Wang XJ, Xuan XC, Sun ZC, Shen S, Yu F, Li NN, Chu XC, Yin H, Hu YL. Risk factors associated with intraoperative persistent hypotension in pancreaticoduodenectomy. World J Gastrointest Surg 2024; 16(6): 1582-1591 [DOI: 10.4240/wjgs.v16.i6.1582]
Corresponding Author of This Article
You-Li Hu, FACE, MD, Associate Chief Physician, Associate Professor, Department of Anesthesia and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Gulou District, Nanjing 210029, Jiangsu Province, China. huyouli@njmu.edu.cn
Research Domain of This Article
Anesthesiology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Xing-Jun Wang, Xi-Chen Xuan, Zhao-Chu Sun, Shi Shen, Fan Yu, Na-Na Li, Xue-Chun Chu, Hui Yin, You-Li Hu, Department of Anesthesia and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Author contributions: Wang XJ, Sun ZC, and Hu YL contributed to study conception and design; Wang XJ, Xuan XC, Shen S, Yu F, Chu XC, and Yin H contributed to data collection; Wang XJ, Sun ZC, and Li NN contributed to data analysis and interpretation; Wang XJ and Hu YL drafted the manuscript; and all authors have reviewed and approved the final manuscript version.
Institutional review board statement: This study received approval from the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Approval No. 2023-SR-890).
Informed consent statement: This research is a retrospective analysis utilizing anonymized patient data from the hospital system, posing no risk of harm to patients. An exemption from patient informed consent has been requested from the hospital’s ethics committee.
Conflict-of-interest statement: The authors have no financial conflicts of interest to declare.
Data sharing statement: Data supporting this study’s findings can be obtained upon request from the corresponding author and are not publicly accessible due to privacy and ethical considerations.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: You-Li Hu, FACE, MD, Associate Chief Physician, Associate Professor, Department of Anesthesia and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Gulou District, Nanjing 210029, Jiangsu Province, China. huyouli@njmu.edu.cn
Received: March 7, 2024 Revised: April 27, 2024 Accepted: May 16, 2024 Published online: June 27, 2024 Processing time: 114 Days and 10.2 Hours
Abstract
BACKGROUND
Intraoperative persistent hypotension (IPH) during pancreaticoduodenectomy (PD) is linked to adverse postoperative outcomes, yet its risk factors remain unclear.
AIM
To clarify the risk factors associated with IPH during PD, ensuring patient safety in the perioperative period.
METHODS
A retrospective analysis of patient records from January 2018 to December 2022 at the First Affiliated Hospital of Nanjing Medical University identified factors associated with IPH in PD. These factors included age, gender, body mass index, American Society of Anesthesiologists classification, comorbidities, medication history, operation duration, fluid balance, blood loss, urine output, and blood gas parameters. IPH was defined as sustained mean arterial pressure < 65 mmHg, requiring prolonged deoxyepinephrine infusion for > 30 min despite additional deoxyepinephrine and fluid treatments.
RESULTS
Among 1596 PD patients, 661 (41.42%) experienced IPH. Multivariate logistic regression identified key risk factors: increased age [odds ratio (OR): 1.20 per decade, 95% confidence interval (CI): 1.08-1.33] (P < 0.001), longer surgery duration (OR: 1.15 per additional hour, 95%CI: 1.05-1.26) (P < 0.01), and greater blood loss (OR: 1.18 per 250-mL increment, 95%CI: 1.06-1.32) (P < 0.01). A novel finding was the association of arterial blood Ca2+ < 1.05 mmol/L with IPH (OR: 2.03, 95%CI: 1.65-2.50) (P < 0.001).
CONCLUSION
IPH during PD is independently associated with older age, prolonged surgery, increased blood loss, and lower plasma Ca2+.
Core Tip: This study examines risk factors for intraoperative persistent hypotension (IPH) in pancreaticoduodenectomy. Key risk factors include patient age, prolonged surgery duration, greater blood loss, and lower calcium levels. Prompt recognition and early intervention can effectively mitigate IPH in these operations.
Citation: Wang XJ, Xuan XC, Sun ZC, Shen S, Yu F, Li NN, Chu XC, Yin H, Hu YL. Risk factors associated with intraoperative persistent hypotension in pancreaticoduodenectomy. World J Gastrointest Surg 2024; 16(6): 1582-1591
Intraoperative hypotension, even brief episodes lasting 1-5 min, is closely associated with postoperative adverse outcomes[1]. Intraoperative persistent hypotension (IPH), generally requiring a continuous administration of vasopressors, can lead to severe complications and poor prognoses during and after extensive surgical procedures[2-4]. Such phenomena may arise from impaired blood pressure regulation resulting from the vasodilatory effects of anesthetics, surgery-related inflammation or insufficient circulating blood volume[5].
