Introduction
Anesthesia is an uncomplicated event for the majority of horses, with reported mortality rates ranging from 0.12% to 2% and most horses standing 30 to 60 minutes after anesthesia concludes.1–3 Postanesthetic myopathy (PAM) affects 0.81% to 2% of anesthetized horses, with a reported mortality rate of 16% to 20% for affected horses.3–8
A focal PAM/neuropathy can develop when horses are placed in lateral recumbency, affecting the triceps and extensor carpi radialis muscles or thigh muscles in the dependent limb, resulting in the inability to bear weight on that limb.6,9–11 A more generalized PAM impacting bilateral triceps, semimembranosus, semitendinosus, gluteal, hind limb adductor, pectoral, and epaxial muscles can also occur.11 This PAM is characterized by pain and distress, inability to remain standing, muscle fasciulations, markedly firm muscles, myoglobinuria, and severely increased muscle enzyme activity.11
The cause of PAM/neuropathy is complex, with heavy body weight, body position, mean arterial pressure (MAP) < 65 mm Hg, intracompartmental muscle pressure, and venous stasis believed to contribute to ischemia and muscle degeneration.4,9,12,13 In the histopathology reports of skeletal muscle associated with PAM, hyaline necrosis of myofibers, macrophage infiltration of fragmented fibers, and, in some draft breeds, amylase-resistant polysaccharide are described.14–16
Similar to draft horses, warmblood horses are those of a specific phenotype and can include many different breeds that share predispositions toward certain diseases.17–21 Draft breeds are known to have a high risk of PAM/neuropathy, with reported prevalence ranging from 7% to 8.3% compared to approximately 2% or less in a general horse population.3,6,7,22,23 The high prevalence of type 1 polysaccharide storage myopathy (PSSM1) in Belgian and Percheron draft breeds likely also increases the risk of PAM.16,24–26 In other breeds, such as the Quarter Horse, Paint, and Appaloosa breeds, heritable myopathies such as PSSM1, hyperkalemic periodic paralysis, and malignant hyperthermia (MH) increase susceptibility for postanesthetic complications, including PAM.14,27–29 No such predisposition for PAM has been described in warmblood breeds, despite a known predilection for type 2 PSSM and myofibrillar myopathy.30,31 The objective of this case series was to describe a unique and severe form of PAM identified in 7 warmblood horses.
Methods
Records from the Michigan State University and Valberg Neuromuscular Diagnostic Laboratory (NMDL) were reviewed from 2016 to 2023 to identify horses with PAM (N = 2,962). Complete medical records were requested from referring veterinarians for the warmblood horses. The anesthetic period was defined as the time from induction to standing.
Routine skeletal muscle histopathology was based on postmortem reports. Formalin-fixed skeletal muscle or unstained formalin-fixed paraffin-embedded slides submitted to the NMDL were stained with periodic acid–Schiff (PAS; hematoxylin counter stain) stain for glycogen and immunohistochemically labeled for desmin. Results were summarized by 1 author (SJV). Control PAS stains included a semimembranosus biopsy submitted fresh and placed in formalin 24 hours later and postmortem muscle samples from horses obtained at necropsy approximately 5, 12, and 24 hours after euthanasia (Supplementary Figure S1).
Results
Thirteen cases of PAM were identified, including 2 Quarter Horses, 2 Clydesdales, 1 Belgian, 1 Belgian/warmblood cross, and 7 warmbloods. Results of muscle histopathology were obtained for the non-warmblood horses (Supplementary Table S1). Complete medical records were obtained for 6 of the 7 warmbloods (horses 1 through 6). Limited information for horse 7 was obtained from the biopsy submission form. There were 6 geldings and 1 mare. Specific data regarding anesthesia are summarized in (Table 1). The 6 horses with complete medical records had a median age of 9 years (range, 4 to 18 years) and median weight of 615 kg (range, 550 to 703 kg) and were anesthetized for a median 146 minutes (range, 60 to 230 minutes). American Society of Anesthesiologists (ASA) classifications were recorded and based on a scale of 1 to 5, with 1 assigned to patients that were systemically healthy and not expected to have complications and 5 assigned to animals that were extremely ill and considered unlikely to survive.2 Four of 7 horses had an ASA score of 1, 1 horse each had an ASA score of 4 and 5, and 1 horse’s ASA score was unknown due to limited case details (horse 7). Mean arterial pressure was measured in 4 horses, and creatine kinase (CK) activity and lactate were measured at various time points in 5 of 6 horses (Figure 1; Supplementary Table S2).
