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Anca Dragan1, Ioanel Sinescu2,3

1 „Prof. Dr. C. C. Iliescu” Emergency Institute for Cardiovascular Diseases, Bucharest, Romania
2 Department of Urology, Fundeni Clinical Institute, Bucharest, Romania
3 „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Abstract: Objectives – Surgical treatment with extracorporeal circulation represents often the only therapeutic option in patients with renal tumours with cavo-atrial venous extension. Intraoperative hypotension occurs in such surgical ope-rations involving both signifi cant blood loss and eventual embolic events. Its influence on the subsequent evolution of the patient depends on its level and duration. This study aims to identify the impact of prolonged intraoperative hypotension on postoperative outcome quntifi cated by the occurrence of severe complications (organ dysfunction and death), postoperati-ve Acute Kidney Injury stage 3 (AKI 3) and neurological complications. Methods – The retrospective study included all the patients who underwent the complex surgery of radical nephrectomy with cavo-atrial thrombectomy under extracorporeal circulation in Prof. C.C. Iliescu Emergency Institute for Cardiovascular Diseases in Bucharest during 2004-2018. The medi-cal records have been studied, after obtaining the approval of the ethical commitee of the institution regarding this study. The pacients who died intraoperatively were excluded from the statistical analysis. Prolonged intraoperative hypotension was defined as mean intraoperative blood pressure below 60 mm Hg for more than 20 cumulated minutes (pre-, intra- and post-extracorporeal circulation). Postoperative complications were graded according to Clavien Dindo classification, acute postoperative renal injury according to Kidney Disease Improving Global Outcomes (KDIGO) criteria and neurological complications included postoperative encephalopathy and acute stroke. Results – There were identified 30 consecutive patients undergoing nephrectomy with cavo-atrial thrombectomy using extracorporeal circulation. Only 28 patients were included in the study because there were two intraoperative death. Aplying Fisher exact test in the 2×2 contingency tables we found out that the presence of prolong intraoperative hypotension was associated with postoperative organ dysfunction and death (Clavien Dindo IV and V), but also with postoperative AKI 3 and neurological complications. Conclusion – Pro-longed intraoperative hypotension correlates with severe postoperative complications. At the same time, it represents a risk factor in the occurrence of postoperative AKI 3 and neurological complications. That is why the medical team has to work together to minimize and reduce the duration of intraoperative hypotension.

Keywords: acute renal injury, arterial hypotension, neurological complications, severe complications.

INTRODUCTION
The prevalence of kidney cancer is low1,2. Approxi-mately 80% of these are renal cell carcinomas2. Some of them have venous extensions, including infra- or supradiaphragmatic inferior vena cava level or even in right atrium-1% of cases3. Their treatment consists in surgical intervention that aims at removing the pri-mary tumor, as well as its extension. In the case of the supradiaphragmatic venous extension, with or without the involvement of the right atrium, surgical intervention involves excision of the involved kidney together with the tumor, but also the removal of the venous extension under extracorporeal circulation, with or without cross-clamping the ascending aorta, arresting the heart, in normothermia or moderate hypothermia. These complex surgeries involve an en-tire multidisciplinary team: urologists, surgeons, cardi-ac surgeons, anesthetists and intensive care physicians, cardiologists, perfusionists.
Major intraoperative risks are massive bleeding, but also embolic events with dramatic consequences. Thus, this study aims to identify the impact of pro-longed intraoperative hypotension, defined as intra-operative mean blood pressure below 60 mmHg for more than 20 minutes during the pre-, intra- and post-cardiopulmonary bypass period, on the postoperative outcome: occurrence of postoperative severe compli-cations (Clavien Dindo IV and V), postoperative AKI3 and neurological complications. The Clavien-Dindo classifi cation4 (Table1) is recommended and validated by the European Association of Urology as a standardized reporting method for postoperative complications5.