Pancreaticoduodenectomy (PD) as a complex and challenging abdominal operation has been reported to have a high incidence with IPH following long surgical procedures of extensive digestive tract reconstruction and multiple anastomoses[6]. IPH during PD is suggested to be related to the vascular paralysis seen in cardiac surgery; primarily characterized by a reduction in peripheral vascular resistance[7-9]. The small arteries located anterior to the capillaries predominantly determine peripheral vascular resistance, which is influenced by the autonomic nervous system, self-regulation, endothelial-cell-derived molecules and inflammatory factors[10]. The increased inflammatory markers, such as C-reactive protein, can increase the risk for severe hypotension and vasopressor dependency during postoperative day 1 after PD[11]. A more positive fluid balance commonly seen in PD implicates inadequate circulating blood volume in the risk of IPH. However, the underlying risk factors for PD-related IPH are still not clear. Identifying such risk factors is crucial for early detection and treatment of IPH, thereby reducing severe postoperative complications.
Given the limited research on IPH in PD, we conducted a comprehensive retrospective data analysis to investigate its associated risk factors. We found that these risk factors for the IPH during PD were linked to older patients, longer surgical procedures, more blood loss and decreased plasma Ca2+ concentration.
MATERIALS AND METHODS
Study population
We retrospectively analyzed 2432 patients who underwent open PD at the First Affiliated Hospital of Nanjing Medical University between January 2018 and December 2022. We included 1596 patients based on the inclusion and exclusion criteria. Among them, 661 patients were assigned to the IPH group, and the remaining 935 patients who did not experience persistent hypotension were assigned to the non-IPH group.
Inclusion and exclusion criteria
Inclusion criteria: Patients who underwent open PD under general anesthesia; American Society of Anesthesiologists (ASA) class I-III; aged 18-80 years.
Exclusion criteria: Patients diagnosed with distant metastasis; patients undergoing local or palliative pancreatic surgery; ASA class IV or higher; patients exhibiting cancerous changes in organs other than the metastasis site; patients undergoing neoadjuvant chemotherapy prior to surgery; age < 18 years or > 80 years; and pregnant women.
Clinical data and indices
The digitized anesthesia records were automatically reviewed to identify patients meeting the inclusion criteria. Only data from eligible patients were included in subsequent analyses. To minimize the impact of missing data, we conducted a comprehensive manual review and collected supplementary information from medical records. Key medical indicators, such as age, gender, body mass index (BMI), ASA classification, pre-existing comorbidities, long-term medication, surgery duration, total intake, excess intake, blood loss, urine output, and blood gas analysis (including pH, PaCO2, HCO3-, hemoglobin, lactic acid, Ca2+, mean blood glucose concentration, and glucose variability), were extracted. Supplementary data encompassing preoperative surgery and anesthesia-related details, along with hemodynamic measurements, were compiled for evaluation.
IPH
The definition of perioperative hypotension remains undecided. However, the majority of studies adopt mean arterial pressure (MAP) < 65 mmHg as a benchmark for defining preoperative hypotension[12-15]. In our study, IPH was characterized by hemodynamic instability with MAP < 65 mmHg, necessitating continuous deoxyepinephrine administration for > 30 min, even after repeated bolus administration of deoxyepinephrine and fluid therapy.
Outcome measures
The primary outcomes involved factors associated with IPH, comprising age, ASA classification, preoperative hypertension, preoperative albumin concentration, surgical duration, arterial blood Ca2+ concentration, total intake, excess intake, blood loss, lactic acid concentration, mean blood glucose, and glucose variability. The secondary outcome focused on the incidence of IPH during PD.
Statistical analysis
Patient baseline characteristics were compared between the IPH and non-IPH groups for the normality of continuous data using the Kolmogorov-Smirnov test. Results were presented as mean ± SD for normally distributed data and as median (interquartile range) for non-normally distributed continuous data. The independent samples t-test and Mann-Whitney U test were utilized to compare mean and median data, respectively, between the groups. The categorical variables were analyzed using the χ2 or Fisher’s exact test, with results presented as percentages. For ordered categorical variables, such as the ASA classification, comparison was conducted using the Mann-Whitney U test, and outcomes were likewise expressed in terms of percentages. Univariate logistic regression analyses were used to assess the relationship of various factors with IPH during PD. Significant variables (P < 0.05) were incorporated into a backward elimination multivariate logistic regression model to identify independent risk factors associated with IPH. Statistical analysis was conducted using R 4.3.1 software (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). The study was reviewed by our biostatistics expert (Nana Li).