The reason for anesthesia, anesthetic duration, induction and maintenance protocols, mean arterial pressure (MAP), arterial oxygen (po2), oxygen saturation (Spo2), quality of recovery, time until the horse was standing in recovery, diagnosis at imaging/surgery, and day euthanized for 7 warmblood horses that developed postanesthetic myopathy (PAM).
| Horse 1 | Horse 2 | Horse 3 | Horse 4 | Horse 5 | Horse 6 | Horse 7 | |
|---|---|---|---|---|---|---|---|
| Body weight (kg) | 619 | 610 | 550 | 560 | 703 | 637 | Unknown |
| ASA score | 1 | 4 | 1 | 1 | 1 | 5 | Unknown |
| Reason for anesthesia | Cervical CT | Exploratory | Exploratory | Bicipital bursa | Arthroscopy | Exploratory | Exploratory |
| Myelogram | celiotomy | celiotomy | injection | injection | celiotomy | celiotomy | |
| Duration of anesthesia (min) | 60 | 200 | 150 | 25 | 126 | 130 | Unknown |
| Premedication dose (mg/kg) | Xylazine: 0.2 | Xylazine: 1.1 | Xylazine: 0.5 | Xylazine: 1.1 | Detomidine: 0.01 | Xylazine: 0.8 | Unknown |
| Detomidine: 0.01 | Hydromorphone: 0.03 | Butorphanol: 0.01 | Acepromazine: 0.01 | ||||
| Induction (mg/kg) | Ketamine: 2.4 | Ketamine: 2.3 | Ketamine: 2.9 | Ketamine: 2.7 | Ketamine: 2.3 | Ketamine: 2.8 | Unknown |
| Midazolam: 0.1 | Midazolam:0.1 | Midazolam: 0.1 | Diazepam: 0.1 | Midazolam: 0.1 | Propofol: 0.3 | ||
| Recumbency | Lateral and dorsal | Dorsal | Dorsal | Left lateral | Dorsal | Dorsal | Dorsal |
| Anesthesia maintenance | Guaifenesin | Isoflurane | Isoflurane | Xylazine | Isoflurane | Isoflurane | Unknown |
| Ketamine | Ketamine | ||||||
| Xylazine | |||||||
| Intraoperative infusions/medications | None | Dobutamine | Dobutamine | None | Detomidine | Lidocaine | Unknown |
| Dexmedetomidine | Lidocaine | Dobutamine | Dobutamine | ||||
| Lidocaine | Ephedrine | Polymyxin B | |||||
| Butorphanol | |||||||
| Median MAP (range) (mm Hg) | Not assessed | 90 (68–105) | 75 (60–105) | Not assessed | 78 (58–92) | 80 (70–100) | Unknown |
| Median po2 (range) (mm Hg) | Not assessed | 301 (75–301) | 70 (58–158) | Not assessed | 122 (113–151) | 179 (98–294) | Unknown |
| Median Spo2 (range) (%) | Not assessed | 97 (92–99) | Not assessed | Not assessed | 99 (90–99) | 98 (97–98) | Unknown |
| Quality of recovery | Prolonged, poor | Prolonged, poor | Prolonged, poor | Prolonged, poor | Prolonged, poor | Prolonged, poor | Unknown |
| Time to standing (h) | Unknown | 4.5 | 6.5 | 4.5 with sling assistance | Never stood, sling assistance | 3 with sling assistance | Unknown |
| Diagnosis | Narrowed left intervertebral foramen at C7-T1 | Left dorsal displacement | Segmental volvulus | Lameness | Osteochondrosis | Entrapped jejunum | Colon torsion |
| Euthanized for PAM | Day 7 | No | Day 11 | Day 10 | In recovery | Later day 1 | Later day 1 |
ASA = American Society of Anesthesiologists classification.
Changes in mean arterial pressure and creatine kinase over time in 7 warmblood horses that developed postanesthetic myopathy. A—Mean arterial pressure (mm Hg) for the 4 horses (horses 2, 3, 5, and 6) in which it was measured during anesthesia. Mean arterial pressure was measured at 5-minute intervals for the duration of anesthesia in each case. The dotted line indicates 70 mm Hg. B—Serum creatine kinase activity for 7 horses experiencing postanesthetic myopathy. Day 0 is preanesthesia values, followed by the day of or preceding anesthesia.
