Original Investigation
Efficacy of Intravenous Mannitol in the Management of Orbital Compartment Syndrome: A Nonhuman Primate Model Davin Johnson, M.D.*, Andrew Winterborn, D.V.M., D.A.C.L.A.M.†, and Vladimir Kratky, M.D., F.R.C.S.C..* *Department of Ophthalmology, †Office of the University Veterinarian, Queen’s University, Kingston, Ontario, Canada
Purpose: To report the efficacy of intravenous mannitol in the treatment of orbital compartment syndrome. Methods: An experimental study was conducted on 4 nonhuman primates (8 orbits). Orbital compartment syndrome was simulated by injecting autologous blood into both orbits of each nonhuman primate until a pressure of 80 mm Hg was reached (time 0). After 10 minutes, nonhuman primates were randomized to receive an infusion of either mannitol or saline, given over 15 minutes. Five minutes after the infusion was complete, lateral canthotomy and cantholysis was performed on both orbits in isolated steps every 5 minutes. During the study protocol, orbital and intraocular pressures were recorded every 5 minutes, with a final set of measurements at 60 minutes. The primary outcome measures were the mean change in pressure from time 0 to 60 minutes, as well as the mean change in pressure during the infusion period. Results: There was no statistically significant difference in the mean changes in orbital or intraocular pressure from time 0 to 60 minutes of the protocol. However, during the infusion period there was significantly greater decrease in both orbital and intraocular pressure in the mannitol compared with saline group (-34.0 vs. -9.3 mm Hg for orbital pressure [p = 0.03]; -34.8 vs. -9.7 mm Hg for intraocular pressure [p = 0.04]). Conclusions: While the definitive treatment of orbital compartment syndrome is lateral canthotomy and cantholysis, mannitol results in a rapid and clinically meaningful drop in orbital and intraocular pressure. The authors believe that their data support the routine use of mannitol in orbital compartment syndrome, especially when there is a delay in timely surgical management. (Ophthal Plast Reconstr Surg 2015;XX:00–00)
O
rbital compartment syndrome (OCS) is a potentially devastating ocular emergency characterized by an acute rise in orbital pressure that decreases perfusion to the retina and optic nerve.1,2 Most often it is caused by retrobulbar hemorrhage,1 but may be due to a variety of causes including orbital cellulitis, nonspecific orbital inflammation, and others.1,3 Accepted for publication January 23, 2015. The study was funded by a Research Initiation Grant through Queen’s University (#383-150). Presented at ASOPRS Fall Scientific Symposium (October 2014; Chicago, IL). The authors have no financial or conflicts of interests to disclose. Address correspondence and reprint requests to Dr. Vladimir Kratky, M.D., F.R.S.C., Associate Professor of Ophthalmology, Department of Ophthalmology, Queen’s University, Hotel Dieu Hospital, 166 Brock Street, Kingston, Ontario K7L5G2, United Kingdom. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000463
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2015
The gold-standard treatment for OCS is a lateral canthotomy and cantholysis, which allows orbital contents to expand forward and increase orbital volume, thereby decreasing pressure.1,4 Cadaver models in humans have demonstrated that this results in a significant decrease in orbital pressure,5,6 and if performed within 60 to 90 minutes may prevent permanent vision loss.7 As an adjunct to lateral canthotomy and cantholysis, many experts advocate the use of medical treatment, in particular intravenous mannitol, in the treatment of OCS.1,8–13 Mannitol is an osmotic diuretic that draws interstitial and intracellular fluid into the intravascular space, and is frequently used in the treatment of acute angle closure glaucoma and cerebral edema.14 In the setting of OCS, it is proposed that mannitol decreases vitreous and possibly orbital volume, thereby helping to restore perfusion to the globe. Because OCS has a varied presentation and occurs rarely and unexpectedly, there are few evidence-based guidelines regarding the treatment of the condition.6 While cadaver models have studied the efficacy of surgical measures to relieve OCS, there are no studies available evaluating the efficacy of mannitol.1 In addition to a lack of supporting evidence, many experts avoid the use of mannitol due to concern over the potential for serious systemic adverse effects. The purpose of this study was to determine the effectiveness of intravenous mannitol as an adjunct to lateral canthotomy and cantholysis in the treatment of OCS using a nonhuman primate (NHP) model.