RESULTS
Baseline characteristics
Our study included 1596 patients, among whom 661 (41.42%) experienced IPH (Figure 1). There were no observed significant differences in gender, BMI, preoperative blood gas analysis, and biochemical indicators between the two groups. However, significant differences were noted in age, ASA classification, and preoperative history of hypertension, diabetes mellitus (P < 0.001) and albumin level (P < 0.01) (Table 1). Notably, patients aged > 60 years showed a higher propensity for IPH. Patients experiencing IPH were older, had higher ASA classification, and had a documented history of hypertension and diabetes mellitus, in addition to lower preoperative albumin levels, in comparison to those without IPH.
The patients in the IPH group underwent longer surgical procedures (4.75 h vs 4.45 h, P < 0.001) and received higher volumes of intraoperative fluids (3100 mL vs 2760 mL, P < 0.001), comprising crystalloids, colloids and blood transfusion (Table 2). Additionally, this group experienced more blood loss (350 mL vs 300 mL, P < 0.001), with a higher proportion exhibiting 500-1000 mL of bleeding. In terms of blood gas analysis conducted 3 h after surgery, the IPH group showed lower pH and HCO3-, along with higher lactic acid, increased blood glucose concentrations and the coefficient of variation of blood glucose. Arterial blood Ca2+ concentrations significantly decreased in the IPH group compared with the non-IPH group (1.05 mmol/L vs 1.07 mmol/L, P < 0.001). Since the difference of arterial blood Ca2+ concentration between these two groups was marginal, we further divided these patients into two subgroups using arterial blood Ca2+ 1.05 mmol/L as a cutoff. The proportion of patients in the IPH group with arterial Ca2+ ≤ 1.05 mmol/L was higher than in the non-IPH group (56.73 % vs 38.50%, P < 0.001).
Table 2 Comparison of general conditions between two groups during surgery.
We categorized preoperative and intraoperative factors that could potentially affect blood pressure, encompassing age, ASA level, pre-existing conditions, preoperative albumin level, surgery duration, blood loss, arterial blood glucose, and Ca2+ concentrations. Multivariate logistic regression analysis further indicated that older age, extended surgery duration, increased blood loss, and reduced intraoperative arterial Ca2+ levels constituted independent risk factors for IPH during PD. The relative risk increased by 1.20-fold for each additional decade of age [odds ratio (OR): 1.20; 95% confidence interval (CI): 1.08-1.33] (P < 0.001); 1.15-fold (OR: 1.15; 95%CI: 1.05-1.26) (P < 0.01) for an additional hour of surgery; 1.18-fold (OR: 1.18; 95%CI: 1.06-1.32) (P < 0.01) for every 250 mL increase in blood loss; and 2.03-fold (OR: 2.03; 95%CI: 1.65-2.50) (P < 0.001) for the arterial blood Ca2+ < 1.05 mmol/L (Figure 2).
Figure 2 Forest plot illustrating risk factors associated with intraoperative persistent hypotension during pancreaticoduodenectomy.
OR: Odd ratio.
DISCUSSION
In the present retrospective cohort study, we found that the risk factors associated with IPH during PD were age, prolonged surgical procedures, more blood loss, and even more notably, decreased arterial Ca2+ concentration. The incidence of IPH during PD was 41.42; similar to the report by Pitter and colleagues[11]. Our study confirms findings from previous studies, which indicated a close relationship of prolonged surgery and increased blood loss to intraoperative hypotension[4,16,17]. The risk of intraoperative hypotension escalates with age, especially in older patients, likely attributable to diminished cardiac function, reduced vascular elasticity from atherosclerosis, and decreased sympathetic nerve sensitivity, which impair blood pressure regulation[18-20]. Extended surgery and significant blood loss are indicative of substantial surgical trauma, resulting in prolonged anesthesia exposure and alterations in internal homeostasis[21]. These changes may impair sympathetic nervous system function, leading to reduced myocardial contractility and vascular smooth muscle function, ultimately resulting in hypotension[22,23]. Therefore, IPH during PD seems to be associated with imbalances in internal homeostasis that potentially disrupt blood pressure regulation, especially in older patients with extended surgical stress.
A novel finding of our study concerns the close association between decreased arterial blood Ca2+ concentration and the occurrence of IPH during PD. Our observations indicate that the risk of hypotension escalated when arterial Ca2+ concentration fell below 1.05 mmol/L, which led us to establish this level as a threshold to analyze the potential role of Ca2+ concentration in IPH during PD. It is known that Ca2+ ions perform a pivotal role in numerous physiological processes, such as blood coagulation, muscle function, neural signal transmission, and cellular signaling[24]. Arterial Ca2+, comprising primarily free ions, constitute approximately 50% of venous Ca2+ levels[25]. Reduced arterial Ca2+ during PD might adversely affect the myocardium, vascular smooth muscle, sympathetic nervous system and hormone secretion; all of which act as critical components in modulating intraoperative blood pressure[26].