PATIENTS AND METHODS
The retrospective study included all the patients who underwent complex surgery (radical nephrectomy with extraction of the venous thrombus under extra-corporeal circulation) in Prof. C.C. Iliescu Emergen-cy Institute for Cardiovascular Diseases in Bucharest during 2004-2018. The pacients who died intraope-ratively were excluded from the study, because the endpoints are represented by postoperative complications.
The patients were previously diagnosed clinically and imagistically (echocardiography, computer tomo-graphy or magnetic resonance imaging, transesopha-geal echocardiography) with kidney tumor with veno-us extension in the supradiaphagmatic inferior vena cava and/or at atrial level by the urologists. Surgery is performed under general anesthesia with orotrache-al intubation, with advanced noninvasive and invasive intraoperative monitoring, having at hand blood pro-ducts, but also rapid infusion and cell saver devices for life-threatening bleeding. Transesophageal echocar-diography was used for the location and description of venous thrombus in the inferior vena cava or right atrium during the intraoperative period, prior to initi-ating cardiopulmonary bypass, as well as for monito-ring the patient after weaning from extracorporeal cir-culation, to highlight any possible remaining thrombi or possible embolization. The surgical interventions involved a mixed team: urologists, cardiac surgeons, anesthetists, perfusionists. The data, including mean arterial pressure measured using an intraarterial ca-theter, was recorded manually in the intraanesthetic monitoring charts at every 5-15 minutes, depending on the anesthetist. Postoperatively, the pacients were transported in ICU.
The study was performed with the approval of the ethical commitee of the institution in order to per-form this retrospective study. The medical records were analyzed.
Prolonged intraoperative hypotension was defined in this study as the presence of a mean intraoperative blood pressure below 60 mm Hg for more than 20 minutes, cumulatively pre-, intra- and post-extracor-poreal circulation.
For the quantification of postoperative complicati-ons, the Clavien-Dindo classification4 was used. Those graded IV and V in Clavien Dindo classification were considered in this study severe postoperative complications.
Post-operative acute kidney injury was diagnosed (Table 2) and staged (Table 3) according to KDIGO criteria6, while postoperative neurological complicati-ons were diagnosed as postoperative encephalopathy (clinical diagnosis made by the intensivist and recor-ded in the medical sheets) or as a vascular accident (clinical and imaging diagnosis).

STATISTICAL ANALYSIS
The statistical analysis was performed using the IBM SPSS Statistics 20 software. The quantitative variables are expressed by mean and standard deviation. The grade of postoperative complications and postoperati-ve AKI grade are ordinal variables. The data represen-ting the number of patients with or without prolon-ged intraoperative hypotension was presented in 2×2 contingency tables, as a function of the occurrence or not of severe postoperative complications, AKI 3 or postoperative neurological complications. In order to identify the statistical association of the category va-riables, we used the Fisher exact test, as it was not possible to use the Chi square test. This is because the contingency tables do not meet the requirement that the expected values should be more than 5 in more than 80% of the cells7,8. The degree of associa-tion between variables is done using the Cramer test and the Odds ratio7,8. Relative risk was also calculated. The Kendall tau test was used to test the statistical correlation between the category variables or betwe-en the category variable and the ordinal variables. The threshold of statistical signifi cance is 95% (p <0.05).

RESULTS
There were identified 30 consecutive patients who underwent radical nephrectomy with extraction of the venous thrombus under extracorporeal circulati-on in Prof. C.C. Iliescu Emergency Institute for Car-diovascular Diseases in Bucharest during 2004-2018. Intraoperatively, there were two deaths: one patient with massive intraoperative bleeding and one patient with major pulmonary embolism. Thus, only 28 of the pacients were analyzed in this study. Postoperatively, there were another four deaths (one patient with enteric infarction, two with multiple organ dysfunction and one patient with major bleeding).
The 28 patients aged 57.29+/-9.85 years old had the preoperative characteristics presented in table 4. The intraoperative data is presented in table 5.
The postoperative complications of the 28 surgery survivors graded through the Clavien Dindo classifica-tion are exemplified in the following table (Table 6).
Prolonged intraoperative hypotension was found in the case of 11(39.28%) patients. Vassopressors were used in 26 (92.85%) pacients, with higher doses and longer duration in the case of patients with prolong intraoperative hypotension. The following contingen-cy table 2×2 presents the number of pacients with or without prolong intraoperative hypotension in the 2 groups of patients classified according to postoperati-ve complications graded Clavien Dindo.
Between the two variables, namely the presence of prolonged intraoperative hypotension and the occur-rence of severe postoperative complications (graded IV and V in Clavien Dindo classification) there is an association relationship (p =0.001 exact Fisher test). The strong intensity of this relationship is given by the Cramer test (coefficient V 0.781, p = 0.0 01), but also the odds ratio OR=75 (CI 95%: 5.973, 941.79). The relative risk is 8.18. Kendall tau b correlation coeffici-ent is 0.652 (p=0.001).
Postoperative acute kidney injury was present in 26 (92.85%) patients, but only 9 (32.14%) had AKI 3 renal injuries. (Table 8).
The relationship between prolonged intraoperative hypotension and the occurrence of acute kidney injury AKI 3 is illustrated in the contingency table 2×2 (Table 9).
Fisher’s exact test shows that the two variables, in this case, the presence of prolonged intraoperative hypotension and the postoperative occurrence of AKI 3 are dependent variables (p= 0.01). The Odds ratio is OR=13.12 (CI 95%: 1.924, 89.515) and the Cramer coefficient is 0.542 (p = 0.004), measuring this associ-ation as a medium-intensity one. The relative risk was 3.69. The correlation coefficient Kendall tau b is 0.542 (p = 0.005).
Regarding postoperative neurological complicati-ons, these were found in 7 (25%) patients, 2 of whom had a stroke diagnosed by imaging, while the rest had postoperative encephalopathy. The contingency table 2×2 below (Table 10) identifies patients considering 2 criteria: prolonged intraoperative hypotension as defi-ned by the study, and the occurrence of postoperative neurological complications.
The two variables, prolonged intraoperative hypo-tension and the occurrence of postoperative neuro-logical complications are dependent variables (p = 0.007, Fisher exact test). The intensity of the asso-ciation between the variables is measured with Cra-mer coefficient of 0.549 (p= 0.004) and odds ratio OR=19.20 (CI 95%: 1.844, 199.937). Relative risk is 9.27. The correlation coefficient Kendall tau b is 0.549 (p=0.004).

