Association of preoperative electrocardiographic markers with sepsis in elderly patients after general surgery

Background Electrocardiographic markers, as surrogates for sympathetic excitotoxicity, are widely predictive of cardiovascular adverse events, but whether these markers can predict postsurgical sepsis (SS) is unclear. Methods We retrospectively analyzed patients who underwent abdominal surgery from March 2013 to May 2023. We collected basic data, comorbidities, blood samples, echocardiology, electrocardiogram, and surgical data, as well as short-term outcome. The primary endpoints were postsurgical SS, in which logistic regression analyses can identify independent risk factors. The optimal cut-off value predictive postsurgical SS both P wave and PR interval were calculated in the receiver operating characteristic curve (ROC). Results A total of 1988 subjects were analyzed, and the incidence of postsurgical SS was 3.8%. The mean age at enrollment was 68.6 ± 7.1 years, and 53.2% of the participants were men. In the ROC analysis, the areas under the curve (AUC) for P wave and PR interval predictive postsurgical SS were 0.615 (95%CI, 0.548–0.683; p = 0.001) and 0.618 (95%CI, 0.554–0.682; p = 0.001), respectively. The P wave and PR interval predicted postoperative sepsis with optimal discrimination of 103 and 157 ms, with a sensitivity of 0.744 and 0.419, and a specificity of 0.427 and 0.760. P-wave less than 103 ms or PR interval less than 157 ms associated with a 2.06 or 2.33 fold increase occurred risk postsurgical SS. Conclusions Shorter P-wave and PR intervals were both independently associated with postsurgical SS. These preoperative electrophysiological markers could have potential useful for early recognition of postoperative SS.


Introduction
Sepsis is a systemic chaos response to infection [1] that afflicts over 1,000,000 patients per year in the USA [2].Severe sepsis accounts for 27% of ICU admissions in the UK [3] and affects over 30 million sufferers around the globe [4].Perioperative sepsis is deadly and tricky, 40% of which is closely associated with cardiac arrest, and the mortality rate is over 70% for these cases [5].Current guidelines are based on the belief that the cornerstone of effective sepsis treatment is early recognition, which is associated with improved outcomes [6].There are limited tools for the early identification or screening of sepsis.
Previous animal experiments suggested that colon puncture ligation (early sepsis) may induce gut-derived norepinephrine within 2 h [7,8].Sympathetic toxicity may precede the diagnosis of sepsis, whereas sympathetic stimulation can secondarily change various electrocardiographic markers [9], including P wave, PR interval, and QT duration [10,11].Sympathetic tachycardia and sympathetic-induced disorder with sodium, L-type Ca 2+ , and K + current channels were associated with complicated infection [12].The presence of Q-waves, left bundle branch block, QTc interval prolongation, J-waves, ST-segment changes, atrial fibrillation (AF), and high sharp T-waves can be detected on ECG [13,14] in septic patients (diagnosed septic stage), representing the possibility of sympathetic-induced current channels disorder.Sympathetic toxicity (abnormal electrocardiogram markers) in the undiagnosed stage predicts sepsis is not fully understood.
The primary aim of this study was to explore the association of preoperative electrocardiographic markers (sympathetic toxicity) in the undiagnosed stage with postoperative sepsis.

Ethical statement and clinical trial registration
This study was authorized by the institutional ethics review committee before recruiting patients (Ethical Committee approval number: IRB-2022-080).This trial was registered at Chictr.org.cn(registration number: ChiCTR2200063917).

Inclusion and exclusion criteria
In this study, we included in elderly patients over 60 years who underwent general surgery, including biliary, gastrointestinal, appendix, pancreatic, liver, and other surgeries.Some patients will be excluded with missed ultrasound electrocardiogram recording, electrocardiogram (ECG) recording, laboratory test results, medical records, and P wave or PR interval loss in ECG.

The main outcomes and follow-up at the internal hospital
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.Postsurgical sepsis is defined as new-onset sepsis meeting the diagnostic criteria of "Sepsis-3" [1] after intraabdominal surgery based on the recently updated Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).Cases were followed during their hospitalization, and the follow-up for clinical outcomes included 100% of the patients (1988 cases).

Clinical data collected
All clinical data collected was derived from Qingyuan People's Hospital Big Database.In the retrospective cohort study, we included the following covariates.Subject characteristics included age, sex, emergency surgery, and ASA III-IV.Comorbidities included hypertension, diabetes, COPD, a history of MI, coronary disease, valvular disease, pulmonary hypertension, and stroke.Surgical data included operative or anesthetic duration, laparoscopic surgery, conversion laparotomy, surgical indications, and blood transfusion.Echocardiography data included left or right atrial hypertrophy, left ventricular hypertrophy, pulmonary hypertension, cardiomegaly, and LVEF ≤ 50%.Laboratory tests included procalcitonin, WBC count, and C-reactive protein ≥ 40 mg/L.The outcomes were all-cause mortality, major cardiovascular events, ventricular tachycardia, moderate to severe anemia, malnutrition, incision infection, ARI or ARI requiring CRRT, and hospital stay.

