ABSTRACT
Background: The safety of preoperative chemoprophylaxis for deep venous
thrombosis (DVT) prevention in patients undergoing head and neck
oncologic surgery with free tissue transfer (HNS-FTT) remains
undetermined.
Methods: Retrospective chart review of HNS-FTT patients receiving versus
not receiving intraoperative subcutaneous enoxaparin (Px-LMWH) was
performed. Outcomes included estimated blood loss (EBL), hematoma, flap
compromise, DVT or pulmonary embolus (PE). Fisher’s exact test and
Wilcoxon Rank Sum test were performed between groups (p-value
< 0.05).
Results: 44 of 134 patients (33%) received Px-LMWH. There was no
significant difference in EBL, hematoma, or flap complications between
groups. Patients without Px-LMWH had higher rates of DVT and PE (p =
0.999, 0.09, respectively).
Conclusion: Px-LMWH can be used in major head and neck reconstructive
surgery without increased intraoperative blood loss or postoperative
complications. Larger studies will need to be done to determine the
impact of Px-LMWH on DVT and PE in this patient population.
KEY POINTS
- Preoperative LMWH has the potential to prevent thrombotic events and
its use is recommended by several surgical subspecialties.
- Preoperative low-molecular weight heparin (LMWH) therapy is not widely
used in head and neck oncologic and reconstructive surgery due to
concerns over adverse events.
- Our results show preoperative LMWH given on the day of surgery is safe
and does not increase blood loss or adverse events.
- Given the morbidity of thrombotic events, preoperative LMWH should be
administered to patients undergoing major head and neck surgery with
reconstruction.
- The effect of preoperative LMWH on thrombotic events in this patient
population should be explored at a multi-institutional level.
-
INTRODUCTION
Perioperative venous thromboembolism (VTE) remains a significant
contributor in morbidity and mortality. Studies estimate rates of VTE
between 1.2-1.9 per 1000 person years1,2,3. 20% of
VTE is associated with a cancer diagnosis, and cancer patients are at a
4-7 times increased risk of VTE events4,5,6. Cancer
patients who develop VTE have a 3-fold increased risk of death from
subsequent pulmonary embolus (PE) as compared to non-cancer
patients7.
Several factors go into the increased risk of VTE for patients with a
cancer diagnosis, including dehydration, chemotherapy, and neoplastic
activation of the clotting cascade8. Surgery is an
independent risk factor for cancer-related VTE, with patients undergoing
oncologic surgery having twice the risk of VTE as non-cancer patients
undergoing similar procedures9,10. Unfortunately,
development of VTE in cancer patients increases the risk of recurrent
VTE and is an independent predictor of mortality11.
There has been increasing interest in the role of preoperative
chemophrophylaxis in preventing the downstream morbidity and mortality
from VTE in cancer patients. Guidelines from the European Society of
Medical Oncology, the American Society of Clinical Oncology, and the
American College of Chest Physicians recommend preoperative chemical
prophylaxis for cancer patients undergoing surgery with either
low-molecular weight heparin (LMWH) or unfractionated heparin
(UFH)12,13,14. A large cohort study examining the
safety of preoperative chemoprophylaxis in major oncologic surgery found
no increased risk of bleeding complications and a significant decrease
in VTE rates in patients who received preoperative
VTE15.
Major head and neck surgery with free tissue reconstruction represents a
relatively small subset of all major oncologic surgery and large studies
on VTE in this patient population are lacking. Prospective studies have
found VTE rates as high as 13% in patients undergoing head and neck
cancer surgery without chemoprophylaxis16. However,
other centers report a low VTE rate and the addition of chemoprophylaxis
has been implicated in increased risk of bleeding
complications17,18. The decision to use preoperative
chemoprophylaxis in major head and neck surgery remains controversial,
with the risk of bleeding complications coinciding with a potential for
failure of free flap reconstruction from hemorrhage or hematoma.
The purpose of this study was to examine the use of preoperative VTE
chemoprophylaxis with LMWH in patients undergoing head and neck cancer
surgery with microvascular reconstruction, and the impact on operative
time, blood loss, hemorrhagic complications, overall free flap survival,
and thrombotic events.
METHODS
An IRB-approved retrospective review was conducted at our academic
institution of all head and neck patients undergoing free flap
reconstruction over a 5 year period. During this time, one faculty
member used preoperative chemical VTE in the form of subcutaneous 40mg
of low molecular weight heparin (LMWH) administered in the pre-operative
area or immediately on entry in the operating room. Subsequent doses of
LMWH were administered starting post-operative day one. Two faculty
members used either no chemoprophylaxis, or an intraoperative dose of
intravenous heparin at the time of venous anastomosis. For the purposes
of analysis, patients who received intravenous heparin were excluded to
avoid confounding data. As such, only patients who received
perioperative enoxaparin were compared with only patients who received
no chemoprophylaxis.
