A 10-year-old sexually intact male Bulldog mix (dog 1) was examined at the University of Florida Small Animal Hospital because of an acute onset of pleural effusion and ventricular tachycardia. Echocardiography and an ECG were performed, and a heart base tumor with secondary ventricular tachycardia was diagnosed. The ventricular tachycardia was controlled with oral medications, while the heart base tumor was further evaluated by means of CT with an 8-slice scanner.a For CT, the patient was premedicated with methadone (0.3 mg/kg [0.14 mg/lb], IV) and acepromazine (0.01 mg/kg [0.0045 mg/lb], IV), and anesthesia was induced with etomidate (0.46 mg/kg [0.21 mg/lb], IV; chosen because of the patient's preexisting arrhythmia) and diazepam (0.26 mg/kg [0.12 mg/lb], IV). The patient was orotracheally intubated, and anesthesia was maintained with isoflurane in oxygen (3 L/min) delivered via a circle rebreathing system. A multiparameter monitor, including lead II ECG to evaluate heart rate and rhythm, pulse oximeter to measure oxygen saturation, and capnograph to measure end-tidal partial pressure of CO2, was used. Respiratory rate was recorded; blood pressure was measured indirectly by means of Doppler ultrasonic flow detection. The patient was positioned in sternal recumbency in a vacuum bead mattressb with the forelimbs pulled cranially and the hind limbs stretched caudally for radiation therapy planning purposes. The vertebral column and head were positioned as straight as possible. Two fiducial markers were placed in the same plane, with 1 located on the patient and 1 located on the mattress to allow for a clear origin point to be defined in the planning system. The patient was mechanically ventilated with an inspiratory pressure of 20 cm H2O held each time the thorax was scanned. The thorax was scanned before and after contrast (iohexol; 600 mg/kg [272 mg/lb], IV) administration.
Stereotactic body radiation therapy was performed with a linear acceleratorc with the patient positioned in the same vacuum bead mattress as used for CT. Radiation therapy planning was performed with a comprehensive integrated computerized radiation treatment planning systemd by either a board-certified radiation oncologist (LNK) or a medical physicist. A tumor volume of 8 × 5 × 4.5 cm plus a 0.5-cm PTV expansion to allow for interfraction and intrafraction movement was used. Radiation exposure of surrounding normal tissue was limited in accordance with published recommendations.1–3 A total of 25 Gy was delivered to the tumor in five 5-Gy fractions on 5 consecutive days; prior to each SBRT session, patient positioning was first confirmed by means of cone-beam CT.
The patient was anesthetized for radiation therapy with the same premedication, induction, and maintenance agents used for the initial CT, except that on the second treatment day, hydromorphone (0.02 mg/kg [0.009 mg/lb], IV) was used in place of methadone for premedication and, on treatment days 3 through 5, butorphanol (0.2 mg/kg [0.09 mg/lb], IV) was used as the sole premedication agent. Anesthesia was induced with the patient in the radiation vault. Following anesthetic induction, the patient was attached to a circle rebreathing system with inspiratory and expiratory limbs that were 15 m (50 feet) long and had previously been filled with 100% oxygen. The anesthesia tubing was run from the treatment couch to the entrance of a vault wall maze, the opening of which was a 6.5-cm circular hole 30 cm above the floor. The tubing was passed through the maze tunnel within the vault wall and exited through another 6.5-cm hole located in the control room at a similar height above the floor (Figure 1), where it was attached to the anesthesia machine. This area of the vault wall was tested for radiation leakage by a medical physicist, and none was found. In addition, the area was continually monitored for radiation leakage with a film badge dosimeter. The patient was monitored throughout the anesthetic period with a multiparameter monitore that incorporated an ECG to evaluate heart rate and rhythm, pulse oximeter to measure oxygen saturation, capnograph to measure end-tidal partial pressure of CO2, and Doppler ultrasonic flow detector to indirectly measure mean arterial pressure. The monitor remained in the vault with the patient and was observed via cameras within the vault and monitors in the control room.