MATERIALS AND METHODS An experimental model was designed to simulate OCS caused by retrobulbar hemorrhage. The authors utilized NHPs due to the close resemblance of orbital anatomy and function to humans,15–17 most importantly the completely enclosed orbital cavity which is not seen in lower mammals.18 The objective of the study was to investigate whether the addition of intravenous mannitol prior to a lateral canthotomy and cantholysis results in an added benefit in lowering orbital and/or intraocular pressure. A total of 4 Macaca fascicularis monkeys (8 orbits) were used in the study, with all NHPs being otherwise healthy and naive to any other research. Sample size calculations were performed using data from cadaver studies of canthotomy and cantholysis using a power of 0.80 and α of 0.05. The protocol was designed to be as minimally invasive as possible and to not result in vision loss. Thus, the authors avoided use of balloon catheters to raise orbital pressure as performed in previous NHP studies,19,20 and instead used fresh autologous blood. The authors also limited the duration of their study protocol to 60 minutes, far less than the 100 to 120 minutes known to be the minimum duration of high orbital pressure needed to cause permanent vision loss in NHPs.18,21 During the study period, intraocular pressure was measured with a portable tonometer (Tonopen), while orbital pressure was measured using a Stryker Intra-Compartmental Pressure Monitor system, a technique initially described by Kratky et al.22 for orbital application.
1
Copyright © 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2015
D. Johnson et al.
Nonhuman primates used in the study were sedated with a single intramuscular injection of ketamine (10 mg/kg) and diazepam (0.5 mg/ kg), and subsequently intubated and maintained under general anesthesia using isoflurane gas (1.5% to 2.0%). After a baseline measurement of intraocular pressure in both eyes, the orbital pressure probe was introduced in the superior medial orbit of both sides through a large bore needle to a depth of 1.5 to 2 cm. The needle was then removed and the plastic measuring probe secured in place using steri-strips. After baseline measurements of orbital pressure, blood was collected from the saphenous vein in a nonheparinized syringe and immediately injected into the inferior medial aspect of both orbits between the floor and muscle cone until the orbital pressure reached approximately 80 mm Hg (time 0). These sites were chosen to be anatomically away from the lateral canthal surgery. Orbital and intraocular pressures were repeated on both sides every 5 minutes during the 60-minute-study period. At the 10-minute mark, NHPs were randomized to receive an infusion of either mannitol (1 g/kg of 20% solution) or an equal volume of normal saline, both of which were infused over 15 minutes. At the 30-minute mark (5 minutes after infusions had ended), approximately 1 ml of 0.5% bupivacaine was injected into the lateral canthus on both sides, followed immediately by a lateral canthotomy. This was followed 5 minutes later by an inferior cantholysis on both sides (at 35 minutes), and 5 minutes later by a superior cantholysis (at 40 minutes). At 60 minutes, a final set of pressure measurements were recorded. Periocular incisions were then meticulously repaired using 5-0 vicryl sutures and the NHPs were awoken and transferred to the animal housing facility. During the study, animal handling and anesthesia induction and monitoring were carried out by the supervising veterinarian. The primary outcomes of the study were the change in orbital and intraocular pressure from time 0 to the end of the study period at 60 minutes, as well as the changes in orbital and intraocular pressure during the infusion period from 10 to 30 minutes. Secondary outcomes included the changes in pressure after each step of the lateral canthotomy and cantholysis, as well as the correlation between intraocular and orbital pressure. Differences between groups were compared using a t test, and the authors examined correlation between intraocular and orbital pressure using the Pearson correlation coefficient. During the entire study protocol, all pressure measurements and surgical procedures were performed by the principal investigator (VK), who was blinded to the group allocation. The protocol was approved by the Queen’s University Animal Care Committee and followed guidelines of the Canadian Council on Animal Care. Nonhuman primates used in the study were not euthanized following the study and fully recovered from the procedure without consequences.
