levels ≥ 0.13 at admission had higher 28-daymortality(40.6%vs6.8%,p<0.001,HR7.39(IC954.28-12.76)).At admission, LAR is an easy and reliable marker independently associated to 28- daymortalityinpatientswithsevereburninjury,butpredictionbyLARdoesnot perform better than lactate levelalone.

Liu Yu et al (2022) conducted a retrospective study total 40 pediatric patients admitted to the Tongren Hospital of China Capital Medical University with traumatic brain injury between January 2018 and December 2019. Immunoturbidimetric assay and electrochemiluminescence were used to detect the serum levels of LDH, hs-CRP, and NT-proBNP. Correlation analysis was used to determine the degree of association between the indicators and the sensitivity and specificity of each indicator. The serum levels of LDH, hs-CRP, andNT-proBNPinthepoor-prognosisgroupwerehigherthanthoseinthegood- prognosisgroup,andthedifferenceswerestatisticallysignificant(P<0.05).The detectionofserumLDH,hs-CRP,andNT-proBNPmightbe of greatsignificance for the evaluation of the severity of a traumatic brain injury, disease progression, andtheprognosisofpediatricpatientswithtraumaticbraininjury.Thecombined detection of the relevant indicators could provide more effective sensitivity and specificity and therefore offer better guidance and assistance in clinicalpractice.

Wang Y et al (2022) conducted a study that the age, sex, burn area, burn depth, length of hospitalization, and mortality rate between the sepsis group and non- sepsis group and compared NT-proBNP, procalcitonin (PCT), platelet count, Sequential Organ Failure Assessment (SOFA) score, and quick SOFA (qSOFA) score between the survivors and nonsurvivors in the sepsis group. Receiver operatingcharacteristic(ROC)curveswereusedinsepsispatientstoevaluatethe prognostic value of NT-proBNP, PCT, SOFA score, qSOFA score, etc. Kaplan- Meier survival curves were used to compare the 90-day survival curves of patients. Logistic regression analysis was used to analyze the risk factors that affect the prognosis of sepsis patients. There were 90 major burn patients with sepsisand114majorburnpatientswithoutsepsis.Themortalityrateforthemajor burnsepsisgroupwassignificantlyhigherthanthatforthenon-sepsisgroup. The NT-proBNP level in sepsis patients in the nonsurvivor group was 2900 pg/ml, whichwassignificantlyhigherthanthatinpatientsinthesurvivorgroup.Survival analysisshowedthatthemeansurvivaltimefortheNT-proBNP>2000pg/ml group was 15.08 days. Multivariate regression analysis indicated that NT- proBNPwasanindependentriskfactorformortalityinburnpatientswithsepsis. NT-proBNPcanbeusedasaprognosticmarker inpatientswithmajorburnsand sepsis.

 AIMS AND OBJECTIVES

Aim:

To study the lactate albumin ratio and pro b type natriuretic type peptide as predictor of 28 days mortality in severe burn patients

Primary objective:

·        To see the association between lactate albumin ratio and NT PROBNP levels and 28-day mortality.

 Secondary objective:

·        To see the association between lactate albumin ratio, NT PROBNP levelsand outcomes(days on ventilators support, acute kidney injury, required renal replacement therapy, acute respiratory distress syndrome, required surgery within 24 hrs)

Material and methods

Study settings:

The study will be conducted in Department of Anaesthesiology in collaboration with Plastic surgery Burn ICU, King George’s Medical University, Lucknow.

Study duration: One year

Study design: Prospective Observational study

Sample Size: 55 patients

Sample size is calculated on the basis of risk of raised L/A ratio for in-hospital mortality using the formula:

Image

Image, Image

OR = 3.98, odds ratio of raised L/A ratio for in-hospital mortality

(Ref. Emmanuel Dudoignon, Thomas Quennesson, Christian De Tymowski Lactate albumin ratio at admission predict 28 days mortality in critically Ill severe burn patients: a retrospective cohort study)

e = 0.5, the risk ratio consider to be clinically significant

d = 1.0, the design effect

Type I error α=5 %, for the significance level of 95%.

