Intraoperative Diastolic Hypotension-Prolonged Postoperative Hospital Stay in Patients with Gastric Cancer: A Retrospective Cohort Study with Propensity Score Matching

Introduction

Surgical resection remains the primary treatment for gastric cancer, one of the most common and lethal cancers worldwide.1,2 The perioperative period is often accompanied by hemodynamic fluctuations, which can affect organ perfusion, increase the incidence of postoperative complications, and prolong postoperative hospital stay.3,4

Studies have shown that intraoperative hypotension can cause an imbalance between oxygen supply and demand and can increase the incidence of postoperative cardiovascular complications,3,5 acute renal injury,6,7 and other postoperative complications.5 Blood pressure is a complex signal that varies considerably over time and includes several components, including diastolic, mean, systolic, and pulse pressures.8,9 Studies have suggested that diastolic, mean, and systolic pressures from radial arterial catheters can be used comparably to predict perioperative myocardial and renal injury and other postoperative complications.5 However, most recent studies on the impact of perioperative hemodynamic fluctuations on postoperative recovery have focused on systolic blood pressure (SBP) and mean arterial pressure (MAP), with few studies investigating the effect of diastolic blood pressure (DBP). For example, in a review that investigated the relationship between intraoperative hypotension and postoperative adverse outcomes after noncardiac surgery, of the 42 studies included, 29 (69%) used a definition of intraoperative hypotension that was based on an absolute MAP threshold, 17 (40%) used a definition that was based on an absolute SBP threshold, and no studies used a definition that was based on DBP.10

Therefore, based on the fact that DBP also plays an important role in organ perfusion,11 the present study sought to explore the relationship between intraoperative diastolic hypotension and postoperative recovery after gastrectomy.

Methods

This study is a retrospective cohort study that included propensity score matching. The study protocol was approved by the clinical research ethics committee of Peking University Cancer Hospital (Approval No. 2018YJZ71). The study was designed and conducted in accordance with the Helsinki Declaration. As the study was observational, the ethics committee waived the requirement for written informed consent.

Participants

We used the hospital’s electronic medical record to retrospectively identify patients who underwent resection for gastric cancer in the Department of Gastrointestinal Surgery at Peking University Cancer Hospital from April 1, 2015, to October 30, 2018. Exclusion criteria were reoperation for postoperative recurrence of gastric cancer and missing data (tumor stage, differentiation grade, patient follow-up information, etc.).

Anesthesia, Surgery, and Perioperative Management

All patients underwent general anesthesia with endotracheal intubation and received invasive arterial pressure monitoring. Anesthesia was induced by intravenous anesthetics (propofol and/or etomidate) and opioids (fentanyl or sufentanil). Inhalational anesthetics (sevoflurane or isoflurane) and opioids (fentanyl and/or sufentanil and/or oxycodone and/or dizocine and/or pentazocine and/or remifentanil) were used to maintain anesthesia. Some patients received combined epidural block (lidocaine and/or ropivacaine) or intravenous nonsteroidal anti-inflammatory drugs (NSAIDs; including flurbiprofen axetil and parecoxib) for supplemental analgesia during anesthesia maintenance. Glucocorticoids (dexamethasone or methylprednisolone) were given to some patients to prevent postoperative nausea and vomiting before induction of anesthesia and/or during postoperative analgesia, in accordance with the guidelines for postoperative nausea and vomiting management.12 Vasoactive drugs were used in accordance with relevant guidelines.13,14

Some patients received tumor-related treatment, such as neoadjuvant chemotherapy, before their operation. Depending on the location of the tumor, total gastrectomy, proximal gastrectomy, distal gastrectomy, or palliative surgery alone was performed.15 Reconstruction methods (Roux-en-Y esophagojejunostomy, gastroduodenostomy, gastrojejunostomy, or dual-channel reconstruction) and methods (in vitro or in vitro) were selected in accordance with the surgeon’s preference.