TABLE 1. Changes in orbital and intraocular pressure during study protocol (mm Hg)
RESULTS
TABLE 2. Mean changes in orbital and intraocular pressure after each step of canthotomy and cantholysis (mm Hg [standard error])
A total of 4 NHPs were utilized in the study (3 males, 1 female), with a mean weight of 8.2 kg (range 4.6–9.9 kg). Two NHPs (n = 4 orbits) were randomized to the saline group and 2 NHPs (n = 4 orbits) were randomized to receive mannitol. The mean orbital and intraocular pressures at all time points during the study period are displayed in Figure A and B, respectively. There was no statistically significant difference in orbital or intraocular pressure between the 2 groups at either time 0 or 60 minutes. Table 1 displays the mean decrease in orbital and intraocular pressure from start to finish of the protocol, as well as during the infusion period from 10 to 30 minutes. While the overall mean decreases in orbital and intraocular pressures from time 0 to 60 minutes were not significantly different between the 2 groups, there was a significantly greater reduction of both orbital and intraocular pressure in the mannitol group during the infusion period (-34.0 vs. -9.3 mm Hg for orbital pressure [p = 0.03]; -34.8 vs. -9.7 for intraocular pressure [p = 0.04]). The mean changes in orbital and intraocular pressures with each step of the canthotomy and cantholysis are displayed in Table 2.
2
Saline group (n = 4 orbits) Total change OP IOP Infusion change* OP IOP
Mannitol group (n = 4 orbits)
p
-54.7 -63.7
-62.8 -63.8
0.25 0.99
-9.3 -9.7
-34.0 -34.8
0.03 0.04
*Difference between pressures at 10 and 30 minutes. IOP, intraocular pressure; OP, orbital pressure. bolded figures indicate statistical significance (p
Efficacy of Intravenous Mannitol in the Management of Orbital Compartment Syndrome: A Nonhuman Primate Model Davin Johnson, M.D.*, Andrew Winterborn, D.V.M., D.A.C.L.A.M.†, and Vladimir Kratky, M.D., F.R.C.S.C..* *Department of Ophthalmology, †Office of the University Veterinarian, Queen’s University, Kingston, Ontario, Canada
Purpose: To report the efficacy of intravenous mannitol in the treatment of orbital compartment syndrome. Methods: An experimental study was conducted on 4 nonhuman primates (8 orbits). Orbital compartment syndrome was simulated by injecting autologous blood into both orbits of each nonhuman primate until a pressure of 80 mm Hg was reached (time 0). After 10 minutes, nonhuman primates were randomized to receive an infusion of either mannitol or saline, given over 15 minutes. Five minutes after the infusion was complete, lateral canthotomy and cantholysis was performed on both orbits in isolated steps every 5 minutes. During the study protocol, orbital and intraocular pressures were recorded every 5 minutes, with a final set of measurements at 60 minutes. The primary outcome measures were the mean change in pressure from time 0 to 60 minutes, as well as the mean change in pressure during the infusion period. Results: There was no statistically significant difference in the mean changes in orbital or intraocular pressure from time 0 to 60 minutes of the protocol. However, during the infusion period there was significantly greater decrease in both orbital and intraocular pressure in the mannitol compared with saline group (-34.0 vs. -9.3 mm Hg for orbital pressure [p = 0.03]; -34.8 vs. -9.7 mm Hg for intraocular pressure [p = 0.04]). Conclusions: While the definitive treatment of orbital compartment syndrome is lateral canthotomy and cantholysis, mannitol results in a rapid and clinically meaningful drop in orbital and intraocular pressure. The authors believe that their data support the routine use of mannitol in orbital compartment syndrome, especially when there is a delay in timely surgical management. (Ophthal Plast Reconstr Surg 2015;XX:00–00)
O
