Management of Medical Comorbidities

258Perioperative Management of Medical Comorbidities

ENHANCED RECOVERY PATHWAYS IN GYNECOLOGIC ONCOLOGY

Accelerated recovery with multimodal postoperative clinical pathways has been shown to improve outcomes. It starts in the preoperative period and continues through hospitalization.

• Bowel prep continues to be controversial: infection and anastomotic leak were reviewed in patients with a bowel preparation; results were 9.6% and 4.4%, respectively, with a preparation compared to 8.5% and 4.5%, respectively, for those without a preparation.

• Overnight fasting: longer fasting causes untoward metabolic changes and depletion of liver glycogen stores. Therefore, a 6-hour no solid food and a 2-hour no clear liquid regimen is advised.

• Intraoperative fluid management: euvolemia is the goal. 7% versus 24% of patients had cardiovascular complications when zero balance was the goal versus standard 3 kg to 7 kg increase of too much fluid. In patients with sepsis, an average 12 L of fluid overload occurred, which took 3 weeks to mobilize. Pulmonary congestion, edema, hyponatremia, and congestive heart failure (CHF) tend to occur with too much intravenous fluid (IVF).

• Postoperative pain control: epidural versus patient controlled analgesia (PCA) have shown different lengths of stay in gynecologic oncology patients favoring earlier discharge with PCA. Those with an epidural had a longer time to first ambulation, higher rate of pressor use during surgery, and pain control was equivalent to lower than those with a PCA (due to a 30% failure rate of epidural analgesia). Toradol has been shown to provide superior pain control and is equivalent to opioid relief with no increase in postoperative bleeding or anastomotic leaks.

• Prophylactic drains are not indicated except in those with very low anterior resections (an anastomosis within 6 cm of the anal verge). Nasogastric tube (NGT) drainage is contraindicated prophylactically (1).

VASCULAR THROMBOEMBOLISM

• Deep vein thrombosis and venous thromboembolism (DVT/VTE) prophylaxis should be given to most hospitalized patients. The gynecologic oncology patient population is a high-risk group.

Pneumatic sequential compression devices (SCDs) should be used. Use should start preoperatively, continue intraoperatively, and continue postoperatively.

A low-dose injectable anticoagulant should be considered prior to surgery. The normal dose of heparin is 5,000 units SC before surgery. Dalteparin dosed at 5,000 units SC can be given before surgery. Enoxaparin can also be used at 40 mg SC before surgery.

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In-hospital prophylaxis of DVT: the combination of SCDs and injectable anticoagulants is especially helpful for the prevention of VTE complications. The use of SCDs has taken the incidence of VTE from 25% to 8%. The use of combination therapy then took the VTE occurrence from 8% to 2%. Dosing is usually with unfractionated heparin (UFH) 5,000 q8 hours or enoxaparin 30 to 40 mg daily. The risk of DVT with laparoscopic surgery in high-risk cancer patients with appropriate prophylaxis is 1.2% (2). Care should be taken and SCDs not used if an active superficial or deep vein thrombosis (SVT)/DVT is present because of potential embolization. Graduated compression stockings have not been found to decrease DVTs (3). If there is a contraindication to anticoagulation prophylaxis, mechanical prophylaxis alone should be used.

Contraindications to mechanical prophylaxis:

Absolute: acute SVT/DVT, severe arterial insufficiency

Relative: large hematoma, skin ulcerations or wounds, thrombocytopenia (platelets <20,000/mcL) or petechial, mild arterial insufficiency, peripheral neuropathy

Contraindications to prophylactic or therapeutic anticoagulation:

Absolute: recent central nervous system bleed, intracranial or spinal lesion at high risk for bleeding, active bleeding (major) with more than two units PRBC transfused in 24 hours.

Relative: chronic clinically significant measurable bleeding for more than 48 hours, thrombocytopenia (platelets <50,000/mcL), severe platelet dysfunction (uremia, medications, dysplastic hematopoiesis), recent major operation at high risk for bleeding, underlying hemorrhagic coagulopathy, high risk for falls (head trauma).

