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Excessive intravenous fluid therapy in head and neck cancer surgery Haapio Eeva MD 1, Kinnunen Ilpo MD, PhD 1, Airaksinen Juhani K.E. MD, PhD 2, Irjala Heikki MD, PhD 1, Kiviniemi Tuomas MD, PhD 2 1 Department of Otorhinolaryngology, Turku University Hospital and University of Turku, Turku, Finland. 2 Heart Center, Turku University Hospital and University of Turku, Turku, Finland. Grant support: This study was supported by the Finnish Foundation for Cardiovascular Research, Helsinki, Finland; by State Research Founding (EVO); Kirsti and Tor Johansson Cancer and Heart Foundation, Raasepori, Finland. Corresponding author: Ilpo Kinnunen, MD, PhD Turku University Hospital, Kiinamyllynkatu 4-8 FIN-20521, Turku, Finland, Tel: +, fax: +358 2 3132030 E-mail: [email protected] Key words: perioperative fluid management; red blood cell; transfusion; cardiovascular complication; head and neck cancer Abstract Background: In this retrospective study we sought to assess modifiable perioperative factors for major cardiac and cerebrovascular events (MACCE). Methods: This study included unselected cohort of head and neck patients (n=456) treated in Turku University Hospital between 1999-2008. Results: Peri- and postoperative univariate predictors of MACCE at 30 days follow-up were total amount of fluids (24h) over 4000ml, any red blood cell infusion, treatment in the intensive care unit, tracheostomy and microvascular reconstruction surgery. Median time from operation to MACCE was 3 days. Patients receiving >4000ml fluids had more often MACCE compared to those receiving <4000ml (10.8% vs. 2.4%, p=<0.001, respectively). Moreover, every red blood cell unit transfused; or every liter of fluid administered over 4000ml/24h increased the risk of MACCE 18% per unit/liter, respectively. Conclusion: Head and neck cancer patients receiving excessive intravenous fluid administration peri- and postoperatively are at high risk for cardiac complications, especially heart failure. Introduction Patients undergoing head and neck cancer surgery are at high risk (>5%) to get cardiovascular complications 1 . Comorbidities such as pre-operative coronary artery disease or congestive heart failure are known independent predictors of survival in this patient group 2 3 But less evidence exists about perioperative and postoperative factors that could be modified to prevent cardiac complications in head and neck surgery. Peri- and postoperative care of patients undergoing surgery includes intravenous fluid administration and – in case of anemia or major bleeding red blood cell (RBC) transfusion; - or care in intensive care unit (ICU) and many other measures to insure the best possible outcome. The goal of perioperative fluid administration is often maintenance of euvolemia 4-6 and adequate perfusion pressure to the heart and kidneys. The influence of perioperative fluid administration and red blood cell transfusion on cardiac and cerebrovascular complications, however, is not well documented in this patient group. In this study we sought to assess modifiable perioperative and postoperative factors for major cardiac and cerebrovascular complications (MACCE) in consecutive series of patients undergoing head and neck cancer surgery. Methods The present single-center retrospective study was performed at the tertiary care center at Department of Otorhinolaryngology-head and neck surgery at Turku University Hospital, Finland. The catchments area of the hospital is about 1 million residents and the center takes care of all head and neck cancer patients irrespective of ages and comorbidities. This study was conducted in accordance with the Helsinki declaration as revised in 2002. The study protocol was reviewed and approved by the Ethics Committee of the Hospital District of Southwest Finland. Informed consent was not required because of the registry nature of the study. This registry is part of wider protocol assessing thrombotic and bleeding events in patients undergoing surgery 7, 8 Study is registered in Clinical Trials.gov (identifier NCT02563470). Patients and source of data Inclusion criteria consisted of all the consecutive patients (n=456) diagnosed with head and neck cancer at Turku University Hospital between 1999 and 2008. Patients receiving palliative procedures were included. Patients whose treatment had started in another institute or whose treatment was not finished in our institute were excluded from this study. All head and neck cancer operations (n=591) were evaluated. Information was collected by the first author of this article from referral letters, patient