rbital compartment syndrome (OCS) is a potentially devastating ocular emergency characterized by an acute rise in orbital pressure that decreases perfusion to the retina and optic nerve.1,2 Most often it is caused by retrobulbar hemorrhage,1 but may be due to a variety of causes including orbital cellulitis, nonspecific orbital inflammation, and others.1,3 Accepted for publication January 23, 2015. The study was funded by a Research Initiation Grant through Queen’s University (#383-150). Presented at ASOPRS Fall Scientific Symposium (October 2014; Chicago, IL). The authors have no financial or conflicts of interests to disclose. Address correspondence and reprint requests to Dr. Vladimir Kratky, M.D., F.R.S.C., Associate Professor of Ophthalmology, Department of Ophthalmology, Queen’s University, Hotel Dieu Hospital, 166 Brock Street, Kingston, Ontario K7L5G2, United Kingdom. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000463
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2015
The gold-standard treatment for OCS is a lateral canthotomy and cantholysis, which allows orbital contents to expand forward and increase orbital volume, thereby decreasing pressure.1,4 Cadaver models in humans have demonstrated that this results in a significant decrease in orbital pressure,5,6 and if performed within 60 to 90 minutes may prevent permanent vision loss.7 As an adjunct to lateral canthotomy and cantholysis, many experts advocate the use of medical treatment, in particular intravenous mannitol, in the treatment of OCS.1,8–13 Mannitol is an osmotic diuretic that draws interstitial and intracellular fluid into the intravascular space, and is frequently used in the treatment of acute angle closure glaucoma and cerebral edema.14 In the setting of OCS, it is proposed that mannitol decreases vitreous and possibly orbital volume, thereby helping to restore perfusion to the globe. Because OCS has a varied presentation and occurs rarely and unexpectedly, there are few evidence-based guidelines regarding the treatment of the condition.6 While cadaver models have studied the efficacy of surgical measures to relieve OCS, there are no studies available evaluating the efficacy of mannitol.1 In addition to a lack of supporting evidence, many experts avoid the use of mannitol due to concern over the potential for serious systemic adverse effects. The purpose of this study was to determine the effectiveness of intravenous mannitol as an adjunct to lateral canthotomy and cantholysis in the treatment of OCS using a nonhuman primate (NHP) model.
MATERIALS AND METHODS An experimental model was designed to simulate OCS caused by retrobulbar hemorrhage. The authors utilized NHPs due to the close resemblance of orbital anatomy and function to humans,15–17 most importantly the completely enclosed orbital cavity which is not seen in lower mammals.18 The objective of the study was to investigate whether the addition of intravenous mannitol prior to a lateral canthotomy and cantholysis results in an added benefit in lowering orbital and/or intraocular pressure. A total of 4 Macaca fascicularis monkeys (8 orbits) were used in the study, with all NHPs being otherwise healthy and naive to any other research. Sample size calculations were performed using data from cadaver studies of canthotomy and cantholysis using a power of 0.80 and α of 0.05. The protocol was designed to be as minimally invasive as possible and to not result in vision loss. Thus, the authors avoided use of balloon catheters to raise orbital pressure as performed in previous NHP studies,19,20 and instead used fresh autologous blood. The authors also limited the duration of their study protocol to 60 minutes, far less than the 100 to 120 minutes known to be the minimum duration of high orbital pressure needed to cause permanent vision loss in NHPs.18,21 During the study period, intraocular pressure was measured with a portable tonometer (Tonopen), while orbital pressure was measured using a Stryker Intra-Compartmental Pressure Monitor system, a technique initially described by Kratky et al.22 for orbital application.