• Risk factors for VTE include: known malignancy, surgery, surgical time greater than 2 to 3 hours, postoperative immobility, a past history of VTE, body mass index (BMI) greater than 30, hereditary coagulopathy, age 60 years or above, hypertension, renal disease, pulmonary disease, estrogen use, inflammatory bowel disease, and hereditary coagulopathies (methylenetetrahydrofolate reductase [MTHFR] deficiency, protein C/protein S deficiencies, prothrombin gene mutation, antithrombin III and factor V Leiden gene mutations, antinuclear antibodies, antiphospholipid antibodies; Table 4.6).

• Symptoms of an SVT/DVT are: leg edema, erythema, size discrepancy between the legs, pain, heaviness, persistent cramping, cyanosis of extremity, swelling in the neck of supraclavicular area.

• Positive physical signs are: the Pratt’s, Homan’s, and Moses’s tests.

• Diagnosis is with Doppler ultrasound.

• Treatment

SVT that is not close to the deep venous system or is a peripheral catheter-related clot: remove the catheter, symptomatic treatment with heating pad, anti-inflammatory medications, elevation of extremity

SVT in close proximity to deep venous system in a surgical or oncologic patient: strongly consider therapeutic anticoagulation for 6 weeks and up to 12 weeks if close to the femoral system

260Table 4.6 VTE Risk Factors in Cancer Patients: Khorana Predictive Model for Chemotherapy-Associated VTE

Patient characteristic		Risk score
Site of primary cancer		2
Very high risk: stomach, pancreas		1
High risk: lung, lymphoma, gynecologic, bladder, testicular		1
Prechemotherapy platelet count 350 × 10–9 or higher		1
Hemoglobin level less than 10 g/dL or use of red cell growth factors		1
Prechemotherapy leukocyte count higher than 11 × 10–9/L		1
BMI 35 kg/m² or higher		1
Total score	Risk category	Risk of symptomatic VTE
0	Low	0.8%–3%
1.2	Intermediate	1.8%–4%
3 or more	High	1%–41%
Source: Adapted from Refs. 4, 5. VTE, venous thromboembolism.

Pelvic/iliac/inferior vena cava (IVC)/femoral/popliteal DVT:

Therapeutic anticoagulation is indicated.

If there is contraindication to anticoagulation:

Placement of an IVC filter is indicated

If there is a calf DVT and a contraindication to anticoagulation: follow-up for DVT progression should occur at the first week. If there is no progression, consider following clinically; if progression then treat with IVC filter.

Upper extremity or superior vena cava DVT:

Therapeutic anticoagulation is indicated.

If there is contraindication to anticoagulation: follow clinically until contraindication is resolved or progression of DVT.

Catheter-related DVT:

therapeutic anticoagulation is indicated for as long as the catheter is in place. If the catheter is removed, the total duration of anticoagulation should be at least 3 months. Consider catheter-directed pharmaco-mediated thrombolysis in appropriate patients.

If there is a contraindication to anticoagulation, remove the catheter.

• Pulmonary embolism (PE) can occur following a DVT. If DVT is untreated, 15% to 25% progress to PE. If treated, 1.6% to 4.5% can still progress to PE, with 0.9% being fatal.

Symptoms include tachypnea (90%), tachycardia (45%), hemoptysis (30%), cyanosis (20%), and a sense of impending doom (50%–65%).

Workup includes: CT angiogram/spiral CT of the chest, identification of the original thrombus with lower extremity Doppler (if Dopplers are negative a pelvic CT should follow), a chest x-ray (CXR), an enzyme-linked immunosorbent assay (ELISA) D-dimer (which has a negative predictive value [NPV] 99.5%), an arterial blood gas (ABG) (the PO₂ is often <80 in 85% of patients) with calculation of the A-a gradient, cardiac enzymes to include troponin, and baseline coagulation studies.

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A normal A-a gradient is: 5 to 10 mmHg but increases with age and FiO₂. A conservative estimate is: (age in years/4) + 4.

