High Intraoperative Pulse Pressure Is A Risk Factor For A Postoperative Organ Injury In A Cohort of Abdominal Surgery Patients: An Exploratory Study


 Background: Both intraoperative hypotension and hypertension have been reported to increase the occurrence of either acute kidney injury (AKI), myocardial infraction (MI) or stroke. However, intraoperative pulse pressure’s (PP) impact on the latter complications remains relatively unknown.Methods: This is a cohort study in which patients who underwent abdominal surgery between 1 October 2018 and 15 July 2019 in university hospital in Katowice were included in the analysis. Pre- and intraoperative data, including blood pressure measurements, were acquired via medical charts. Several PP thresholds were applied: >50, >55, >60, >65, >70, >75, >80, >85, >90 mmHg. Additionally, by analysing the maximal PP during procedures, a cut-off point for the occurrence of outcomes was estimated. Postoperative complications were defined as occurrence of either AKI, MI or stroke. Univariable and multivariable analyses were performed to assess PP’s relationship with hypoperfusive organ injury.Results: 508 patients were included in the analysis. Hypoperfusion was present in 38 (7.5%) cases. ROC curve analysis estimated a cut-off point of > 74 mmHg of maximal PP to be associated with the outcomes. PP values above 65 mmHg onward were included in the multivariable statistical models. A model in which PP > 90 mmHg (OR=4.21; 95%CI 1.73-10.24; p=0.0015) was included, had the best predicting value in predicting hypoperfusive injury. Apart of PP, intraoperative hypotension, presence of chronic arterial hypertension and procedure duration were independently associated with postoperative complications. Conclusions: High intraoperative pulse pressure may be associated with the occurrence of hypoperfusion-related organ injury. However, the effect of high pulse pressure should be confirmed in other non-cardiac populations to prove generalizability of our results.

Although ambulatory pulse pressure (PP) is considered as one of the best predictors of cardiovascular risk [6] it has been poorly investigated in the perioperative period. The association between high preoperative PP values and the relationship with postoperative complications (mainly myocardial infraction, acute kidney injury and stroke) has been explored mostly in cardiosurgical patient populations.
POQI has called for further research on the matter in non-cardiac surgery [7]. Therefore, in an exploratory fashion, we sought to verify whether elevated intraoperative PP values are associated with hypoperfusion-related organ injury in abdominal surgery.

Methods
The data used in this study comes from a prospective cohort study published previously by our team [8].
We screened 576 consecutive patients who underwent abdominal surgery between 1 October 2018 and 15 July 2019 in a university hospital. Procedures of organ procurement (n = 11), reoperations (n = 24), procedures performed in local anaesthesia or monitored anaesthetic supervision (n = 33), and those classi ed as immediate according to the NCEPOD Classi cation of Intervention [9] (n = 14) were excluded ( Fig. 1). Demographic and medical data were recorded, including sex, age, weigh, height, comorbidities and its pharmacological treatment, according to the ICD 10 criteria. Body mass index (BMI) and Charlson Comorbidity Index (CCI) were subsequently calculated. Type and duration of anaesthesia, and type, duration and urgency of surgery were recorded. Perioperative risk was assessed based on individual patient's risk, according to the American Society of Anaesthesiology (ASA) physical status (PS) classi cation [10], and procedural risk, according to the European Society of Cardiology and European Society of Anaesthesiology recommendations [11]. Primary arterial hypertension was diagnosed based on medical records. Systolic (SBP) and diastolic blood pressure (DBP) were measured on a non-dominant arm with an automated oscillometric non-invasive BP monitoring device (Dräger In nity Gamma XL) with a cuff of appropriate size depending on patient's arm circumference and recorded in ve-minute intervals during anaesthesia, from the rst pre-induction measurement until the last measurement during recovery from anaesthesia in the operating theatre. Mean (MAP) blood pressure values were automatically calculated.
Pulse pressure was calculated as the difference between SBP and DBP. A need for norepinephrine (NE) use, its doses and duration of infusion, together with intraoperative uid balance were analysed.
As PP revolves usually around values of 40 mmHg and that, based on other studies on clinical consequences of abnormal PP, we distinguished the following absolute PP thresholds: >50 mmHg, > 55 mmHg, > 60 mmHg, > 65 mmHg, > 70 mmHg, > 75 mmHg, > 80 mmHg, > 85 mmHg and > 90 mmHg [5,[12][13][14]. Additionally, by analysing the maximal PP during a procedure, the best cut-off point associated with the occurrence of outcomes was estimated. Moreover, we analysed the occurrence of high systolic (de ned as SBP > 160 mmHg [15]), low diastolic (de ned as DBP < 50 mmHg [16]) and low mean arterial pressure (de ned as MAP < 60 mmHg [17]. We excluded pre-induction measurements in order to assess only those blood pressure values that occurred during anaesthesia.
In the postoperative period, the incidents of hypoperfusion of vital organs were recorded, and included the occurrence of AKI, stroke and MI according to their international de nitions [18][19][20]. This composite endpoint was considered as the outcome.