files, anesthesiology reports, intensive care unit reports, laboratory database, radiology database, electrocardiograms and pathology reports. Endpoints The primary endpoints was a composite of major adverse cardiac and cerebrovascular events (MACCE) including acute coronary syndrome ACS), decompensated heart failure, new-onset of atrial fibrillation, transient ischemic attack (TIA), stroke, pulmonary embolism and venous embolism, and all-cause mortality; during 30 days follow-up period. Perioperative myocardial infarction was screened with normal anesthesia monitoring, and if suspected, a troponin level > 3x normal 99th percentile level was required for the diagnosis. ST elevations, ST depressions and T wave inversions were classified according to the guidelines of the European society of Cardiology. Transient ischemic attack (TIA) was defined as a focal transient (<24h) neurological deficit adjudicated by a neurologist; and stroke as a permanent focal neurological deficit adjudicated by a neurologist and confirmed by computed tomography or magnetic resonance imaging. Systemic embolism was defined as signs/symptoms of peripheral ischemia associated with a positive imaging test. Decompensated heart failure was documented in case of clinical evidence of dyspnea and positive findings in chest X-ray and/or diagnosis confirmed by a cardiologist. Atrial fibrillation was documented using ECG if clinically indicated. The adjudication of endpoints was performed case by case by an adjudication committee consisting of a cardiologist and an otorhinolaryngologist. Major bleeding was defined when patient received 4 or more red blood cell (RBC) units or had a fatal bleeding event. The limit of blood transfusion was hemoglobin value ≤9.0g/dL.Patients were divided into two groups based on the amount of intravenous fluids that they received within the operation day (≥4000mL vs. <4000mL). Normal daily fluid demand for a healthy adult is 25-35mL/kg (f.e. for a 70kg patient 2450mL) and if the 8h fasting before operation is taken into consideration the need is ~3300mL. A limit of 4000ml takes into consideration the possible tissue vaporization and normal bleeding during operation. Statistical analysis Data are presented as means ± standard deviations, median [interquartile range] and frequencies (%) where appropriate. Continuous variables were analyzed using independent samples t-test. Categorical variables were analyzed using chi-square test. Univariate and multivariate analysis were used to evaluate possible predicting factors for ACS, decompensated heart failure, atrial fibrillation, stroke, pulmonary embolism and venous thrombosis. Adjusted odds rations (OR), 95% confidence intervals (CI) and P-values were calculated for each predictor. Significance was set at p value <0.05. Analysis was performed with SPSS-statistics 22.0 software for MAC (SPSS Inc., Chicago, IL). Results Median volume of intravenous fluid administration in operation day (24h) was 3000ml [IQR=4000]. Baseline characteristics of patients with moderate (≤4000ml/24h) vs. liberal (>4000ml/24h) intravenous fluid administration are presented in Table 1. Patients receiving fluids liberally had lower preoperative hemoglobin values than patients who had moderate fluid administration (Median 12.3 vs. 13.3 g/dL, p>0.5) they were also younger (Median 60 vs. 65, p>0.5) and more often women (OR 1.47, 95% CI 1.02-2.14, p=0.042), but no differences in comorbidities or prior medications were observed. Main patient subsets for liberal fluid administration were patients undergoing microvascular reconstruction surgery (57%) and patients undergoing neck dissection (26%). From liberally hydrated patients only 33% had a major bleeding. Patients who received fluids liberally (>4000ml/24h) had more often MACCE at 30d followup compared to those who had ≤4000ml fluids (10.8% vs. 2.4%, p=<0.001). Mortality was also slightly higher in patients who received over 4000ml fluids /24h (3.9% vs. 1.6%, p=0.088). (Figure 1) Median bleeding in patients receiving fluids liberally was 1000ml [IQR=975] and 300ml [IQR 350] in patients with moderate fluid administration. Patients who had red blood cell infusions peri- and postoperatively had higher risk for MACCE (11.4% vs. 2.7%, p=<0.001) and a trend for higher 30d mortality (3.9% vs. 1.7%, p=0.132) (Figure 2). Moreover, patients who received RBC had lower preoperative Hb-values compared to those who didn’t (median 119 vs. 135, respectively). Median time from operation to MACCE was 3 days. In a binary logistic regression analysis, peri/postoperative univariate predictors of MACCE at 30 days follow-up were total amount of