A-a gradient = [(FiO₂) × (Atmospheric pressure − H₂O pressure) − (PaCO₂/0.8)]—PaO₂

A CXR has a sensitivity of 33%, a specificity of 59%. Signs on CXR are an elevated hemidiaphragm (50%), the Hampton’s hump due to a pleural-based infiltrate pointed toward the hilum, Westmark’s sign (dilated proximal vessels with a distal cutoff), a pleural effusion, and atelectasis.

An EKG showing right bundle branch block (RBBB) or a right axis shift can be helpful. If chest spiral CT/CT angiogram is contraindicated, a V/Q scan can be obtained with probabilities of PE represented as low, intermediate, or high. If the probabilities are intermediate or high, it is important to confirm with echocardiogram (ECHO) to evaluate right heart strain.

ECHO can contribute to primary workup in the diagnosis of PE.

• Treatment of PE is with supportive care and therapeutic anticoagulation. Oxygen is titrated to keep saturations greater than 92%. ECHO can evaluate for pulmonary hypertension and right heart failure. Cardiac support can be given with IV or PO medications. Consider thrombolytic therapy for massive PE or submassive PE with moderate to severe right heart enlargement or dysfunction. Embolectomy either via interventional radiology or surgery is another option, with IVC filter placement. Anticoagulants are dosed the same as for DVT. If there is a contraindication to anticoagulation: consider an IVC filter and embolectomy with frequent evaluation for change in clinical status, assessing for therapeutic anticoagulation. IVC filter removal is recommended if anticoagulation therapy is tolerated. Filters are only permanent for rare patients with contraindications to anticoagulation.

Thrombolytic agents:

Altplase (tPA) 0.5 to 1 mg/hr IV; or 100 mg IV over 2 hours

Reteplase 0.25 to 0.75 units/hr IV

Tenecteplase 0.25 to 0.5 mg/hr IV

Contraindications to thrombolysis:

Absolute: history of hemorrhagic stroke; intracranial tumor; ischemic stroke in prior 3 months; history of major trauma, surgery, or head injury in prior 3 weeks; platelet count below 100,000/mm³; active bleeding; bleeding diathesis

Relative: age greater than 75; pregnancy or first postpartum week; noncompressible puncture sites; traumatic resuscitation; refractory hypertension (HTN) greater than 180/100; advanced liver disease; infective endocarditis; gastrointestinal (GI) bleed in last 3 months; life expectancy less than 12 months.

An IVC filter can be placed to prevent re/embolization: indications are the following: absolute contradiction to therapeutic anticoagulation; a PE despite adequate anticoagulation, chronic PE with associated pulmonary HTN; the patient is status post a pulmonary embolectomy; baseline cardiopulmonary dysfunction is severe enough to make a new or recurrent PE life-threatening; significant heparin-induced thrombocytopenia; patient noncompliance with anticoagulation. Another indication is the need for urgent surgery in a patient with a recent history of DVT, on anticoagulation, but needing temporary discontinuation for a procedure.

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• Therapeutic anticoagulation is with: heparin, dalteparin, enoxaparin, or fondaparinux. It is important to not use SCDs when a DVT is diagnosed due to the risk of clot embolization.

Dosing:

Heparin is given IV and dosed at 80 units/kg bolus, then 18 units/hr with a targeted activated partial thromboplastin time (aPTT) of 2 to 2.5 × hospital control.

Dalteparin is dosed at 200 units/kg SC every 24 hours or 100 units/kg SC every 12 hours.

Enoxaparin is dosed at 1 mg/kg SC every 12 hours. It is possible to convert to a daily dosing schedule of 1.5 mg/kg after 3 days of every-12-hour dosing.

Fondaparinux is dosed at 5 mg if less than 50 kg; 7.5 mg if 50 to 100 kg, or 10 mg if greater than 100 kg body weight SC daily.

Heparin SC 333 units/kg load then 250 units/kg every 12 hours.

Direct oral anticoagulants are not recommended.