Electrocardiography data
All ECG data were digitally recorded and stored in a MedEx multilead ECG analysis system for MECG-300 type (Beijing Maddix Technology Co., Ltd., Beijing, China) and later automatically analyzed by ECG physicians using the processing software that came with the system.The assessment recording speed was set to more than 25 mm/s, and the sensitivity was set to 10 mm/mV.QT intervals were corrected for heart rate using Bazett's formula (QTc = QT/RR 1/2 ) [15].The Tpeak-Tend interval (Tpe) is defined as the interval from the peak to the end of the T-wave in the V 2 lead [16].Tpe-Max is the longest Tpe among the 12 leads, and Tpe-Min is the shortest.Tpe dispersion is equal to the difference between Tpe-Max and Tpe-Min [17].The P-wave duration is measured from the P-wave onset to its offset [18].The maximum P-wave duration (P-wave-Max) is defined as the longest duration, and the minimum P-wave duration (P-wave-Min) is defined as the shortest duration on a standard 12-lead ECG.P-wave dispersion is equal to the difference between P-wave-Max and P-wave-Min [19].The PR interval is defined as the duration from the onset of the P-wave to the initiation of the QRS segment [20].

Statistical analyses
An analysis of postsurgical sepsis during hospitalization was conducted for this study.Discrete variables are presented as frequencies with their respective percentages, with continuous variables presented as the mean ± SD or median (IQR).For comparisons between two groups, continuous variables were analyzed by using Student's t test or the Wilcoxon rank-sum test; if appropriate, categorical variables were analyzed with the Pearson chi-square test or Fisher's exact test.Candidate variables with a p value < 0.05 in univariate analysis or the 2-group comparisons were entered into the models.Odds ratios of logistic regression analyses that can analyze independent markers for sepsis were calculated, with 95% CIs and associated P values.We analyzed the association between both presurgical electrocardiogram markers and sepsis in univariate and multivariate logistic regression models.Pre-and postsurgical clinical risk factors (including age, sex, ASA III-IV, emergency surgery, imipenem and vasoactive drugs used) entered the model.
The receiver operating characteristic curve (ROC) and area under the curve (AUC) were analyzed for P wave or PR interval.Subsequently, the optimal cut-off value predictive postsurgical SS both P wave and PR interval were calculated, with sensitivities and specificities relative to predictive postsurgical SS confirmed.Based on the optimal cut-off value of P-wave and PR intervals, we turned them into categorical variables, we again analyzed the association between both the optimal cut-off value and postsurgical SS in univariate and multivariate logistic regression models.Statistical significance was defined as a 2-sided p-value < 0.05.SPSS 25.0 software was used for all analyses.

Results
A total of 2688 subjects were screened, and 1988 subjects who met the inclusion criteria were included in this study (Fig. 1).Table 1 shows the demographic, preoperative echocardiographic, laboratory, clinical, surgical, and prognostic characteristics of the included patients, as well as the preoperative electrocardiographic markers stratified by the occurrence of postsurgical SS.

ROC analyses for the P wave and PR interval predictive postsurgical SS
Figure 2 showed that the areas under the curve (AUC) for P wave and PR interval were 0.615 (95%CI, 0.548-0.683;p = 0.001) and 0.618 (95%CI, 0.554-0.682;p = 0.001), respectively.The P wave and PR interval predicted postoperative sepsis with optimal discrimination of 103 and 157 ms, with a sensitivity of 0.744 and 0.419, and a specificity of 0.427 and 0.760.2).Table 2 also showed results for univariate and multivariate Logistics Regression Analysis about postoperative SS.Age, ASA III-IV, emergency surgery, CHA 2 DS 2 VASc score, white blood cell, gastrointestinal perforation, conversion laparotomy,atrial fibrillation, major cardiovascular events, CRRT, acute renal injury, incision infection, hospital stay, and all-cause mortality were independent risk factors for postoperative SS.