Photographs (A and B) and a schematic diagram (C) illustrating the anesthetic machine setup used during SBRT for treatment of a heart base tumor in a dog. A—Corrugated tubing (length, 15 m [50 feet]) was used to connect the patient to the anesthetic machine, which was located in the control room for the radiation therapy unit. This allowed the anesthesiologist to control the patient's ventilation by holding the pop-off valve and applying pressure to the reservoir bag. B—Inside the radiation vault, the patient was positioned on the treatment couch and connected to the anesthetic tubing. C—Schematic showing the 50-foot-long anesthetic tubing connecting the patient to the anesthetic machine and running through a maze in the vault wall to prevent radiation leakage.
Citation: Journal of the American Veterinary Medical Association 250, 2; 10.2460/javma.250.2.199
Neuromuscular blockade was achieved with atracurium besylate (0.1 mg/kg [0.045 mg/lb], IV). A second dose was administered 2 minutes after the first on the first treatment day, but on subsequent days, a single dose of atracurium was sufficient to achieve neuromuscular blockade. Neuromuscular blockade was monitored by means of electrodes placed on the skin over the right peroneal nerve and by testing responses to train-of-4 stimuli with a nerve stimulatorf and visual assessment. Nerve stimulation was performed immediately prior to administration of atracurium, 2 minutes after administration of atracurium, prior to administration of reversal agents, and 2 to 5 minutes after administration of reversal agents. The patient was ventilated by means of a mechanical ventilatorg or manual ventilation throughout the anesthetic period, with the mechanical ventilator located in the control room. Immediately prior to cone-beam CT and radiation delivery, hyperventilation was performed by administering 3 to 6 rapid breaths at a peak inspiratory pressure of 20 cm H2O. This was then followed by an inspiratory breath hold for the duration of CT or radiation beam delivery. The breath hold was performed by closing the pop-off valve and maintaining manual pressure on the rebreathing bag at 20 cm H2O. Radiation delivery lasted between 21.8 and 33.6 seconds for each field at a dose rate of 600 MU/min. Immediately following CT or radiation delivery, assisted or mechanical ventilation was resumed. This was repeated for all 7 treatment fields. Total anesthesia time (from anesthetic induction to the cessation of isoflurane administration) for the 5 treatment days ranged from 54 to 63 minutes. At the end of the procedure on treatment day 1, the patient was given neostigmine methylsulfate (0.02 mg/kg, IV) and atropine (0.01 mg/kg, IV). On subsequent treatment days, the patient was given only neostigmine (0.04 mg/kg [0.018 mg/lb], IV). Dopamine was delivered as a constant rate infusion (5 μg/kg/min [2.3 g/lb/min], IV) when mean arterial pressure decreased below 70 mm Hg. On the third treatment day, oxygen saturation was 77% to 92% once oxygen delivery was discontinued. Thoracentesis was performed, and oxygen saturation subsequently improved. Prednisone (0.5 mg/kg [0.23 mg/lb], PO, q 24 h) was administered for at least 30 days in an attempt to reduce radiation-induced inflammation following treatment.
An 8-year-old castrated male Bulldog (dog 2) was examined at the University of Florida Small Animal Hospital because of coughing, a heart base tumor, and supraventricular tachycardia. The heart base tumor was further evaluated by means of CT with the patient under general anesthesia. For this procedure, the patient was premedicated with butorphanol (0.2 mg/kg, IV), and anesthesia was induced with propofol (0.2 mg/kg, IV) and midazolam (0.22 mg/kg [0.1 mg/lb], IV). The patient was orotracheally intubated, and anesthesia was maintained with isoflurane in oxygen (3 L/min) delivered via a circle rebreathing system. Monitoring was the same as described for dog 1, except that blood pressure was also directly measured. The patient was positioned in the same fashion as described for dog 1, and CT was performed.