DISCUSSION
Our study found a strong association between the in-traoperative prolong hypotension and the occurrence of severe postoperative complications (Clavien-Din-do IV and V), postoperative AKI3 and postoperative neurological complications. Intraoperative prolong hypotension was defi ned as intraoperative mean ar-terial blood pressure below 60 mmHg for a duration greater than 20 minutes (cumulatively pre-, intra- and post- cardiopulmonary bypass).
Surgery to remove kidney tumors with venous ex-tensions in the supradiaphragmatic inferior vena cava and/or in the right atrium level represents a major surgical intervention of a fairly high duration (6-8 ho-urs), involving extracorporeal circulation, signifi cant blood loss, embolic events, with major haemodyna-mic manifestations and hypotension. Early detection of the haemodynamic changes and a good venous access are mandatory9. The monitoring of the intraoperative hypotension is essential because its magnitude, expre-ssed by value and duration, influences organ perfusion and consequently the postoperative evolution of the patients. The use of cardiopulmonary by-pass, which is often used in such surgery, seems to be safe from an oncologic perspective, but is known to be associa-ted with the risk of bleeding, coagulopathy and longer operating times10.
The complexity of the diagnostic and surgery treat-ment in these cases was discussed in the Romani-an medical literature by Sinescu et al.11, emphasizing the importance of haemodinamic monitoring, without showing the impact of prolong intraoperative hypo-tension on postoperative outcome.
The radical nephrectomy with thrombectomy has been shown to be associated with major perioperative morbidity (up to 70%) and mortality (3-16%)12. The review of Gaudani et al. in 2016 finds surgical risk to be substantial in these cases, with in-hospital morta-lity up to 40% and postoperative complications in up to 47% of cases3. International Renal Cell Carcinoma-Venous Thrombus Consortium identified the factors infl uencing perioperative mortality: patient comorbi-dities, performans status, distant metastatic spreading and the extent of the tumour thrombus above the diaphragm12. However, the impact of intraoperative haemodynamic changes or hypotension have not been studied in the medical literature regarding this kind of surgery.
This study showed the association of the intrao-perative hypotension with the prognostic in the case of patients with radical nephrectomy with throm-bectomy. The team work is important, but also the haemodynamic monitoring and the action aswell. The medical team’s attention should be focused mainly on mitigating this risk factor by minimizing intraoperati-ve blood loss, avoiding embolic phenomena, achieving adequate volume replacement, using vasopressor or inotropic medication as needed to avoid hypotension episodes as much as possible and limit their duration. Reducing intraoperative hypotension and limitation of exposure to nephrotoxic agents seems to be more cheap and effective in limiting AKI than any other method13.
The use of the 5Ts in perioperative goal directed haemodynamic therapy was proposed by a recent edi-torial14: target population, timing of intervention, type of intervention, target variable, target value. Thus, hi-gh-risk patients have to be selected (target populati-on)14. Haemodynamic optimization should start before induction of general anaesthesia (timing of interven-tion)14. The editorial proposes different types of in-terventions: volume replacement, vassopressors and inotrops and the target variables has to be personali-zed. The team should focus on the dynamic and static preload variables, but mainly on the variables reflec-ting blood fl ow14. The patients undergoing surgery to remove kidney tumour together with its high venous extension are high risk patients because of the signi-ficant blood loss, embolic events and comorbidities. Echocardiography provides also important diagnostic information and can modify surgical management, especially when an atrial thombus is identified15.