Patients were given patient-controlled analgesia for 3 days postoperatively. Ropivacaine was used for epidural analgesia, and opioids were used for intravenous analgesia. Intravenous analgesia included dexamethasone, serotonin-3 receptor antagonist, and/or metoclopramide, at the anesthesiologist’s discretion, to prevent postoperative nausea and vomiting.12 Other perioperative treatments were performed in accordance with routine clinical practice. Patients were discharged when they were able to move independently and without surgery-related comorbidities.

Perioperative Data

We used the hospital’s electronic medical record to collect the following data: basic preoperative data (sex, age, height, weight, smoking history, drinking history, combined preoperative diseases, preoperative laboratory results, American Society of Anesthesiologists [ASA] grade, and preoperative chemotherapy); anesthesia-related information (type of anesthesia, type and dose of anesthetic drugs, intraoperative blood transfusion and rehydration volume, occurrence and duration of intraoperative systolic or diastolic hypotension [as hypotension is defined as blood pressure below 90/60 mmHg, we defined systolic hypotension of 90 mmHg and diastolic hypotension of 60 mmHg], use of intraoperative vasoactive drugs, postoperative analgesia, and use of perioperative glucocorticoids, NSAIDs, and opioids [equivalent doses of perioperative glucocorticoids,16 NSAIDs,17 and opioids18–20 were calculated]); operation-related information (type of procedure, range of gastrectomy, duration of surgery, and estimated intraoperative bleeding); tumor-related information and postoperative information (tumor pathological diagnosis, tumor differentiation, tumor pTNM stage, incidence of complications during hospitalization, and length of postoperative hospital stay).

Outcomes

The primary outcome was length of postoperative hospital stay (LOS), defined as the time from postoperative day 1 to the first discharge. The secondary outcome was incidence of postoperative complications, which were defined as new medical events that were harmful to the patient’s recovery during the hospital stay and that required interventional therapy (ie, class II–V on the Clavien-Dindo classification21).

Data Analysis

To conduct the analyses, we divided the patients into two groups: those with intraoperative diastolic hypotension (defined in this study as DBP <60 mmHg for >10 min) and those without intraoperative diastolic hypotension (DBP >60 mmHg or DBP <60 mmHg for ≤10 min). Between-group differences in the baseline and intra- and postoperative variables used for propensity score matching were compared using the absolute standardized difference (ASD), which is defined as the absolute difference in means, mean ranks, or proportions, divided by the pooled standard deviation, and calculated using the formula published by Austin.22 An ASD ≥0.109—that is, was considered imbalanced between the two groups in the present study.

All baseline and intra- and postoperative variables for the two groups were used for propensity score matching. Baseline data included age, sex, body mass index, smoking history, drinking history, ASA classification, preoperative comorbidities, preoperative laboratory test results, preoperative chemotherapy, pathological diagnoses, pathological tumor-node-metastasis (pTNM) stage of gastric cancer, and degree of cancer differentiation. Intra- and postoperative data included type of procedure; range of gastrectomy; duration of surgery; type of anesthesia; type and dose of anesthetic drugs; estimated blood loss; intraoperative blood transfusion and rehydration volume; the use of intraoperative vasoactive drugs; equivalent doses of perioperative glucocorticoids, NSAIDs, and opioids; and the occurrence of SBP <90 mmHg for >10 min. Patients were matched in a 1:1 ratio using nearest-neighbor matching, with caliper widths equal to 0.2 of the standard deviation of the logit of the propensity score.

For both the full cohort and the matched cohort, continuous data (ie, length of postoperative hospital stay) were compared using Student’s t-test (normal distribution) or the Mann–Whitney U-test (nonnormal distribution); categorical data (ie, postoperative complications) were analyzed using the χ2 test. Missing data were not replaced. Univariable associations between baseline and perioperative variables and postoperative hospital stay were analyzed using logistic regression models. Variables with P<0.20 on univariable analysis and variables that were considered clinically important were included in the multivariable models to assess the adjusted association between diastolic hypotension and postoperative hospital stay.

Statistical analyses were performed using SPSS 25.0 software (IBM SPSS, Chicago, IL) and the free software package “R” (version 2.15.3), including the “Matchit” and “ROC” plug-ins. A two-sided P<0.05 was considered statistically significant.