Stereotactic body radiation therapy was subsequently performed as described for dog 1, with daily cone-beam CT used to confirm patient positioning. A total of 21 Gy was delivered in three 7-Gy fractions on 3 consecutive days. A tumor volume of 7.8 × 7.4 × 8.0 cm plus a 0.5-cm PTV expansion for interfraction and intrafraction movement was used. Radiation exposure of surrounding normal tissue was limited in accordance with published recommendations.1–3
For anesthesia for radiation therapy, the same premedication, induction, and maintenance agents used for the initial CT were administered. Isoflurane and oxygen were delivered with the same circle rebreathing system, incorporating 15-m hoses, described for dog 1. On the second treatment day, a higher dose of butorphanol (0.3 mg/kg, IV) premedication was used. Dexamethasone (0.14 mg/kg [0.064 mg/lb], IV) was given each day during treatment.
Neuromuscular blockade was achieved with atracurium besylate (0.1 mg/kg, IV). The response to atracurium was monitored with a nerve stimulator and visual assessment as described for dog 1.
Treatment delivery and breath holds lasted between 42.5 and 59.9 seconds for each field at a dose rate of 600 MU/min. Immediately following each breath hold, assisted or mechanical ventilation was resumed. This was repeated for all 7 treatment fields. Total anesthesia time (from anesthetic induction to cessation of isoflurane administration) for the 3 treatment days ranged from 77 to 92 minutes. At the end of the procedure on each treatment day, the patient was given neostigmine (0.02 mg/kg, IV).
A 7-year-old spayed female Dogue de Bordeaux (dog 3) was examined at the University of Florida Small Animal Hospital because of appendicular osteosarcoma. Thoracic CT was performed as part of tumor staging, and a heart base tumor was identified. For CT, the patient was premedicated with hydromorphone (0.1 mg/kg, IV), and anesthesia was induced with propofol (2 mg/kg [0.9 mg/lb], IV). The patient was orotracheally intubated, and anesthesia was maintained with isoflurane in oxygen (3 L/min) delivered via a circle rebreathing system. Monitoring was the same as described for dog 1. Dopamine was delivered as a constant rate infusion (5 μg/kg/min, IV) when mean arterial pressure decreased below 70 mm Hg. The patient was positioned in the same fashion as described for dog 1.
Stereotactic body radiation therapy was performed as described for dog 1, with daily cone-beam CT to confirm patient positioning. A total of 24 Gy was delivered in three 8-Gy fractions on 3 consecutive days. A tumor volume of 2.5 × 3.2 × 2.8 cm plus a 0.5-cm PTV expansion for interfraction and intrafraction movement was used. Radiation exposure of surrounding normal tissue was limited in accordance with published recommendations.1–3
For anesthesia for radiation therapy, the same premedication and maintenance agents used for the initial CT were administered, except that midazolam (0.2 mg/kg, IV) was used in addition to propofol for anesthetic induction. Isoflurane and oxygen were delivered with the same circle rebreathing system, incorporating 15-m hoses, described for dog 1. On subsequent days, the anesthetic protocol remained the same, except on treatment day 2 when atropine (0.008 mg/kg [0.0036 mg/lb], IV) was used in addition to butorphanol for premedication.
Neuromuscular blockade was achieved with vecuronium (0.1 mg/kg, IV). The response to vecuronium was monitored with a nerve stimulator and visual assessment as described for dog 1.
Treatment delivery and breath holds lasted between 11.1 and 15.9 seconds for each field at a dose rate of 600 MU/min. Immediately following the breath hold, assisted or mechanical ventilation was resumed. This was repeated for all 12 treatment fields. Total anesthesia time (from anesthetic induction to cessation of isoflurane administration) for the 3 treatment days ranged from 80 to 120 minutes. At the end of the procedure on treatment days 1 and 2, the patient was given neostigmine (0.02 mg/kg, IV [treatment day 1] and 0.1 mg/kg, IV [treatment day 2]). Neostigmine was not given on the third treatment day. Prednisone (0.5 mg/kg, PO, q 24 h) was administered for at least 30 days in an attempt to reduce radiation-induced inflammation following treatment.
