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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.
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