Value of N-Terminal Pro-Brain Natriuretic Peptide in Predicting Perioperative Complications Following Spine Surgery

Journal Pre-proof Value of N-terminal Pro-brain Natriuretic Peptide in Predicting Perioperative Complications Following Spinal Surgery Arsal Acarbaş, MD, Assistant Prof PII:

S1878-8750(19)32627-0

DOI:

https://doi.org/10.1016/j.wneu.2019.10.012

Reference:

WNEU 13483

To appear in:

World Neurosurgery

Received Date: 16 August 2019 Revised Date:

30 September 2019

Accepted Date: 1 October 2019

Please cite this article as: Acarbaş A, Value of N-terminal Pro-brain Natriuretic Peptide in Predicting Perioperative Complications Following Spinal Surgery, World Neurosurgery (2019), doi: https:// doi.org/10.1016/j.wneu.2019.10.012. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.

Value of N-terminal Pro-brain Natriuretic Peptide in Predicting Perioperative Complications Following Spinal Surgery

Arsal Acarbaş, MD, Assistant Prof Department of Neurosurgery, Faculty of Medicine, Mugla Sıtkı Kocman University

Address correspondence to Arsal Acarbaş Mugla Sitki Kocman Universitesi Tip Fakultesi Orhaniye Mah. Haluk Özsoy Cad. 48000/MUĞLA Phone: +90 252 214 13 26, E-mail: [email protected]

ABSTRACT Objective: The utility of preoperative biomarkers for assessing perioperative complications in patients undergoing spine surgery (SS) is unclear and no study has assessed the ability of preoperative natriuretic peptides to predict adverse events following SS. This study aimed to evaluate the prognostic importance of N-terminal pro-brain natriuretic peptide (NT-proBNP) in a cohort of patients undergoing SS. Patients and methods: We prospectively followed 154 consecutive adult patients aged ≥50 years, hospitalized for elective SS. The outcomes of interest were length of stay in hospital and perioperative medical complications during hospitalization which is defined as pneumonia, deep or organ space surgical site infection, bacteremia, prolonged mechanical ventilation >48 hours, unplanned reintubation, acute renal failure, sepsis or septic shock, venous thromboembolism (deep vein thrombosis or pulmonary embolism), cardiac arrest, stroke, myocardial infarction, return to operating room, and in-hospital mortality. Results: A total 32 episodes of medical adverse events occurred in 21 (13.6%) patients. Older patients and those with more co-morbid conditions such as heart failure, diabetes, cerebrovascular diseases, coronary artery diseases and chronic obstructive pulmonary diseases tended to have a higher rate of adverse events. Patients with adverse events had higher NTproBNP, and troponin levels on admission compared to patients without adverse events. Multivariate analysis showed that NT-proBNP > 242 pg/ml (OR 2.374, 95% CI 1.000–2.958, p = 0.001) and presence of diabetes (OR: 2.16; 95% CI: 1.86–7.89; p =0.008) were significant and independent predictors of perioperative adverse events. Conclusion: This study is the first to demonstrate that the preoperative assessment of NTproBNP level in SS patients could be a valuable diagnostic method for predicting several postoperative complications. Key words: Spine surgery; medical adverse events; N-terminal pro-brain natriuretic peptide.

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INTRODUCTION In patients undergoing spinal surgery (SS), the presence of multiple comorbid conditions and utilization of complex surgical procedures is not uncommon, particularly among elderly patients (1). These factors lead to an increased risk of perioperative complications and readmissions. Preoperative laboratory testing has been frequently performed as a component of the preoperative workup for patients undergoing various surgical procedures such as cardiac surgery, general surgery or orthopedic surgery (2). However, very few studies have examined the association between preoperative laboratories and complications following SS. Natriuretic peptides are secreted primarily by ventricular myocytes in response to increased wall stress induced by volume expansion, pressure overload, or ischemia of the left or right ventricle of the heart (3,4). Elevated plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a marker of myocardial dysfunction, and a predictor of major adverse cardiovascular events in multiple cardiologic settings (3,4). With NT-proBNP established as clinically relevant in nonsurgical cohorts, efforts have moved to determining whether preoperative NT-proBNP can be used to improve risk stratification of surgical patients. This interest is prompted by the fact that the majority of significant postoperative complications are cardiovascular. Several studies have shown that preoperative NT-proBNP elevation has been independently associated with adverse outcomes after cardiac and noncardiac surgeries (5,6). However, SS procedure is distinguished from other procedures and it is of necessity to investigate predictive value of NT-proBNP for adverse events in patients undergoing SS in order to obtain individualized care and guidance. There are no data in the literature regarding the importance of preoperative natriuretic peptide levels in SS patients. The purpose of the present study was thus to explore the relationship between preoperative NT-proBNP levels and perioperative adverse events in patients undergoing elective SS.