fluids (24h) >4000ml (OR 4.84, 95% CI 2.18-10.75, p<0.001); RBC infusion (OR 4.63, 95% CI 2.18-9.84, p<0.001); treatment in intensive care unit (OR 2.65, 95% CI 1.28-5.47, p=0.009); tracheostomy (OR 2.34, 95% CI 1.134.88, p=0.023); microvascular reconstruction surgery (OR 2.28, 95% CI 1.07-4.88, p=0.033). Moreover, when analyzed per units of red blood cells transfused or per liters of fluid administered over 4000ml/24h, in both cases the risk of MACCE increased 18% per unit/liter (RBC OR 1.18, 95% CI 1.08-1.30, p<0.001; fluids OR 1.18, 95% CI 1.04-1.34, p=0.012). In a multivariate model, >4000ml fluid administration/24h remained as the only predictor for MACCE (OR 4.84, 95% CI 2.19-10.75, p<0.001). Use of vasopressors had no influence on MACCE (p=0.540). Perioperative univariate predictors of decompensated heart failure were total amount of fluids (24h) >4000ml (OR 7.64, 95% CI 2.13-27.42, p=0.002); RBC infusion (OR 7.03, 95% CI 2.24-22.10, p=0.001); use of papaverin (OR 6.74, 95% CI 2.40-18.93, p<0.001); and treatment in intensive care unit (OR 5.65, 95% CI 2.02-15.83, p=0.001). Perioperative univariate predictors of ACS were RBC infusion (HR 6.93, 95% CI 1.85-25.89, P=0.004); total fluids (24h) > 4000ml (OR 4.99, 95% CI 1.31-19.03, p=0.019); and treatment in ICU (OR 4.65, 95% CI 1.45-14.89, p=0.010). Discussion In this unselected cohort of patients undergoing head and neck cancer surgery, it appeared that patients receiving excessive intravenous fluid administration within the operation day (24h) had nearly 5-fold risk for MACCE. Strikingly, every liter of fluids administered exceeding 4000ml increased the risk of MACCE by 18%. Moreover, red blood cell use was associated with over 4-fold risk for MACCE, and likewise every unit of red blood cells transfused increased MACCE by 18%. This study provides evidence that operated head and neck cancer patients receiving more than 4000ml fluids perioperatively (24h) had clearly elevated risk for MACCE (OR 4.8-7.6) irrespective of comorbidities. The amount of fluids given to patient is largely dependent on the type of surgery. In patients undergoing major head and neck surgery such as microvascular reconstruction, operations usually take many hours and fluids are needed to maintain adequate perfusion pressure levels and replace blood loss and evaporation of tissue fluid. In this study the median bleeding for patients who were given fluids liberally was 1000ml, and only 33% of patients had major bleeding. Therefore, it is likely that the reason for liberal fluid therapy was inadequate perfusion pressure, reduced diuresis, or tissue evaporation. Our findings are in line with a recent review by Della Rocca et al., which summarized that only low risk patients undergoing minor surgery should have fluids liberally. All other patient groups should have either restrictive or goal-directed fluid therapy.9 Earlier it has been shown that protocol-based fluid restriction reduced the incidence of perioperative complications such as cardiopulmonary events in major non-cardiac surgery 6, 10. Moreover, goal-directed fluid therapy reduced hospital stay in high-risk surgical patient 11 and shortened ICU and hospital stay in older coronary artery disease patient undergoing gastrointestinal surgery 12. An adequate replacement of fluids seems to have a power to improve patient outcome 5. In patients undergoing head and neck surgery the incidence of cardiovascular complications is highest within the first day after operation 13, and therefore it is plausible that the amount of fluids given to patient peri- and postoperatively is likely to be one of the important contributors of this finding. Excessive intraoperative fluid administration was associated with higher complication rates in head and neck patients undergoing operation with free tissue transfer 14 and it was found to be an independent predictor of surgical complications for patients undergoing major head and neck surgery 15. Previous studies have failed to set the limit for liberal fluid administration. We set the limit of 4000ml which takes the possible tissue vaporization and normal bleeding during operation into account. In this study we could verify that administration of over 4000ml intravenous fluids will lead to increased risk for MACCE. Other notable perioperative risk factor for adverse cardiovascular events in this study was red blood cell transfusion. Patients receiving RBC peri- or postoperatively had 4.9-fold risk for 30-day MACCE. It is evident that the need to RBC is based on either major operative bleed or anemia. Notably, patients receiving excessively intravenous fluid may also encounter