The importance of intraoperative hypotension is highlighted in the literature. Althought intraopera-tive hypotension, a common occurrence in general anesthesia, is recognized to be involved in inadequa-te organ perfusion, the literature is not consistent in defi ning intraoperative arterial hypotension. In 2007, there were identified 140 different definitions fromn130 studies16. Classically, it was defined as a function of the patient’s preoperative blood pressure values, accepting an intraoperative blood pressure within a 20% margin from the preoperative blood pressure va-lues of the patient17. However, more recent studies have discussed various definitions of intraoperative hypotension, in terms of mean or systolic blood pre-ssure, absolute value or relative to baseline values. In-traoperative blood pressure as a risk factor is easy to measure and control17. The review of Wesselink et al. concludes that organ injury occurs when mean arterial pressure drops below 80 mm Hg for more than 10 minutes, and that this risk increases as blood pressu-re decreases18. Another study found that mean blood pressure below 60 mm Hg for more than 20 minutes and mean blood pressure below 55 mm Hg for more than 10 minutes are risk factors for postoperative acu-te kidney injury in noncardiac surgery19. Salmasi et al. analysed retrospectively a large cohort of pacients also in noncardiac surgery and concluded that mean blood pressure under 65 mm Hg or relative thresholds of 30% from the baseline were related to myocardial and kidney injury20. In cardiac surgery, postoperative acute kidney injury occurs in nearly 30% of interventions, severe acute kidney injuries occurring in about 2-5%, with an associated mortality of 50%21. Regarding the effect of intraoperative hypotension on neurological function, Drummond et al. showed that the mean of the lowest limit of arterial blood pressure at which cerebral fl ow autoregulation takes place in normoten-sive adults is no less than 70 mmHg22. The average of the mean blood pressure limit at which cerebral ischemic symptoms are established is 40-50 mmHg at Willis’s polygon in normotensives in the vertical posi-tion and 45-55 mmHg with the patient in dorsal decu-bitus which corresponds to an mean blood pressure of 65-70 mmHg22.
Hypotension is proved to be also associated with 30 day mortality23. Studies showed that maintaining the mean arterial pressure above 60-70 mm Hg is more important than avoiding blood pressure variability23. Moreover, the duration of hypotension is strongly en-volved in organ-specific injury24.
In 2019, the Perioperative Quality Initiative publi-shed a consensus statement on intraoperative blood pressure. This established that mean arterial pressure below 60-70 mm Hg during surgery is associated with myocardial injury, acute kidney injury and death, injury being a function of hypotension severity and durati-on25.
Thus, the medical literature points to the fact that intraoperative hypotension is associated with posto-perative complications, both in cardiac and noncar-diac surgery. Our study refers to the patients who underwent a combined surgery: radical nephrectomy with thombectomy using extracorporeal circulation. We showed that prolong intraoperative hypotension is strongly associated with organ dysfunction, death, postoperative AKI 3 and postoperative neurological complications.
The limitations of the study are given by the fact that it is retrospective, with a relatively small number of patients included, operated in our center. This was, however, to be expected, given the low incidence of the diagnostic. Another limitation is represented by the intermitent manual intraoperative records of the mean arterial pressure, despite the continuously mean arterial pressure measurement via an arterial catheter. The proved association between prolong intraoperati-ve hypotension and postoperative outcome is relevant only in our medical center and only for the type of surgery described, due to the limitations of the study. The results need to be validated in a multicenter pro-spective study.

CONCLUSION
Prolonged intraoperative hypotension, defi ned as mean blood pressure below 60 mm Hg for more than 20 minutes (calculated cumulatively pre-, intra- and post-extracorporeal circulation) was associated with the occurrence of severe postoperative complications (Clavien Dindo IV and V), neurological complications and severe postoperative acute kidney injury (AKI3). The medical team should work together to reduce the length of hypotension that is inherent to this surgery, in order to minimize its postoperative impact.

Conflict of interest: none declared.

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