A 9-year-old castrated male Miniature Schnauzer (dog 4) was examined at the University of Florida Small Animal Hospital because of syncopal episodes. Thoracic CT was performed, and a heart base tumor was diagnosed. For CT, the patient was premedicated with methadone (0.5 mg/kg, IV), and anesthesia was induced with etomidate (1.16 mg/kg [0.53 mg/lb], IV) and midazolam (0.25 mg/kg [0.11 mg/lb], IV). The patient was orotracheally intubated, and anesthesia was maintained with isoflurane in oxygen (3 L/min) delivered via a circle rebreathing system. Monitoring was the same as described for dog 1. Dopamine was delivered as a constant rate infusion (5 μg/kg/min, IV) when mean arterial pressure decreased below 70 mm Hg. The patient was positioned in the same fashion as described for dog 1.
Stereotactic body radiation therapy was performed in the same manner as described for dog 1, with daily cone-beam CT to confirm patient positioning. A total of 21 Gy was delivered in three 7-Gy fractions on 3 consecutive days. A tumor volume of 3.8 × 3.7 × 3.0 cm plus a 0.5-cm PTV expansion for interfraction and intrafraction movement was used. Radiation exposure of surrounding normal tissue was limited in accordance with published recommendations.1–3
For anesthesia for radiation therapy, the patient was premedicated with butorphanol (0.2 mg/kg, IV), and anesthesia was induced with propofol (5 mg/kg [2.3 mg/lb], IV) and midazolam (0.3 mg/kg, IV). Anesthesia was maintained either with isoflurane in oxygen (3 L/min) delivered with the same circle rebreathing system, incorporating 15-m hoses, described for dog 1 or with a constant rate infusion of propofol (200 to 400 μg/kg/min [91 to 182 g/lb/min], IV, to effect) and administration of 100% oxygen.
Neuromuscular blockade was achieved with atracurium (0.25 mg/kg, IV). The response to atracurium was monitored with a nerve stimulator and visual assessment as described for dog 1. Following administration of the first dose of atracurium, a constant rate infusion (10 μg/kg/h [4.5 μg/kg/h], IV) was administered.
Treatment delivery and breath holds lasted between 6.9 and 9.5 seconds for each field at a dose rate of 600 MU/min. Immediately following each breath hold, assisted or mechanical ventilation was resumed. This was repeated for all 14 treatment fields. Total anesthesia time (from anesthetic induction to the cessation of isoflurane or propofol administration) for the 3 treatment days ranged from 125 to 210 minutes. At the end of the procedure on each treatment day, the patient was given edrophonium chloride (0.02 mg/kg, IV) and glycopyrrolate (0.01 mg/kg, IV). Prednisone (0.5 mg/kg, PO, q 24 h) was administered for at least 30 days in an attempt to reduce radiation-induced inflammation following treatment.
Discussion
With SBRT, radiation therapy is performed with larger doses of radiation delivered to the patient per fraction but at a lower total dose, compared with doses used with conventional fractionated radiation therapy protocols. Stereotactic body radiation therapy also requires fewer anesthetic events.4 However, because larger radiation doses are being used, protecting normal tissues from radiation is critical. Meticulous care is required to ensure accurate patient positioning, which is achieved through the use of patient positioning devices, bite blocks, thermoplastic masks, and indexed vacuum mattresses, along with daily image guidance. Stereotactic body radiation therapy requires a steep dose gradient; therefore, if the patient is even slightly out of position, a large dose of radiation may be delivered to adjacent normal tissues, with inadequate dose delivery to the tumor. When patients can be positioned accurately and without motion, the PTV can be decreased, with less radiation delivered to normal tissues. Delivery of radiation to normal tissues in the thorax may result in severe acute and chronic adverse effects, including pneumonitis, pericarditis, esophagitis, esophageal stricture, and myocardial, pericardial, and pulmonary fibrosis.1,2 These adverse effects can be associated with considerable morbidity; thus, measures should be used to avoid them whenever possible.