dilution anemia. In patients undergoing vascular surgery it has been shown that perioperative red blood cell transfusion was associated with independently increased risk of 30-day cardiovascular events 16, 17. The number of red blood cell units given to patient in CRIT-study was an independent predictor of worse clinical outcome 18. In this study every unit of RBC given to patient increased the risk for MACCE by 18%. Hebert et al. 1999 studied critical ill patients and found that liberal red-blood cell transfusion strategy was not more effective and could even be harmful when compared to restrictive transfusion strategy -, and restrictive strategy seemed to be superior with patients who were less ill and had no significant cardiac disease 19. In our study RBC infusion was associated with 6.9-fold risk for peri-or postoperative acute coronary syndrome. Blood transfusion to patients suffering acute coronary syndrome is associated with higher 30-day mortality 20. On the other hand there is evidence that anemia in patients with coronary artery disease will lead to higher in-hospital and long-term mortality and morbidity 21, 22. In a previous study patients after acute coronary syndrome benefited from RBC when hemoglobin was under 8.0g/dL, however RBC appeared harmful when given at hemoglobin levels >1.10g/dL 23. Anemia in advanced heart failure patients has also increased mortality 24. This finding underscores the value of individual assessment of red blood cell transfusion according to patient status, comorbidities, amount of bleeding and the level of hemoglobin. Postoperative care in ICU proved to be a marker of cardio- and cerebrovascular complications (OR 2.75). Patients treated in ICU after cancer operations have overall 1.4% mortality 25 . In our study mortality rate for patients treated ICU was as high as 4.4%. Soares et al. 2010 pointed that the mortality for cancer patients treated in ICU is not dependent on severity of cancer, but more due to multi organ failure, overall performance status and need of mechanical ventilation 26. There are some preliminary studies indicating that early extubation and spontaneous breathing and treatment in non-ICU unit should be considered for head and neck cancer surgery patient also after complex microvascular surgery 27-29. Clinical implication of these findings is that we need to pay attention to excessive fluid administration. Individual fluid and blood transfusion plan should be made for all patients having major head and neck surgery. In head and neck surgery in general perioperative fluid administration should be considered more carefully if patient has prior coronary artery disease or congestive heart failure. Presence of comorbidities is well established in head and neck cancer patients and those should be taken in to consideration when surgical treatment is planned. The use of modern surgical technology may shorten the duration of surgery and minimize the evaporation of tissue fluid, reduce the blood loss and that way reduce the administration of fluids and RBC peri- and postoperatively. Limitations This study has all the limitations of retrospective study. Treatment options where at treating physicians’ discretion. Urine outcome was systematically measured only for patients undergoing microvascular surgery, and was not therefore analyzed. Nevertheless, this cohort represents an unselected set of patients undergoing head and neck cancer surgery. The amount of fluids given was derived from patient files, anesthesiology reports, and ICU reports. The information about fluids administered was documented in files (97% of cases). Conclusion Head and neck cancer patients receiving excessive intravenous fluid administration peri- and postoperatively were at high risk for cardiac complication, especially decompensated heart failure. Perioperative fluid administration should be considered more carefully especially in patients with prior coronary artery disease or congestive heart failure. Patients undergoing oncologic head and neck surgery need to have individual risk assessment preoperatively considering the type of operation, possible need of tracheostomy, the critical evaluation of the need of postoperative care in ICU, goal-directed peri- and postoperative fluid therapy and individual RBC transfusion strategy. References 1. Datema FR, Poldermans D, Baatenburg de Jong RJ. Incidence and prediction of major cardiovascular complications in head and neck surgery. Head Neck 2010;32:1485-1493. 2. Piccirillo JF. Importance of Comorbidity in Head and Neck Cancer. Laryngoscope 2000;110:593-602. 3. 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