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Material and Methods Study design The study was a prospective, observational, and single-center study, conducted at the Muğla Sıtkı Koçman University Hospital from January 2018 to January 2019. All patients were followed up during hospitalization or until death. This project was approved by the regional ethics committee and all patients or their relatives gave informed written consent. Selection of participants All patients with ≥ 50 years of age undergoing laminectomy, arthrodesis, discectomy, and/or laminectomy in any region of the spine were prospectively recruited. Demographic data, comorbidities, and medical history were obtained for all identified patients. Complete blood count and routine biochemical analyses icluding NT-proBNP (electrochemiluminescence sandwich immunoassay; Elecsys ProBNP, Roche Diagnostics) and troponın I (Siemens Healthcare Diagnostics Deerfield, Illinois, United States) concentrations were measured 24 h before surgery. Patients requiring emergency surgery or those undergoing minor-grade surgery were excluded. Study endpoints and definition of outcomes The outcomes of interest were length of stay in hospital and perioperative medical complications during hospitalization which is defined as pneumonia, deep or organ space surgical site infection, bacteremia, prolonged mechanical ventilation >48 hours, unplanned reintubation, acute renal failure, sepsis or septic shock, venous thromboembolism (deep vein thrombosis or pulmonary embolism), cardiac arrest, stroke, severe arrhythmias requiring treatment, acute heart failure, acute coronary syndrome (nonfatal acute myocardial infarction or unstable angina), return to operating room, and in-hospital mortality.

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Perioperative myocardial infarction was defined according to the universal definition of myocardial infarction (7). Pneumonia was defined by the presence of two or more of the following recently acquired symptoms or signs: temperature >38°C, dyspnea, cough, sputum production, pleuritic chest pain, or bronchial sounds or crackles on chest auscultation, plus radiographical findings of pneumonia.

Statistical analysis Data were analyzed using SPSS for Windows (version 15; SPSS Inc, Chicago, IL). The continuous variables were expressed as mean ± standart deviation and were compared between groups by 2-tailed Student t test. Nonparametric tests were also used when necessary (Mann-Whitney U test). Fisher exact (χ2 ) test was used in comparison of categorical variables. Comparing of patients characteristics from two groups (patients with and without perioperative complications) was done by using chi-square test. Statistical differences among groups were tested by one-way analysis of variance and Kruskal-Wallis tests for parametric and nonparametric variables, respectively. Univariate and multivariate logistic regression analyses were applied to determine crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the relationship between biomarkers and perioperative adverse events. For all analyses, P <0.05 was considered statistically significant.

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Results A total of 154 patients undergoing elective SS (mean age 67.8±12.5 and 48% male) were enrolled. Hypertension was the most frequent comorbidity, followed by coronary artery disease, diabetes mellitus. Median length of stay was 5 days. Perioperative adverse events Thirty-two episodes of medical adverse events occurred in 21 (13.6%) patients (Table 2). No patients died during follow up. The most frequent perioperative adverse medical events were acute coronary syndrome, acute heart failure, severe arrhythmias, deep vein thrombosis or pulmonary embolism, and prolonged mechanical ventilation. Comparison of patients with and without perioperative adverse events Comparison of baseline characteristics, laboratory parameters, and length of stay in patients with and without perioperative adverse events are shown in Table 1. Patients who incurred a complicated course were older, and were more likely to have underlying comorbid diseases such as coronary artery disease, diabetes mellitus, heart failure, cerebrovascular disease or chronic obstructive pulmonary disease. Patients who had perioperative adverse events had significantly higher preoperative NT-pro BNP (851.9 vs 118.8 pg/mL, respectively; p <0.001) and troponin I levels (17.5 vs 11 ng/mL respectively; p = 0.002) compared to patients without perioperative adverse events. Patients with perioperative adverse events had longer length of stay (16 vs 5 days, median, respectively; p <0.001) compared with uncomplicated patients.