• Conversion to PO anticoagulation is usually with warfarin. This is to start after 3 days of IV heparin or SC therapeutic anticoagulation with a 5-day overlap due to rebound coagulopathy. It is important to follow the INR to keep it 2 to ×3 normal. Duration of treatment is 3 to 6 months for DVT diagnosis, and 6 to 12 months for a diagnosis of PE. Consider lifetime anticoagulation if there is a diagnosis of cancer, hereditary coagulopathy, or arterial thrombosis.

• Drug interactions with Coumadin can affect the INR. These include erythromycin, sulphas, INH, fluconazole, amiodarone, corticosteroids, cimetidine, omeprazole, lovastatin, phenytoin, and propranolol. If the patient is malnourished, is vegetarian, or has liver disease, a lower dose may be needed. If the patient eats high amounts of green leafy vegetables, the patient may have increased levels of vitamin K and be more difficult to anticoagulate.

• There are data to suggest that continued injectable anticoagulation is better in patients with malignancy than warfarin (CANTHANOX and LITE studies) (6, 7). There are also data to suggest better progression-free survival (PFS) and overall survival (OS) in patients receiving injectable anticoagulation (FAMOUS and CLOT studies) (8, 9).

• Postoperative outpatient primary VTE prophylaxis is recommended for 4 weeks particularly for pelvic and abdominal cancer surgery patients. Dosing is: dalteparin 5,000 units SC daily, if BMI is greater than 40 consider 7,500; Enoxaparin 40 mg SC daily, if BMI is greater than 40 consider dosing q12 hours; fondaparinux 2.5 mg SC, if MBI is greater than 40 consider 5 mg SC daily; UFH 5,000 units SC every 8 hours, if BMI is greater than 40 consider 7,500 units every 8 hours.

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• Duration of treatment for VTE:

A minimum of 3 months is recommended for patients with proximal DVT or PE.

In patients with advanced or metastatic cancer, or in patients with risk factors for recurrence (genetic), lifelong therapy is recommended. Low–molecular weight heparin (LMWH) is preferred for the first 6 months as monotherapy. Warfarin can then be substituted with the target INR of 2 to 3. Both therapies should be continued for at least a 5-day overlap and until the INR is greater than 2 for at least 24 hours. Direct oral anticoagulants (DOAC) are not recommended.

Catheter-associated thrombosis: continue anticoagulation as long as the catheter is in situ or for at least 3 months.

• Reversal of anticoagulation:

UFH: half-life 1 hour

Reversal with protamine 1 mg/100 units UFH

The maximum dose of protamine is 50 mg, and it can cause anaphylaxis if administered too fast.

LMWH: half-life 12 hours

Reversal with protamine:

If within 8 hours: 1 mg/mg of enoxaparin or 1 mg/100 units of dalteparin within 8 hours of the dose

If greater than 8 hours from dosing, then 0.5 mg/mg of protamine

If greater than 12 hours, consider the clinical scenario.

Warfarin: half-life 20 to 60 hours

INR 4.5 to 10, no bleeding: hold warfarin dose, when INR approaches therapeutic range less than 4, restart at reduced dose by 10% to 20% and recheck INR within 4 to 7 days

INR greater than 10, no bleeding: hold warfarin dose, consider small dose oral vitamin K 1 to 2.5 mg, follow INR every 1 to 2 days, when approaches therapeutic range less than 4, restarted at 20% dose reduction and recheck INR in 4 to 7 days.

Avoid SC administration of vitamin K because of erratic absorption, IV administration can be used for more rapid absorption than PO.

If urgent surgery is needed:

Within 24 hours; hold warfarin and administer vitamin K 1 to 2.5 mg IV over 1 hour and repeat INR pre-surgery to determine need for prothrombin complex concentrate (PCC). Fresh frozen plasma (FFP) is another option.

Within 48 hours: hold warfarin and give vitamin K 2.5 mg orally. Repeat INR at 24 and 48 hours to assess need for supplemental vitamin K, PCC, or FFP.