Results Patient Recruitment

From April 1, 2015, to October 30, 2018, a total of 943 patients underwent surgery for gastric cancer. After data review, 10 patients were excluded, including 8 who underwent reoperation for recurrence of gastric cancer and 2 for whom data were missing (1 was missing pathological cancer stage and 1 was missing tumor differentiation grade). The remaining 933 patients were included in the final analysis: 676 with diastolic hypotension, with a median (IQR) duration of DBP <60 mmHg for 45 (25–65) min, and 257 without diastolic hypotension. After propensity score matching, 246 patients remained in each group (Table 1, Figure 1).

Table 1 Baseline and Perioperative Data and the Results of Propensity Score Matching

Figure 1 Flowchart of the study.

Baseline and Perioperative Data

In the full cohort, patients with diastolic hypotension were older, more likely to be male, and had higher pTNM stage, compared with patients without diastolic hypotension. The following variables were also more frequent among patients with diastolic hypotension: hypoproteinemia (albumin <35 g/L), total gastrectomy, receipt of inhalation anesthesia and inhalational isoflurane, receipt of vasopressors, and intraoperative SBP <90 mmHg for >10 min. In addition, patients with diastolic hypotension were less likely to receive propofol/etoposide and received a lower median volume of intraoperative blood transfusion, a lower median dose of perioperative glucocorticoids, and a higher median volume of intraoperative crystalloids. After propensity score matching, there were no statistically significant differences between the two groups (Table 1; Supplement Tables 13).

Postoperative outcomes

In both the full and the matched cohort, diastolic hypotension was associated with longer postoperative hospital stay (full cohort: mean 14.5 ± standard deviation 10.2 vs 11.6 ± 6.5 days, P<0.001; matched cohort: 13.7 ± 9.9 vs 11.7 ± 6.6 days, P=0.009) and a higher incidence of postoperative complications (full cohort: 170 [25.1%] vs 27 [10.5%] cases, P<0.001; matched cohort: 60 [24.4%] vs 33 [13.4%] cases, P=0.003).

For specific postoperative complications, diastolic hypotension was associated with a higher incidence of postoperative surgical site infections (full cohort: 70 [10.4%] vs 89 [3.1%], P<0.001; matched cohort: 23 [9.3%] vs 7 [2.8%], P=0.004), respiratory infections (full cohort: 47 [7.0%] vs 5 [1.9%], P=0.002; matched cohort: 16 [6.5%] vs 5 [2.0%], P=0.024), and anastomotic leakage (full cohort: 31 [4.6%] vs 1 [0.4%], P<0.001; matched cohort: 13 [5.3%] vs 1 [0.4%], P=0.002) in both the full and the matched cohort. In the full cohort, diastolic hypotension was associated with a higher incidence of postoperative renal injury (11 [1.6%] vs 0 [0%], P=0.041); this association was not present in the matched cohort (2 [0.8%] vs 0 [0%], P=0.499). Other complications were not statistically significantly different on the basis of diastolic hypotension (Table 2).

Table 2 Postoperative Outcomes

Intraoperative Diastolic Hypotension and Postoperative Hospital Stay

The median length of postoperative hospital stay was 11 days. Prolonged postoperative hospital stay was defined as >11 days. Multivariate logistic regression analysis was used to analysis the relationships between length of postoperative hospital stay and potential risk factors. LOS>11 days was used as a dependent variable. For the full cohort, 17 factors were included in the multivariable logistic model, including 14 factors with P<0.20 on univariable analysis (diastolic hypotension, age, history of hypertension, history of diabetes, preoperative hypoproteinemia, ASA grade, pTNM stage, range of gastrectomy, duration of surgery, type of procedure, use of vasopressors, dose of perioperative opioids, intraoperative crystalloids infusion, and intraoperative artificial colloid infusion) and 3 factors that were considered to be clinically important (P<0.20 in matched cohort, including use of etomidate, use of nitroglycerin, and intraoperative SBP <90 mmHg for >10 min).