Results
Total number of patients included in the analysis was 508, 239 (46%) were male. The median age of participants was 65 years (IQR 46-68). The majority (90.4%) of subjects underwent elective surgery.
Older age, higher ASA-PS class, higher CCI were found to be signi cant preoperative risk factors for occurrence of hypoperfusion outcome. Detailed preoperative population characteristics are presented on Table 1, whereas intraoperative population characteristics are presented on Table 2. The composite primary outcome was diagnosed in 38 (7.5%) patients, including 32 cases of AKI (6.3%), 3 cases of MI (0.6%) and one event of stroke (0.2%). Pre-induction PP was not associated with the outcome (Table 1). STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) statement was applied for appropriate reporting [21].
Statistical analysis was performed using MedCalc Statistical Software version 18.1 (MedCalc Software Ltd., Ostend, Belgium). Continuous variables were expressed as median and interquartile range (IQR). Qualitative variables were expressed as absolute values and/or percent. Between-group differences for quantitative variables were assessed using Mann-Whitney U-test. Their distribution was veri ed with Shapiro-Wilk test. Chi-square test were applied for qualitative variables. The correlation was assessed using Spearman's rank correlation coe cient. ROC curve analysis was implemented to assess the relationship between composite outcome and maximal PP values and pre-induction PP values. In order to control for potential confounding factors, we used multivariable logistic regression with all variables that achieved p-value of less than 0.1 in univariable analysis. If applicable, odds ratios (OR) and Area Under the Receiver Operating Characteristics (AUROC) with their 95% con dence intervals (CI) were calculated. All tests were two-tailed. A 'p' value < 0.05 was considered statistically signi cant.      In patients who developed hypoperfusion-related organ injury, PP negatively correlated with DBP than patients without postoperative complications (Table 3). Maximal PP registered over the course of procedure was associated with the outcome (AUROC = 0.75; p < 0.001), with a cut-off point of > 74 mmHg (Fig. 2). In univariable analyses, all PP thresholds, except from > 50 mmHg, were statistically signi cant predictors of hypoperfusion (Fig. 3). In multivariable logistic regressions, PP > 50 mmHg, > 55 mmHg and > 60 mmHg were not included in the nal statistical models. It was discovered that PP above 90 mmHg predicted hypoperfusion-related organ injury with the highest accuracy, even after adjustment for intraoperative hypertension (Table 4). Low DBP (< 50 mmHg) and high SBP (> 160 mmHg) were not signi cant in the multivariable models. Values are presented as odds ratios (con dence intervals) and their 'p' values.

Discussion
The main nding of our exploratory study is that increasing intraoperative values of pulse pressure were associated with the occurrence of hypoperfusion-related organ injury. This association persisted after adjusting for confounding factors (most importantly: high SBP and low DBP). We found a cut-off point of > 74 mmHg of maximal PP to be associated with the outcomes. In regards to the dichotomous thresholds, PP above 65 mmHg and onward was linked to hypoperfusion. Pulse pressure above 90 mmHg, out of all PP thresholds applied, appeared to be the best predictor of hypoperfusion-related organ injury.
To our knowledge, this is the rst study investigating the role of intraoperative pulse pressure in abdominal surgery in such a complex manner. It is known that increased ambulatory pulse pressure is strongly associated with cardiovascular events not only in general population but also in cardiac-surgery setting, irrespectively of the presence of chronic arterial hypertension [6, 22,23]. Pulse pressure stands as a proxy for general vascular health and re ects cardiovascular risk better than isolated measurements of either systolic or diastolic pressure [24]. Generally, a value of PP is determined by stroke volume, left ventricle contractility and arterial compliance. Interestingly, pre-induction pulse pressure values (a re ection of baseline pulse pressure) alone were not signi cantly related to the outcome. In Abbot's and Mitrer's studies, it was found that increasing values of ambulatory and pre-induction PP values were signi cantly related to the increased occurrence of postoperative MI and AKI [5,25]. It must be remembered, however, that those studies were performed among cardiac surgery patients with preexisting cardiac morbidities and the effect of preoperative pulse pressure might be more signi cant than in the non-cardiac setting. The fact that in our cohort pre-induction PP was not associated with hypoperfusion gave us more space to explore the impact of intraoperative values. Nevertheless, intraoperative PP positively correlated with pre-induction values. What's especially interesting, the negative correlation between pulse pressure and diastolic pressure was two times stronger in patients with the compromised outcome. Lowered DBP is known to decrease coronary perfusion and can could be associated with the development of AKI [15,26,27].
We discovered that patients who experienced hypoperfusive outcome, exhibited higher values of PP and the odds ratios varied, depending on the threshold applied.  [31].
What is also worth mentioning is that increased PP causes aortic lumen to decrease which results in ventricular-aortic decoupling characterized by cardiac output that is too great to be accommodated by aortic lumen (leading to impaired cardiac output with preserved systolic function) [5,32].
Above mentioned ndings should be analysed with caution due to possible confounders. Firstly, the true association between high intraoperative pulse pressure and hypoperfusive outcome is, to certain extent, determined by the preoperative PP values. Despite pre-induction PP was not signi cantly related to the outcome in our analysis, it is possible that intraoperative PP is only a re ection of an overall cardiovascular condition and it does not impair organ perfusion in short-term period (such as duration of surgical procedure). Secondly, a pre-induction blood pressure value was de ned as 'baseline' MAP. It is possible that such measurement does not represent the true 'baseline' as it could be in uenced by stress or premedication. Thirdly, the blood pressure measurements were recorded in 5-minute intervals: a risk of underrecognition of pulse pressure changes exists. Additionally, we did not assess the level of preoperative organ injury that could be a result of e.g. prior chronic arterial hypertension. Moreover, we did not analyse any chronic hypotensive treatment. Finally, our analysis was restricted to a limited population of abdominal patients which reduces the generalizability of our results into all non-cardiac surgery settings.

Conclusions
High intraoperative pulse pressure is associated with hypoperfusion-related organ injury in patients undergoing abdominal surgery. However, the effect of high pulse pressure should be con rmed in other non-cardiac populations to prove generalizability of our results. Flow diagram for the patient selection process