Predictors of perioperative adverse events Univariate analysis showed that the following variables were associated with perioperative adverse events: age, presence of diabetes and chronic obtructive pulmonary disease, preoperative NT-proBNP and troponin I (Table 2). The parameters that proved to be

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significant on the univariate analysis were subsequently tested with the multivariate model. Multivariate analysis showed that only NT-proBNP > 242 pg/ml (OR 2.374, 95% CI 1.000– 2.958, p = 0.001) and presence of diabetes (OR: 2.16; 95% CI: 1.86–7.89; p =0.008) were significant and independent predictors of perioperative adverse events. DISCUSSION In this single-center, prospective and observational study of 154 consecutive patients, over the age of 50, undergoing elective SS, the incidence of perioperative adverse medical events was 13.6%. Multivariable analysis revealed that the presence of diabetes mellitus and higher preoperative NT-proBNP levels were independent prognostic factors for perioperative adverse medical events in these patients. To the best of our knowledge, this is the first study to demonstrate an association between preoperative NT-proBNP levels and adverse perioperative events in SS patients. As surgery remains the cornerstone of curative therapy, the number of older patients admitted for SS is increasing rapidly (8,9). Elective SS is commonly performed and is a major component of medical spending in Turkey. Spine surgeries are typically longer than other elective surgeries and are associated with hemodynamic stress due to blood loss, fluid shifts, older age of patients and complex procedures of surgery (10,11). Although complications associated with SS have been evaluated in other series, most of these studies have focused on surgical complications (12,13). However, differentiating complications based on surgical or non-surgical is useful, as the risk factors for each could be potentially different and increasing our awereness of these risk factors may lead to the ultimate goal of identifying ways to decrease the incidence of complications with SS. Moreover, identifying the predictors of surgical and non-surgical complications is valuable for patient selection and counseling SS.

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A number of demographic and clinical risk indices using scoring systems have been developed to evaluate the risk of perioperative complications in SS, but the predictive power is still insufficient (14). Therefore, simple and strongly predictive non-invasive tests are clinically warranted in patients undergoing SS. However, only a few studies have been evaluated the prognostic value of biomarkers for non-surgical complications in SS patients (15,16). In a retrospective study, Lakomkin and colleagues revealed that preoperative sodium, international normalized ratio, creatinine, and platelet counts were associated with various postoperative complications in patients undergoing posterolateral lumbar fusions (15). Salvetti et al. conducted a retrospective review of the medical charts of patients who had undergone posterior spinal surgeries and found that low preoperative prealbumin levels was a major risk factor for surgical site infection in elective SS patients (16). Cardiopulmonary and respiratory complications are among the most common after SS and are known to increase the risk of mortality and morbidity (17). A retrospective review of a prospectively collected database showed that cardiopulmonary complications are the most common cause of death in patients undergoing SS (18). Passias et al. published a retrospective review of the National Surgical Quality Improvement Program which was performed on 60 964 patients undergoing elective SS (19). They found that incidence rates per 1000 elective SS patients were 2.1 myocardial infarctions, 1.3 cardiac arrests, 4.3 unplanned intubations, 3.5 on ventilator >48 hours, 6.1 perioperative pneumonia, and 3.7 pulmonary embolism. Thoracic approach, scoliosis diagnosis, and combined approach independently increased risk for cardiopulmonary complications (19). Previous evidence suggests that cardiac biomarkers such as NT-proBNP and troponin may have potential in predicting perioperative risk in patients undergoing non-cardiac and cardiac surgery (5,6). Despite these evidences, no study to date has analyzed prognostic value of cardiac biomarkers for adverse events in SS patients.