Citation: Journal of the American Veterinary Medical Association 2024; 10.2460/javma.24.08.0522
Horse 1
A 5-year-old Oldenburg gelding weighing 619 kg underwent IV anesthesia to facilitate cervical CT and radiographic myelogram (Table 1). The horse was in regular work prior to anesthesia. Muscle enzyme activity was not measured prior to anesthesia. The horse was premedicated and anesthesia induced routinely, and the horse was maintained in lateral or dorsal recumbency with guaifenesin, xylazine, and ketamine. Imaging identified mild degenerative changes in multiple articulations and a narrowed left intervertebral foramen at the C7-T1 joint without spinal cord compression.
Time to standing was prolonged, and the morning after anesthesia (day 1), the horse appeared stiff and had increased serum AST (842 U/L) and CK activity (Figure 1). On day 2, IA corticosteroid injections were administered in the C6-C7 articular process joints. The horse was trailered approximately 6 hours after discharge and appeared stiff when unloaded. On day 3, bloodwork showed increased serum amyloid A (2,000 µg/mL; reference range, 20 to 50 µg/mL), therapy with sulfadiazine and trimethoprim (30 mg/kg, PO, q 24 h) and methocarbamol (dose unknown) was initiated, and phenylbutazone was continued. When stiffness failed to improve by day 5, the horse was referred to a university veterinary hospital, where bloodwork showed markedly increased activity of serum AST (13,284 U/L) and CK (Figure 1). Genetic tests for myosin-heavy chain myopathy, MH, and PSSM1 were negative.
The horse was administered acepromazine (0.003 mg/kg, IV) at admission, then treated on days 5 and 6 with phenylbutazone (4.2 mg/kg, IV, q 12 h), IV fluid therapy (IVF), a constant rate infusion of lidocaine (0.05 mg/kg/min), and vitamin E (8 IU/kg, PO, q 24 h). On day 6, dantrolene (2 mg/kg, PO, q 6 h) was added. The horse became recumbent and unable to rise on day 7 and was humanely euthanized by barbiturate overdose. Necropsy was performed 16 hours after euthanasia and revealed sharply demarcated pale areas bilaterally, with pinpoint foci of hemorrhage affecting up to 70% of the gluteal, semimembranosus, and caudal epaxial muscles (Figure 2).
Gross and histopathologic changes in skeletal muscle from horses 1 and 4 showing both acute and chronic evidence of myodegeneration. A—Pale friable skeletal muscle from horse 1. B—Hematoxylin and eosin stain of semimembranosus muscle from horse 1 showing severe subacute myocyte vacuolation, loss of cross-striation, and moderate numbers of histiocytes with lesser numbers of lymphocytes and plasma cells infiltrating myocytes. C—Skeletal muscle from horse 2 with pinpoint hemorrhages (arrow). D—Swollen, vacuolated myocytes with a small number of histiocytes and a few small atrophic fibers with internalized nuclei.
Citation: Journal of the American Veterinary Medical Association 2024; 10.2460/javma.24.08.0522
Muscle histopathology
The semimembranosus, gluteal, and caudal epaxial muscles had severe subacute bilateral skeletal myocyte necrosis characterized by swelling, vacuolation, and loss of cross-striation. In addition, chronic myodegeneration was evident, characterized by infiltration by moderate numbers of histiocytes and fewer numbers of lymphocytes and plasma cells (Figure 2). Intact, acutely necrotic, and degenerating myofibers were completely depleted of glycogen (Figure 3). Desmin immunolabeling was absent in degenerating fibers but present in smaller fibers, likely representing later stages of regeneration.
Skeletal muscles from horses 1 through 7 and control sections stained with periodic acid–Schiff stain for glycogen. Horizontal arrows indicate acute necrosis, and vertical arrows indicate chronic myodegeneration. Bar = 50 µm. A—Complete glycogen depletion, acute myofiber necrosis with vacuolation, and chronic myodegeneration with histiocytic and a few lymphocytic infiltrates in muscle from horse 1 obtained at postmortem 7 days after anesthesia (40X magnification). B—Mild glycogen depletion in a few fibers from a biopsy of the semimembranosus muscle of the surviving horse 2 obtained 14 days after anesthesia (40X magnification). C—Complete glycogen depletion, acute myofiber degeneration, and histiocytic and a few lymphocytic infiltrates in an adductor muscle from horse 3 obtained at postmortem 11 days after anesthesia (40X magnification). D—Complete glycogen depletion, acute myofiber necrosis, and chronic myodegeneration with histiocytic and a few lymphocytic infiltrates in semimembranosus muscle of horse 4 in a sample obtained at postmortem 10 days after anesthesia. E—Complete glycogen depletion and acute myofiber necrosis in an unspecified muscle from horse 5 obtained at postmortem within 24 hours of anesthesia (40X magnification). F—Minimal glycogen depletion, acute myofiber necrosis, and a few fibers with internalized myonuclei in semimembranosus muscle from horse 6 obtained at postmortem approximately 24 hours after anesthesia (40X magnification). G—Marked glycogen depletion and acute myonecrosis in a semimembranosus biopsy from horse 7 obtained 12 hours after euthanasia (40X magnification). H—Minimal glycogen depletion evident in a control semimembranosus muscle kept on ice packs and placed in formalin 24 hours after muscle biopsy (40X magnification). I—Moderate glycogen depletion and settling of glycogen in 1 portion of the myofiber in control muscle obtained at postmortem 16 hours after euthanasia (40X magnification).