After correction for confounding factors, intraoperative diastolic hypotension was associated with longer postoperative hospital stay (HR, 1.535 [95% CI, 1.115–2.114], P=0.009). Among other factors, older age, preoperative hypoproteinemia, total gastrectomy, longer duration of surgery, open surgery, higher perioperative opioids dose, and higher volume of intraoperative artificial colloid infusion were associated with longer postoperative hospital stay (Table 3).

Table 3 Risk Factors for Longer Postoperative Hospital Stay After Elective Surgery for Gastric Cancer: Univariable and Multivariable Logistic Regression Analyses (Full Cohort)

In the matched cohort, 17 factors were included in the multivariable model, including 14 with P<0.20 on univariable analysis (diastolic hypotension, age, history of hypertension, history of diabetes, preoperative hypoproteinemia, ASA grade, range of gastrectomy, duration of surgery, type of procedure, dose of perioperative opioids, intraoperative crystalloids infusion, intraoperative artificial colloid infusion, use of etomidate, and use of nitroglycerin) and 3 that were considered to be clinically important (P<0.20 in full cohort, including pTNM stage, use of vasopressors, and intraoperative SBP <90 mmHg for >10 min).

After correction for confounding factors, intraoperative diastolic hypotension was associated with longer postoperative hospital stay (HR, 1.532 [95% CI, 1.032–2.273], P=0.034). Among other factors, older age, preoperative hypoproteinemia, total gastrectomy, open surgery, no use of etomidate and higher volume of intraoperative artificial colloid infusion were associated with longer postoperative hospital stay (Table 4).

Table 4 Risk Factors for Longer Postoperative Hospital Stay After Elective Surgery for Gastric Cancer: Univariable and Multivariable Logistic Regression Analyses (Matched Cohort)

Discussion

In this retrospective study that included propensity score matching, 933 patients were enrolled, of whom 676 had intraoperative diastolic hypotension (defined as DBP <60 mmHg for >10 min), with a median (IQR) duration of DBP <60 mmHg for 45 (25–65) min. The incidence of intraoperative diastolic hypotension in the present study was high (72.5%), but it was in line with another retrospective cohort analysis, aiming to explore the associations of intraoperative radial arterial systolic, diastolic, mean, and pulse pressures with myocardial and acute kidney injury after noncardiac surgery,23 which implied that intraoperative hypotension maybe not a rare thing in our clinical practice. However, most studies on the impact of perioperative hemodynamic fluctuations on postoperative recovery had focused on SBP and MAP, with few studies on DBP,10 that’s also why the present study trying to investigate the significance of intraoperative diastolic hypotension on postoperative recovery.

We chose length of postoperative hospital stay as the primary outcome to comprehensively evaluate the effect of intraoperative diastolic hypotension on postoperative recovery. Length of hospital stay is one of the key performance indicators for hospital management and efficiency of the health care system.23,24 Previous studies have shown that intraoperative hypotension (MAP <60 mmHg for >10 min or MAP <70 mmHg and a decrease in MAP >30% from the baseline value for >10 min) is a risk factor for postoperative complications and may be associated with prolonged hospitalization and worse outcomes in patients who have undergone elective major abdominal surgery.25 But there were rare studies focusing on the relationship between intraoperative diastolic hypotension and postoperative hospital stay. In the present study, patients with diastolic hypotension had longer postoperative hospital stay than patients without diastolic hypotension, and after correction for confounding factors, intraoperative diastolic hypotension was associated with longer postoperative hospital stay in both the full and the matched cohort, while systolic hypotension was not an independent factor for more extended hospital stay in the present study.

Previous studies have shown that DBP below a certain threshold may be associated with adverse outcomes, including a higher incidence of coronary events, stroke, heart failure, and all-cause mortality.26–28 Possible mechanisms underlying this association include lower endocardial perfusion leading to coronary events or coronary stenosis limiting blood flow.29,30 While some studies also have found that DBP <60 mmHg was not associated with myocardial infarction, acute coronary syndrome without myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes.11 In the present study, although the incidence of postoperative complications was higher among patients with diastolic hypotension, the incidence of coronary events or stroke was not statistically significantly different on the basis of hypotension. The lack of a detected difference may be attributable to the low incidence of coronary events or stroke among enrolled patients (stroke, n=5 [0.5%]; coronary heart disease, n=11 [1.2%]) and the small sample size.