Hyperglycemia, oxidative stress and inflammatory reaction are known to enhance intracellular Ca2+ concentration by increasing Ca2+ release from intracellular stores and Ca2+ influx through store-dependent and store-independent channels[27]. Stress response in the endoplasmic reticulum and mitochondria can be induced by the stimulation of surgical stress and inflammatory reaction, which is characterized by the widespread transfer of Ca2+ from the endoplasmic reticulum to the mitochondria[28]. The massive shift of intracellular Ca2+ may lead to membrane-associated calcium channels open, including transient receptor potential channels and Ca2+ release-activated Ca2+ channel protein 1, resulting in an influx of extracellular Ca2+ into the cells[29]. We observed lower plasma Ca2+ along with higher blood glucose and prolonged surgical procedures in patients with IPH, raising the possibility that reduced plasma Ca2+ might result from the extensive surgical-induced release of inflammatory factors and stress-related hyperglycemia during PD[30]. These operative responses might disrupt the balance of intracellular-extracellular Ca2+ transport by remarkable Ca2+ influx into the endothelial cells, leading to a relatively quick drop of plasma Ca2+. Abnormal Ca2+ metabolism or distribution including intracellular Ca2+ overload or insufficient elevation may cause endothelial leakage and severely compromise cardiovascular homeostasis[31]. This can be seen in conditions of acute and chronic hyperglycemia that potentially affect Ca2+ distribution, such as intracellular Ca2+ overload, and subsequently cause aberrant vascular function and endothelial permeability[32,33]. The massive blood transfusions, normally defined as infusion of > 10 units at a time, may result in hypocalcemia[34,35]. However, in our study, the proportion of patients who received blood transfusions > 1040 mL was 1.51% (10 cases in the IPH group). Even after excluding these patients, the group with IPH still exhibited a significant reduction in arterial blood Ca2+ concentration. Therefore, this excluded the possibility of decreased Ca2+ induced by a greater number of blood transfusions contributing to IPH during PD. The surgical stress-inflammation-endocrine response induced decrease in plasma Ca2+ might disrupt endothelial function, reduce peripheral vascular resistance, and then hamper cardiovascular regulation during PD. Arterial Ca2+ levels emerge as a valuable predictor of intraoperative hypotension. Considering the identified risk factors—increased age, prolonged surgical duration, and substantial blood loss—it is plausible that these factors may collectively reduce arterial Ca2+ concentration.
Hypotension is recognized as an independent predictor of myocardial infarction, particularly when intraoperative MAP drops below 40% of preinduction levels for > 30 min, markedly elevating the risk of postoperative myocardial injury. The severity and duration of intraoperative hypotension are related to postoperative acute renal failure[36]. Numerous meta-analyses recommend classifying intraoperative hypotension as an independent predictor of adverse postoperative outcomes[37-39]. Early identification and effective intervention in high-risk patients are imperative to mitigate intraoperative hypotension and expedite patient recovery. Therefore, based on our findings on the risk factors for the IPH, preoperative assessment should include patient’s age, anticipated surgery duration, and potential blood loss.
This study had some limitations. We investigated the relationship between preoperative ASA scores and intraoperative hypotension. While initial univariate analysis suggested higher ASA scores in the IPH group, subsequent analysis with post-adjustment for confounders indicated that ASA score was not an independent risk factor for IPH, possibly owing to the small sample size and stringent selection criteria. The smaller proportion of patients with ASA grade III suggests that some patients may have missed optimal surgical opportunities due to underlying conditions. Moreover, the present study analyzes the impact of preoperative hypertension and history of diabetes on intraoperative hypotension. Although initial analysis revealed differences between groups, these disparities were rendered insignificant after adjusting for other factors. This inconsistency may be attributed to inadequate preoperative knowledge about hypertension and diabetes, resulting in inadequate information being provided during preoperative consultations.
CONCLUSION
The independent risk factors for IPH during PD are patient age, prolonged surgery duration, more blood loss and reduced Ca2+ level. The early identification of these factors and the implementation of appropriate preemptive interventions can significantly aid in preventing IPH in PD.
ACKNOWLEDGEMENTS
We extend our gratitude to the physicians at the Pancreatic Center for their assistance in data collection.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Anesthesiology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade C, Grade C, Grade C
Novelty: Grade B, Grade B, Grade C
Creativity or Innovation: Grade B, Grade B, Grade C
Scientific Significance: Grade B, Grade B, Grade C
P-Reviewer: Soldera J, Brazil; Teragawa H, Japan S-Editor: Chen YL L-Editor: A P-Editor: Chen YX
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