Discussion
We found that (1) abnormal preoperative ECG parameters preceded postsurgical SS. (2) A decreased P-wave and PR interval were both independently associated with postsurgical SS.As a dynamic process, sepsis can turn into conditions of varied severity [21,22].There is an inflammatory response that is determined by the pathogenic agent and the host (genetic characteristics and coexisting illnesses) in patients with sepsis, with differential responses at the local, regional, and systemic levels.The infection source not only extends to the infected tissue or organ but also induces either secondary peritonitis or combined peritonitis in complicated intra-abdominal infections (IAIs).Sympathetic excitotoxicity and released plasma norepinephrine levels were observed in peritonitis patients and experimental peritonitis animals [23].An increased sympathetic tone is thought to be compensatory in the initial infectious stage, but its continuous activation may become pathological.Persistent tachycardia secondary to catecholamine is common [24].In later stages of severe peritonitis, β-adrenoceptor stimulation from maintenance of the sympathetic tone results in various ionic currents being markedly depressed in atrial and ventricular myocytes.The use of β-blockers in patients with sepsis with persistent tachycardia was associated with significantly improved short-term outcomes [25].Alternative mechanisms are associated with reductions of L-type calcium currents and sodium ion currents due to pro-inflammatory cytokines induced by serious peritonitis.Decreased P-waves were independently associated with postsurgical SS.There are few previous studies considering the possibility of using electrocardiography as a screening tool for sepsis [26,27], while numerous studies have focused on using electrocardiographic diagnosis for septic atrial or ventricular tachyarrhythmias.The P-wave represents the time required for a sinus impulse to propagate from the sinus node to the entire atrium [28].A decreased P-wave duration correlates with a fast conduction velocity within the atria [29].Angelo et al. found that a 28% reduction in action potential duration 90 (APD 90 ) yielded a 22% reduction in P-wave duration [30].The underlying mechanisms include a shortened action potential duration (APD) in atrial cells from LPSinduced septic animals associated with a reduced L-type Ca 2+ current and sodium channels and an increased delayed rectifier K + current [31].Sympathetic tachycardia is widely prevalent in critical illnesses, including sepsis, trauma, burns, and cardiac arrest [32].Isoproterenol infusion significantly shortened the P-wave duration for healthy volunteers in an autonomic stimulation test [33].Under physiological and pathological conditions, the PR interval diminishes with increasing HR [34].Although associations between cardiac conduction and sepsis in humans have not been identified so far, there are verified associations between a decreased PR interval and sepsis in animal models [35,36].This is consistent with the results of this study that preoperative shorter PR intervals were strongly predictive of postsurgery SS.Gianfranco Piccirillo et al. also suggested a possible ANS influence on the PR interval [37].In summary, our results confirm the potential value of electrophysiological markers for predicting sepsis in the setting of general surgery.
Elderly patients with complicated IAIs present to physicians with fewer signs of peritonitis and have little inflammatory response [38].In many developing countries worldwide, there is still a significant unacceptable delay in admitting older patients to the hospital [39].Elderly patients may be preseptic in the preoperative stage, but current screening methods do not provide early recognition.The Sepsis-3 criterion requiring already present organ failure has a deficit in its predictive potential and may obstruct early recognition and treatment of sepsis [1].Quick SOFA (qSOFA) does not diagnose sepsis, likely discriminating against low-or high-risk sepsis inside and outside critical care units [40].Early warning scores are based on abdominal signs and symptoms, which are often absent in the elderly [41].A new method of early septic screening is essential to improve patient outcomes.Our study showed that early changes in ion channel currents associated with sepsis could be identified on the Fig. 2 ROC analysis of P wave and PR interval.The areas under the curve (AUC) for P wave and PR interval were 0.615 (95%CI, 0.548-0.683;p = 0.001) and 0.618 (95%CI, 0.554-0.682;p = 0.001), respectively.The P wave or PR interval predicted postoperative sepsis with a Yuden index of 0.171 or 0.179, a sensitivity of 0.744 or 0.419, a specificity of 0.427 or 0.760, and optimal discrimination of 103 or 157 ms

Study limitations
Regarding this study's limitations, the limited population, single-center origin, and lack of randomness should be considered.In addition, information about any unacceptable delay before arriving at the hospital was not included, and this information is necessary to help develop effective screening based on data in the real world.The types of bacterial infections were not clearly identified.Racial heterogeneity can lead to biased data, but negative trends in these markers are dominant.

Conclusion
Electrocardiographic markers as a surrogate for sympathetic excitotoxicity have an independent association with postsurgical SS.Preoperative electrocardiographic markers have potential predictive value for complicated intra-abdominal infections.

Fig. 1
Fig. 1 Flowchart of the research

Table 1
Clinical characteristics of the study cohort

Table 1
(continued) Continuous data are presented as mean ± SD or median (interquartile range); Discrete data are presented as frequencies with their respective percentages.P value of Student's t, Fisher's exact,or the Wilcoxon rank-sum test between groups of patients with and without sepsis

Table 2
Univariate and multivariate logistics regression analyses with possible risk factors predictive postsurgical SS ECG, and anesthesia or critical illness practitioners are able to grasp the characteristics of the electrocardiogram.