Delivery of radiation to tumors within the thoracic cavity poses a challenge because of constant cardiac and respiratory motion. Various efforts have been made in human patients to decrease the effects of motion on the delivery of radiation to intrathoracic tumors, specifically those in the pulmonary parenchyma. Placement of an abdominal compression device that limits inspiration and forces shallow breathing has been reported.5 Respiratory gating is the delivery of radiation while the tumor is within a specific, predetermined phase of respiration or gate as assessed by means of 4-dimensional CT or by tracking tumor position with a radiopaque tumor implant. The beam is turned off when the phase of respiration is outside the treatment parameters.5 Free breathing methods have been used whereby the entire path of the tumor throughout the respiratory phase is irradiated and the patient is allowed to breathe freely. This method ensures tumor coverage at all phases of respiration but deliberately increases the normal tissue dose.6 The application of respiratory gating is not widely available in veterinary hospitals; however, because veterinary patients require general anesthesia for treatment, controlled ventilation and breath-holding techniques are feasible.
We are not aware of previous published reports describing the use of controlled ventilation during radiation therapy in veterinary patients. The 4 dogs in the present report were treated with an inspiratory breath-hold technique to decrease respiratory motion during SBRT and did not exhibit any apparent adverse effects. Implementation of this technique allowed for delivery of radiation in a safe and timely manner. With the anesthesia machine and ventilator positioned outside the vault (ie, in the control room), the anesthesiologist was able to control the phase of respiration without having to enter the radiation vault. Having the ventilator in the control room allowed close monitoring of the patient's respiration. If the patient resumed spontaneous ventilation during radiation delivery, the bellows on the ventilator or the rebreathing bag would move and the beam could be turned off. Alternatively, the anesthesiologist would need to rely on a camera to watch for patient motion or on a capnograph, resulting in a delay in identification of patient motion and potential complications, including misadministration of radiation therapy.
The inspiratory breath-hold protocol was created to reduce respiratory motion during SBRT of structures within the thorax. The protocol we used was developed on the basis of published evidence of the effects of prolonged breath holding in dogs.7 McNally et al7 compared the time to desaturation in a group of healthy dogs breathing either 100% oxygen or room air for 3 minutes prior to induction of anesthesia with propofol (6 mg/kg [2.7 mg/lb], IV, administered over 7 seconds to induce apnea). In that study, oxygen saturation as well as serial arterial blood gas measurements were recorded; mean time to desaturation when dogs were breathing oxygen was 297.8 seconds, compared with 69.6 seconds when dogs were breathing room air. In comparison, patients described in the present report received an inspired oxygen fraction < 100% during anesthesia and had intrathoracic disease. Thus, they may have had less respiratory reserve, compared with healthy dogs, although none had evidence of pulmonary parenchymal disease on the basis of results of CT. Maximum duration of breath holding was < 60 seconds, which was < 25% of the median time to desaturation previously reported for dogs.7 Furthermore, alveolar gas exchange continues even in the absence of ventilation. Overall, therefore, the lack of evidence of desaturation for the 4 dogs described in the present report suggested that the inspiratory breath-hold technique may be feasible and safe in carefully selected and monitored patients.
When using the protocol described in the present report, the length of the inspiratory and expiratory tubes in the circle rebreathing system and the effect this may have on the anesthetic system should be considered. Increased length of tubing will considerably impact the volume of the anesthetic circuit. For this reason, it is important to prefill the system with 100% oxygen before attaching it to the patient. If an inhalant agent is being used, this can be flushed into the system before attachment to the patient to decrease the time needed to reach inspired concentrations adequate to maintain an acceptable plane of anesthesia. If the plane of anesthesia needs to be altered during treatment, doing so simply by changing the delivered inhalant concentration may take longer than desired and would require a high fresh gas flow rate.8 For this reason, the patient should be at a steady plane of anesthesia before the radiation vault is secured for treatment. In addition, inclusion of IV anesthetic agents in the anesthetic protocol may prove beneficial. A potential complication reported for the inspiratory breath-hold protocol in human patients is that increasing the intrathoracic pressure to 20 cm H2O for 1 minute may induce a notable decrease in venous return, increasing the risk for hypotension.9 Hypotension is common in dogs under general anesthesia,10 and 3 of 4 patients described in the present report had hypotension requiring treatment. However, in all 3 dogs, treatment for hypotension was discontinued at the end of the anesthetic period with no apparent adverse sequelae.