Type II error β=10 %,  for detecting the results with 90% power of study,

The minimum sample size required comes out to be n = 55

Inclusion Criteria:

•      Patients, who give the written informed consent will be taken

 â€¢      Age between 18 years and 50years,

 â€¢      Thermal burn injury size between 10- 30% total body surface area(TBSA),

 â€¢      Admission within 8 hours after injury,

 Exclusion criteria:

·        Not giving consent

·        Electrical burn

·        Age of less than18 years

·        any co-morbid condition (e.g., uncontrolled diabetes, renal failure, end stage liver disease and severe cardiovasculardisease)

·        Nephrotic syndrome

·        Exudative enteropathy

·        Malnutrition

Study Protocol:

 Venous blood samples will be taken from each patient on admission (i.e., all samples will be collected in the first hour after arrival at the burn unit) Serum levels of lactate-albumin ratio and PROBNP will be measured with a colorimetric assay by an autochemical analyzer.

Data will be collected from burn intensive care unit including sex, age, baseline body mass index (BMI), total burn of the body skin area surface (TBSA), full thickness skin area (FTSA) burns, inhalation injury diagnosed both by clinical history and physical examination (i.e., carbonaceous deposits in the oropharynx or sputum, facial burns and changes in voice/ phonation, wheezing) or bronchoscopy in ventilated patients (i.e., inflammatory or necrotic bronchial mucosa), mechanism of injury, delay from the time of burn injury to the time of admission to the ICU. First 24-h administered fluid volume including human albumin and transfusion products, escharotomy or fasciotomy in the first 24 h, graft surgery and supportive treatments within the first seven days of admission (vasopressors, renal replacement therapy and mechanical ventilation), episodes of sepsis and septic shock in the first seven days, 28-day. All laboratory measures upon admission, including serum albumin, plasma lactate concentrations and NT PROBNP level.

 Statistical Analysis

 The SPSS (Version 23.0) program will be used for statistical analysis. Descriptivestatisticswillbepresentedasmean,standarddeviation,median, minimum, maximum, frequency and ratios. Categorical data will be analysed using the chi-square test, and continuous data will be analysed usingthestudentt-test.Spearman’srankcorrelationcoefficientwillbeused to determine the association between variables. Significance will be evaluated at a p-value<0.05.

References

 1.      Emmanuel Dudoignon, Thomas Quennesson, Christian De Tymowski, Nabila Moreno, Maxime Coutrot,  Maite Chaussard, Lucie Guillemet, Sonia Abid, Alexander Fratani, Quentin Ressaire, Alexandre Pharaboz, Mourad Benyamina, Alexandre Mebazaa, Matthieu Legrand 3rd January 2022

2.      JeschkeMG,WilliamsFN,GauglitzGG,HerndonDN.Burns.In:Sabiston Textbook of Surgery, Townsend M, Beauchamp RD, Evers MB, Kenneth ML (Eds), Elsevier, Philadelphia 2012. Vol 19,p.521.

3.      Herndon DN, Tompkins RG. Support of the metabolic response to burn injury. Lancet 2004;363:1895.

4.      McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin 2001;17:107.

5.      Santaniello JM, Luchette FA, Esposito TJ, et al. Ten year experience of burn, trauma, and combined burn/trauma injuries comparing outcomes. J Trauma 2004;57:696.

6.      Rafiezadeh Shahi H, Vahedian M, Movahedi M, Bahaadinbeigy K, Hashemian M, Mirafzal A. Measuring serum albumin levels at 0 and 24h: Effect on the accuracy of clinical evaluations in the prediction of burn- related mortality. Burns. 2018 May;44(3):709-717. doi: 10.1016/j.burns.2017.10.020. Epub 2018 Feb 1. PMID:29395396.

7.      Levy B, Gibot S, Franck P, Cravoisy A, Bollaert PE. Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study. Lancet. 2005 Mar 5-11;365(9462):871-5. doi: 10.1016/S0140-6736(05)71045-X. Erratum in: Lancet. 2005 Jul 9- 15;366(9480):122. PMID: 15752531.

8.      Tobiasen J, Hiebert JM, Edlich RF. The abbreviated burn severity index. Ann Emerg Med. 1982 May;11(5):260-2. doi: 10.1016/s0196- 0644(82)80096-6. PMID: 7073049.

9.      WangB,ChenG,CaoY,XueJ,LiJ,WuY.Correlationoflactate/albumin ratio level to organ failure and mortality in severe sepsis and septic shock. J Crit Care. 2015 Apr;30(2):271-5. doi: 10.1016/j.jcrc.2014.10.030. Epub 2014 Nov 11. PMID: 25537574.