All patients received sequential compression devices (SCDs) in the
operating room. Prescription anticoagulation, including aspirin, was
held prior to surgery per hospital guidelines. Post-operatively patients
were started on prophylactic chemical prophylaxis with daily 40mg LMHW
as well as daily aspirin at 81mg or 325mg per surgeon preference.
Patients who were on prior systemic anticoagulation other than aspirin
were restarted on their home anticoagulant per surgeon preference and
were excluded from the analysis final.
Post-operative monitoring was standardized for all patients. At our
institution, all patients receive arterial and venous implantable
dopplers for anastomosis monitoring. In the rare case implantable
dopplers are not available, patients undergo monitoring with manual
doppler checks of the main pedicle. All patients undergo hourly flap
checks by the nursing team for the first 48 hours, and q2 hour flap
checks for the next 48 hours. Resident checks occur 2-3 times a day.
Data on patient sex, tumor site, tumor stage, and history of prior
treatment were recorded. Surgical data recorded included free flap type,
duration of surgery and estimated blood loss, the latter two of which
were determined from the anesthesia record. The incidence of
post-operative surgical site hematoma, donor site hematoma, blood
transfusion, partial flap loss or complete flap loss were recorded based
on chart documentation. Hematoma formation was recorded if inpatient
documentation mentioned a blood collection at either the operative of
donor site. Partial flap loss was defined as a non-viable portion of the
free flap reconstruction noted on clinical exam with or without
operative debridement. Complete flap loss was defined by loss of the
entire free flap with or without salvage. Transfusion requirements
included a Hgb level < 6 and symptomatic hypotension not
responsive to initial fluid bolus.
Assessment of DVT was based on physical exam findings of swollen
extremity and/or pain, or abnormal lab values. Initial assessment with
ultrasound of the affected extremity was performed to confirm the
diagnosis. Assessment of PE was undertaken for patients on a
symptom-based approach which included assessing for tachycardia,
hypoxia, and tachypnea. A thin-slice contrasted CT was used to confirm
the diagnosis of PE. All patients with DVT or PE were started on
systemic anticoagulation.
Fisher’s exact test was used to assess proportions of categorical
variables between patient groups, while Wilcoxon Rank Sum test was used
to assess distributions of continuous variables. A p-value <
0.05 implied statistical significance in this study. Statistical
calculations were performed using statistical software R, version R
3.6.3.
RESULTS
A total of 134 patients were included. 44 (33%) received preoperative
chemoprophylaxis (Px-LMWH). Full demographic data is show in in Table 1.
Tumor staging was available for 35 patients in the Px-LMWH group and 73
in the control group. Nodal and metastatic staging was available in 33
patients in the Px-LMWH group and 70 patients in the control group.
There was no significant difference in T, N, or M stage between the two
study groups. The majority of patients (55%) had T3 or T3 primary
tumors. The most common site of cancer was the oral cavity (53%),
followed by larynx and oropharynx (13%). The most common free flap
donor sites were the anterolateral thigh and radial forearm (39% and
40%, respectively). 26 (19.4%) of patients were taking preoperative
aspirin (ASA) that was held prior to surgery.
Surgical data was analyzed and showed no significant difference in EBL
between patients receiving preoperative chemoprophylaxis and those who
did not (Table 2). There was a significant difference in surgical
duration, with patients receiving LMWH having on average 98 minutes
longer of an operative duration.
Post-operative data was similarly analyzed between patient groups (Table
3). There was no significant difference in the rates of blood
transfusion between groups, with the majority (72%) requiring no blood
transfusion during their stay. There was also no significant difference
in rates of surgical site hematoma. Partial flap loss occurred in one
patient and complete flap loss in four patients. There was no
significant difference in the rates of flap failure between patient
groups. No patients in the Px-LMWH group developed a PE and 1 developed
a DVT (p = 0.09 and 0.9, respectively). Overall, DVT occurred in 3.7%
of all patients, and PE occurred in 5.2%.