The benefits of the inspiratory breath-hold protocol, including potential radiation-sparing effects on adjacent normal tissues, need to be considered against the risk of potential complications. Full inspiration will cause the overall lung volume to be increased, and therefore, lung that may be exposed to radiation will have a higher air-to-tissue ratio, which will theoretically decrease the volume of lung tissue affected, compared with lung tissue exposed at exhalation.6,11 In our opinion and considering current available knowledge, the potential benefits outweigh the risks. Nonetheless, additional research is required to further evaluate SBRT for the treatment of heart base tumors in dogs, and we cannot currently state which modality is most appropriate for delivery of radiation therapy for these types of tumors. The use of the inspiratory breath-hold protocol in the 4 dogs of the present report dogs undergoing SBRT for heart base tumors was relatively inexpensive and without apparent complications. Because many radiation vaults have wall mazes similar to that described in the present report, a similar setup may be applicable to other hospitals for treatment of patients with intrathoracic tumors.
Acknowledgments
Supported by The Olive's Way Foundation, University of Florida College of Veterinary Medicine.
Procedures were performed at the University of Florida College of Veterinary Medicine between 2009 and 2014.
ABBREVIATIONS
| PTV | Planning target volume |
| SBRT | Stereotactic body radiation therapy |
Footnotes
Aquilion CT scanner, Toshiba America Medical Systems Inc, Tustin, Calif.
Vac-Lok mattress, CIVCO Medical Solutions, Coralville, Iowa.
Varian 21EX Linear Accelerator, Varian Medical System, Palo Alto, Calif.
Eclipse Treatment Planning System, Varian Medical System, Palo Alto, Calif.
IntelliVue MP50, Philips Healthcare, Andover, Mass.
Dupaco nerve stimulator, Model 54120, Dupaco Inc, Oceanside, Calif.
Model 2000, Hallowell EMC, Pittsfield, Mass.
References
1. Gillette EL, LaRue SM, Gilette SM. Normal tissue tolerance and management of radiation injury. Semin Vet Med Surg (Small Anim) 1995; 10: 209–213.
2. Harris D, King GK, Bergman PJ. Radiation therapy toxicities. Vet Clin North Am Small Anim Pract 1997; 27: 37–46.
3. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991; 21: 109–122.
4. Benedict SH, Yenice KM, Followill D, et al. Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med Phys 2010; 37: 4078–4101.
5. Keall PJ, Mageras GS, Balter JM, et al. The management of respiratory motion in radiation oncology: report of AAPM Task Group 76. Med Phys 2006; 33: 3874–3900.
6. Hau E, Rains M, Browne L, et al. Minimal benefit of respiratory-gated radiation therapy in the management of thoracic malignancy. J Med Imaging Radiat Oncol 2013; 57: 704–712.
7. McNally EM, Robertson SA, Pablo LS. Comparison of time to desaturation between preoxygenated and nonpreoxygenated dogs following sedation with acepromazine maleate and morphine and induction of anesthesia with propofol. Am J Vet Res 2009; 70: 1333–1338.
8. Dugdale A. Veterinary anaesthesia: principles to practice. Ames, Iowa: Wiley-Blackwell, 2010; 88.
9. Santanilla JI. The crashing ventilated patient. In: Winters ME, DeBlieux P, Marcolini EG, eds. Emergency department resuscitation of the critically ill. Vasalia, Calif: American College of Emergency Physicians, 2011; 15–22.
10. Redondo JI, Rubio M, Soler G, et al. Normal values and incidence of cardiorespiratory complications in dogs during general anaesthesia. A review of 1281 cases. J Vet Med A Physiol Pathol Clin Med 2007; 54: 470–477.
11. Petersen PM, Aznar MC, Berthelsen AK, et al. Prospective phase II trial of image-guided radiotherapy in Hodgkin lymphoma: benefit of deep inspiration breath-hold. Acta Oncol 2015; 54: 60–66.