Other studies have shown that ischemia and reperfusion injury can be associated with postoperative acute renal injury.7 In the present study, in the full cohort, the incidence of postoperative renal injury was statistically significantly higher among patients with intraoperative hypotension, but no statistically significant difference was observed between the two groups in the matched cohort, which may be related to the low incidence of renal injury among the patients in the matched cohort (n=2 [0.8%]) and the small sample size.

Adequate blood pressure is important for proper wound perfusion. Although perioperative hypotension occurs for a short time, it may still can cause adverse outcomes, as previous work has shown that, it is the lowest tissue oxygen saturation, rather than overall mean oxygenation, that is associated with serious complications.31,32 In the present study, we found that in both the full and the matched cohort, patients with diastolic hypotension had a higher incidence of postoperative surgical site infections, respiratory infections, and postoperative anastomotic leakage, compared with patients without diastolic hypotension. That is in line with previous researches which have shown that intraoperative hypotension may be associated with postoperative surgical site infections and other infectious complications.25,33 Another retrospective study also found that perioperative hypotension was an independent predictor of postoperative infectious complications in patients with colon cancer.34,35

In addition, in the present study, other factors, such as older age, preoperative hypoproteinemia, total gastrectomy, longer duration of surgery, open surgery, higher dose of perioperative opioids, and higher volume of intraoperative artificial colloid infusion, were statistically significantly associated with longer postoperative hospital stay, which is consistent with the findings of previous studies.36,37 For instance, another retrospective study performed on 2033 patients who underwent gastric surgery also found that, age, surgical procedure, extent of resection, degree of incision healing, and perioperative blood transfusion are the independent risk factors for prolonged postoperative LOS.38 But as for the association between higher dose of perioperative opioids/higher volume of intraoperative artificial colloid infusion and longer postoperative hospital stay, the OR in the present study was of very low level of significance, so further studies are still needed.

The present study has limitations beyond those normally associated with retrospective studies. In previous studies, it has been suggested that general anesthesia combined with epidural anesthesia may improve postoperative recovery, compared with general anesthesia alone.39 However, in the present study, only 2 (0.2%) patients received general anesthesia combined with epidural anesthesia, and the effect of this factor on postoperative recovery is not known. What’ more, as for the sample size calculation, retrospective studies cannot accurately estimate sample size, so we included all patients underwent surgery for gastric cancer from April 1, 2015, to October 30, 2018. Thirdly, the present study is a single-center study, so the scope of application of the results may be limited.

Conclusion

For patients with gastric cancer, intraoperative diastolic hypotension (DBP <60 mmHg for >10 min) was associated with a higher incidence of postoperative complications and longer postoperative hospital stay. Considering the high incidence of intraoperative diastolic hypotension, prospective studies are urgently needed to clarify its effect on patients’ recovery after gastric cancer surgery.

Data Sharing Statement

The data sets used and/or analyzed in the present study are available from the corresponding author on reasonable request.

Ethics Approval

The study protocol was approved by the clinical research ethics committee of Peking University Cancer Hospital (Approval No. 2018YJZ71). As the study was observational, the ethics committee waived the requirement for written informed consent. During the study period, the patient’s name, gender and other personal data will be replaced by codes or numbers, and will be strictly confidential. Only the relevant doctors know their data, and the patient’s privacy will be well protected. When the research results are published, no personal information of patients will be disclosed.

Acknowledgments

The authors gratefully acknowledge Zi-Yu Li, MD (Professor, the First Department of Gastrointestinal Surgery, Peking University Cancer Hospital, Beijing, China) for his help with data collection.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work.

Funding

There is no funding to report.

Disclosure

The authors declare that they have no conflicts of interest in this work.

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