DISCUSSION
The use of preoperative chemical prophylaxis to prevent surgical VTE in
head and neck surgery patients remains controversial, but of high
importance to investigate. Mortality occurs in 6-11% of patients with
isolated deep venous thrombosis (DVT); however, pulmonary embolus can
result in mortality for up to a third of affected
patients4. Several risk stratification methods exist
for predicting which patients are at higher risk of VTE. Known risk
factors exist and include age > 60 years old, male gender,
increased Charleston comorbidity score, bedrest > 4 days,
surgery duration > 2 hours, inpatient stay > 2
days, and malignancy19,20. Risk stratification in
oncologic patients undergoing surgery is more nuanced. No one system can
completely predict rates of VTE for each surgical subset, though several
methods exist. The Caprini score (Figure 1) has been widely used to
predict VTE risk due to ease of use, validation across multiple types of
surgical patients, and a low risk of bias. Based on the model, the
majority of head and neck cancer patients undergoing reconstruction
would start at a baseline score of 8 (major surgery > 6
hours, present malignancy, age > 45 years old), placing
them at a moderate risk of VTE. Other factors such as cast
immobilization or cardiopulmonary comorbidity, the latter of which is
seen in up to a third of patients undergoing major head and neck
surgery, increase this risk to high with an estimated 2% risk of
symptomatic VTE21,22.
The use of preoperative VTE chemoprophylaxis has not been universally
implemented in head and neck free flap patients due to variable rates of
VTE and the potential for devastating complications from hematoma.
Previous studies had reported low rates of VTE in otolaryngology
patients undergoing surgery; however, recent studies have found rates of
VTE in head and neck free flap patients may be higher than those
previously reported24. Shuman et al additionally found
a correlation with increasing Caprini risk score and the incidence of
perioperative VTE in head and neck patients, with rates of VTE as high
as 18.3% with a score of 9 or above25.
Our study showed no increase in intraoperative blood loss, transfusion
requirements, rates of hematoma, partial flap loss, or total flap loss
with the use of preoperative chemoprophylaxis. There was a significant
difference in surgical duration with the group receiving perioperative
chemoprophylaxis having over an hour longer surgical duration. Several
factors can play a role in operative time, including the difficulty and
extent of planned resection, the timing of flap harvest, anesthetic
considerations and practice differences between surgeons. The increased
operative time seems independent to LMWH administration. Overall
preoperative LMWH administration had a low rate of hemorrhagic or
reconstructive complications in our study cohort. It should be mentioned
that several outcome measures, including hematoma and flap compromise,
are more dependent on post-operative factors than preoperative LMWH use.
However, these were included for completeness and to assess if
intraoperative LMWH had an unintended effect on the ability to provide
adequate hemostasis. While our study was not powered to determine the
occurrence of DVT or PE based on LMWH use, there was a higher incidence
of both DVT and PE in the cohort who did not receive preoperative LMWH.
This effect should be explored further as a multi-institutional
prospective trial. Our study shows that preoperative LMWH administration
can be done safely without increased morbidity from blood loss and with
the potential to prevent thrombotic events.
There are limitations to this study. As a retrospective cohort study,
there exists a selection bias that could impact our findings. Our study
cohorts had no significant differences in tumor stages and sites, rates
of prior treatment, and types of reconstruction, making each population
heterogeneous for study. The incidence of the outcome measures were low
overall and our sample size may be underpowered to make a complete
assessment about all outcomes based on this patient population.
Additionally, while attempts were made to keep the patient cohort
homogenous, a patient’s individual comorbidities and variations in LMHW
processing were not taken into account. Measurement of anti-Xa and
antithrombin III levels can be useful in this regard to determine if the
standard dose of perioperative chemoprophylaxis is biologically and
clinically effective23. Finally, a rigorous method of
assessing intraoperative and post-operative blood loss remains elusive
in this patient population. Measurements of EBL are notoriously
subjective and transfusion requirement can be patient and
provider-dependent. However, clinical outcomes can provide a direct
clinical reference for bleeding complications and are ultimately the
end-point for assessing the safety of Px-LMHW administration in
reconstructive surgery.
In conclusion, we found that standard preoperative VTE chemoprophylaxis
in the form of LMWH does not appear to increase rates of intraoperative
blood loss in major head and neck surgery with reconstruction, and rates
of post-operative complications are were comparable between treatment
groups. An increase in operative time can be due to several factors,
though does not seem to be related to LMWH administration or blood loss.
Head and neck cancer patients undergoing surgical resection with free
flap reconstruction remain a high-risk group for VTE and the downstream
morbidity and mortality that accompanies these events. Preoperative LMWH
can potentially decrease thrombotic complications while maintaining
reconstructive outcomes and safety. Further work should focus on larger,
prospective studies examining the impact of Px-LMWH on hemorrhagic
complications and measure therapeutic endpoints of chemoprophylaxis
administration. Multi-institutional prospective studies should be done
to determine the effect of Px-LMWH on DVT and PE in this patient
population.
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