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Despite being infrequent, cardiac adverse events after SS is a real concern for the neurosurgeons and findings from this study can guide physicians to discuss the risk of cardiac events depending on whether patients have higher preoperative cardiac biomarkers or not. The combination of natriuretic peptides with established risk scores is likely to improve the outcome of SS patients with moderate to high-cardiac risk. Further prospective research is needed to verify the benefit of NT-proBNP -guided management in perioperative medicine among patients undergoing SS.

Limitations The results of this study should be interpreted in the light of several limitations. First, impaired renal function reduce the specificity of NT-proBNP which could have influenced our results, as we did not exclude patients with renal dysfunction. Second, this study included only patients aged ≥50 years undergoing nonemergency SS. Our hospital is a referral hospital, to which patients are referred from peripheral hospitals, which may affect our results Therefore, caution should be taken in extrapolating these results to other surgical populations. Finally, we have no data on perioperative fluid management and postoperative NT-proBNP levels. Conclusions To our knowledge, the relation of preoperative NT-proBNP levels with perioperative adverse events have never been described in patients undergoing SS. Our results suggest that preoperative NT-proBNP measurement can help identify patients at high risk for composite endpoints of adverse non-surgical events after SS. In conclusion, regardless of the underlying mechanism involved, our data suggest that the use of NT-proBNP as a prognostic marker may improve the detection of patients at risk for complications in in patients undergoing SS.

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8. Imajo Y, Taguchi T, Neo M, Otani K, Ogata T, Ozawa H, Miyakoshi N, Murakami H8, Iguchi T. Complications of spinal surgery for elderly patients with lumbar spinal stenosis in a super-aging country: An analysis of 8033 patients. J Orthop Sci. 2017 Jan;22(1):10-15. doi: 10.1016/j.jos.2016.08.014. 9. Mihailidis HG, Manners S, Churilov L, Quan GMY. Is spinal surgery safe in octogenarians? ANZ J Surg. 2017 Jul;87(7-8):605-609. 10. O’Lynnger TM, Zuckerman SL, Morone PJ, Dewan MC, Vasquez-Castellanos RA, Cheng JS. Trends for spine surgery for the elderly: implications for access to healthcare in North America. Neurosurgery. 2015;77:S136-S141. doi:10.1227/NEU.0000000000000945. 11. Carabini LM, Zeeni C, Moreland NC, et al. Development and validation of a generalizable model for predicting major transfusion during spine fusion surgery. J Neurosurg Anesthesiol. 2014; 26:205-215. doi:10.1097/ANA.0000000000000014. 12. Nasser R, Yadla S, Maltenfort MG, Harrop JS, Anderson DG, Vaccaro AR, Sharan AD, Ratliff JK. Complications in spine surgery. J Neurosurg Spine. 2010 Aug;13(2):144-57. doi: 10.3171/2010.3.SPINE09369. 13. Proietti L, Scaramuzzo L, Schiro’ GR, Sessa S, Logroscino CA. Complications in lumbar spine surgery: A retrospective analysis. Indian J Orthop. 2013 Jul-Aug; 47(4): 340–345. 14. McLynn RP, Ondeck NT, Cui JJ, Swanson DR, Shultz BN, Bovonratwet P, Grauer JN. The Rothman Index as a predictor of postdischarge adverse events after elective spine surgery. Spine J. 2018 Jul;18(7):1149-1156. 15. Lakomkin N, Goz V, Cheng JS, Brodke DS, Spiker WR. The utility of preoperative laboratories in predicting postoperative complications following posterolateral lumbar fusion. The Spine Journal 18 (2018) 993–997.

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16. Salvetti D, Tempel ZJ, Goldschmidt E et al. Low preoperative serum prealbumin levels and the postoperative surgical site infection risk in elective spine surgery: a consecutive series. J Neurosurg Spine July 27, 2018. DOI: 10.3171/2018.3.SPINE171183. 17. Soroceanu A, Burton DC, Oren JH, Smith JS, Hostin R, Shaffrey CI, Akbarnia BA, Ames CP, Errico TJ, Bess S, Gupta MC, Deviren V, Schwab FJ, Lafage V; International Spine Study Group. Medical Complications After Adult Spinal Deformity Surgery: Incidence, Risk Factors, and Clinical Impact. Spine (Phila Pa 1976). 2016 Nov 15;41(22):1718-172. 18. Smith JS, Saulle D, Chen CJ, et al. Rates and causes of mortality associated with spine surgery based on 108,419 procedures: a review of the Scoliosis Research Society Morbidity and Mortality Database. Spine (Phila Pa 1976). 2012;37:1975-1982. 19. Passias PG, Poorman GW, Delsole E, Zhou PL, Horn SR, Jalai CM, Vira S, Diebo B, Lafage V. Adverse Outcomes and Prediction of Cardiopulmonary Complications in Elective Spine Surgery. Global Spine J. 2018 May;8(3):218-223. doi: 10.1177/2192568217718817. Epub 2017 Oct 24.