1
Copyright © 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2015
D. Johnson et al.
Nonhuman primates used in the study were sedated with a single intramuscular injection of ketamine (10 mg/kg) and diazepam (0.5 mg/ kg), and subsequently intubated and maintained under general anesthesia using isoflurane gas (1.5% to 2.0%). After a baseline measurement of intraocular pressure in both eyes, the orbital pressure probe was introduced in the superior medial orbit of both sides through a large bore needle to a depth of 1.5 to 2 cm. The needle was then removed and the plastic measuring probe secured in place using steri-strips. After baseline measurements of orbital pressure, blood was collected from the saphenous vein in a nonheparinized syringe and immediately injected into the inferior medial aspect of both orbits between the floor and muscle cone until the orbital pressure reached approximately 80 mm Hg (time 0). These sites were chosen to be anatomically away from the lateral canthal surgery. Orbital and intraocular pressures were repeated on both sides every 5 minutes during the 60-minute-study period. At the 10-minute mark, NHPs were randomized to receive an infusion of either mannitol (1 g/kg of 20% solution) or an equal volume of normal saline, both of which were infused over 15 minutes. At the 30-minute mark (5 minutes after infusions had ended), approximately 1 ml of 0.5% bupivacaine was injected into the lateral canthus on both sides, followed immediately by a lateral canthotomy. This was followed 5 minutes later by an inferior cantholysis on both sides (at 35 minutes), and 5 minutes later by a superior cantholysis (at 40 minutes). At 60 minutes, a final set of pressure measurements were recorded. Periocular incisions were then meticulously repaired using 5-0 vicryl sutures and the NHPs were awoken and transferred to the animal housing facility. During the study, animal handling and anesthesia induction and monitoring were carried out by the supervising veterinarian. The primary outcomes of the study were the change in orbital and intraocular pressure from time 0 to the end of the study period at 60 minutes, as well as the changes in orbital and intraocular pressure during the infusion period from 10 to 30 minutes. Secondary outcomes included the changes in pressure after each step of the lateral canthotomy and cantholysis, as well as the correlation between intraocular and orbital pressure. Differences between groups were compared using a t test, and the authors examined correlation between intraocular and orbital pressure using the Pearson correlation coefficient. During the entire study protocol, all pressure measurements and surgical procedures were performed by the principal investigator (VK), who was blinded to the group allocation. The protocol was approved by the Queen’s University Animal Care Committee and followed guidelines of the Canadian Council on Animal Care. Nonhuman primates used in the study were not euthanized following the study and fully recovered from the procedure without consequences.
TABLE 1. Changes in orbital and intraocular pressure during study protocol (mm Hg)
RESULTS
TABLE 2. Mean changes in orbital and intraocular pressure after each step of canthotomy and cantholysis (mm Hg [standard error])
A total of 4 NHPs were utilized in the study (3 males, 1 female), with a mean weight of 8.2 kg (range 4.6–9.9 kg). Two NHPs (n = 4 orbits) were randomized to the saline group and 2 NHPs (n = 4 orbits) were randomized to receive mannitol. The mean orbital and intraocular pressures at all time points during the study period are displayed in Figure A and B, respectively. There was no statistically significant difference in orbital or intraocular pressure between the 2 groups at either time 0 or 60 minutes. Table 1 displays the mean decrease in orbital and intraocular pressure from start to finish of the protocol, as well as during the infusion period from 10 to 30 minutes. While the overall mean decreases in orbital and intraocular pressures from time 0 to 60 minutes were not significantly different between the 2 groups, there was a significantly greater reduction of both orbital and intraocular pressure in the mannitol group during the infusion period (-34.0 vs. -9.3 mm Hg for orbital pressure [p = 0.03]; -34.8 vs. -9.7 for intraocular pressure [p = 0.04]). The mean changes in orbital and intraocular pressures with each step of the canthotomy and cantholysis are displayed in Table 2.
2
Saline group (n = 4 orbits) Total change OP IOP Infusion change* OP IOP
Mannitol group (n = 4 orbits)
p
-54.7 -63.7
-62.8 -63.8
0.25 0.99
-9.3 -9.7
-34.0 -34.8
0.03 0.04
*Difference between pressures at 10 and 30 minutes. IOP, intraocular pressure; OP, orbital pressure. bolded figures indicate statistical significance (p