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Table 1. Comparison of patients with and without adverse events

Male Age (years) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Medical History Atrial fibrillation Smoking Diabetes mellitus Hypertension Coronary artery disease Cerebrovascular disease Heart failure Chronic obstructive pulmonary disease Laboratory Results NT-proBNP (pg/mL) , median (IQR) Troponin I (ng/mL), median (IQR) White blood count (×10³cells/mL) Hemoglobin (g/dL) Albumin (g/dL) Creatinine (mg/dL), median (IQR) Glucose (mg/dL) Length of stay (days)

No Adverse Event (n=133)

Adverse Event (n=21)

P Value

63 (47.4) 64.5 ± 13.1 125.4 ± 15.3 78.2 ± 8.8

11 (52.4) 76.1 ± 7.6 125.4 ± 13.5 78.1 ± 8.1

0.526 <0.001 0.739 0.423

6 (4.5) 31 (23.3) 22 (16.5) 66 (49.6) 29 (21.8) 11 (8.3) 7 (5.3) 13 (9.8)

3 (14.3) 4 (19) 10 (47.6) 14 (66.7) 11 (52.4) 5 (23.8) 4 (19.0) 8 (38.1)

0.107 0.785 <0.001 0.146 0.003 0.046 0.045 <0.001

118.8 (51.6-233.7) 11(5.4-14.2) 8.8 ± 3.5 12.2 ± 1.9 3.87 ± 0.55 1.0 (0.7-1) 105.8 ± 33.5 5.0 (4.0-9.0)

851.9 (240.4- 2176.8) 17.5 (8.7- 22.8) 8.40 ± 3.2 12.03 ± 1.6 3.70 ± 0.3 1.0 (0.9-1.2) 113.1 ± 58.3 16.0 (10.0-25.0)

<0.001 0.002 0.442 0.228 0.157 0.324 0.153 <0.001

Abbreviations: NT-proBNP : N-terminal pro-brain natriuretic peptide. Values are given as mean ± standard deviation or number (percentage) unless otherwise indicated.

Table 2. Perioperative medical adverse events Complication Reoperation Reintubation Stroke or transient ischemic attack Surgical site infection or bacteremia Acute renal failure Prolonged mechanical ventilation Deep vein thrombosis or pulmonary embolism Severe arrhythmias Acute heart failure Acute coronary syndrome

Number of the Episodes 2 2 2 3 3 4 4 4 4 4

Table 3. Univariate and multivariate analyses of risk factors for perioperative adverse events.

Univariate analysis Variable

Age Diabetes mellitus Heart failure Coronary artery disease NT-proBNP > 242 pg/ml COPD

OR

1.050 1.986 1.854 0.910 1.321 1.122

95% Cl Lower Upper 1.028 4.014 3.901 1.572 1.142 1.025

1.071 9.359 8.461 3.925 1.532 1.265

Multivariate analysis p

OR

0.001 0.000 0.043 0.024 0.000 0.042

1.141 2.165 0.410 1.690 2.374 1.086

95% Cl Lower Upper 1.113 1.860 0.166 0.818 1.000 0.942

1.370 7.894 1.010 3.489 2.958 1.214

Abbreviations: NT-proBNP: N-terminal pro-B-type natriuretic peptide; COPD: Chronic obstructive pulmonary disease.

p

0.065 0.008 0.062 0.156 0.001 0.285

confidence intervals (CIs) N-terminal pro-brain natriuretic peptide (NT-proBNP) odds ratios (ORs) spine surgery (SS)