Citation: Journal of the American Veterinary Medical Association 2024; 10.2460/javma.24.08.0522
Additional histopathology
Histopathology of the spinal cord revealed mild, regionally extensive axonal degeneration at C6-T1.
Horse 2
A 15-year-old Hanoverian gelding weighing 610 kg with no history of myopathy was evaluated for acute onset of signs of colic. Prior to the colic episode, the horse had been in regular dressage training. Muscle enzyme activity (Figure 1) at presentation was unremarkable. The following morning (day 1), the horse underwent exploratory celiotomy, which identified left dorsal displacement of the colon. Pelvic flexure enterotomy was performed, and anesthesia was considered uneventful (Table 1; Figure 1). The horse took 4.5 hours to stand and activity of serum CK increased. Blood lactate was within the normal range (< 2.0 mmol/L) during anesthesia and immediately after anesthesia but increased to 15 mmol/L at 120 minutes after anesthesia (Supplementary Table S1).
Pigmenturia developed after surgery, and the horse was maintained on IVF, flunixin meglumine (1.1 mg/kg, IV, q 12 h), potassium penicillin (22,000 IU/kg, IV, q 6 h), gentamicin (6.6 mg/kg, IV, q 24 h), and methocarbamol (25 mg/kg, PO, q 12 h). Serum activity of AST (1,457 U/L) and CK increased markedly (Figure 1). On day 3, CK activity decreased by > 50%, so methocarbamol was discontinued and dexamethasone was administered (0.05 mg/kg, IV). On day 4, serum CK activity increased slightly and activity of AST was 3,738 IU/L. The horse was tachypneic and anorectic, and the triceps and gluteal muscles were firm, fasciculating, and sensitive to palpation. Nasogastric intubation and abdominal ultrasound were within normal limits, and thoracic ultrasonography revealed mild pneumonia. Metronidazole (15 mg/kg, PO, q 8 h), and vitamin E (15 IU/kg, PO, q 24 h) were added to the treatment; morphine (0.1 mg/kg, IV, q 6 h) and an additional dose of dexamethasone (0.02 mg/kg, IV) were administered; and methocarbamol (25 mg/kg, PO, q 12 h) was restarted.
On day 5, the horse improved so IVF and dexamethasone were discontinued. On day 6, the horse was switched to oral antimicrobials, but shortly thereafter pigmenturia and muscle fasciculations recurred and CK activity increased (Figure 1). Intravenous fluid therapy was restarted, and antimicrobials were discontinued. Activity of CK on day 7 decreased slightly but increased on day 8, at which time routine-screening fecal samples were positive on PCR for Salmonella enterica. On day 9, CK activity decreased and dantrolene (2 mg/kg, PO, q 8 h) was added to the treatment protocol. Serum CK activity decreased by 50% on day 10 (CK, 6,857 U/L), and IVF was discontinued. Muscle fasciculations, pain, and pigmenturia resolved and CK activity decreased from days 11 to 13. Short hand-walks were initiated and flunixin meglumine was discontinued on day 15. On day 17, CK activity decreased and genetic testing for PSSM1 (negative) and biopsy of the semimembranosus muscle was performed. On day 18, there was a small spike in CK activity (1,044 U/L), though the horse remained clinically unchanged.
On day 19, CK activity normalized and the horse was discharged with dantrolene, which was discontinued on day 22. Treatment with methocarbamol and vitamin E continued, and the horse was maintained on a low-starch diet until muscle histopathology became available. One month after surgery, physical examination was unremarkable and CK activity (224 U/L) was within normal limits.
Muscle histopathology
The semimembranosus muscle biopsy from day 15 had no evident myodegeneration or regeneration (Figure 3). A few scattered muscle fibers showed mild to moderate glycogen depletion. Immunohistochemical staining for desmin was unremarkable.
Horse 3
A 4-year-old Holsteiner gelding weighing approximately 550 kg with no history of myopathy was presented with colic signs of approximately 3 hours’ duration. Prior to the colic episode, the horse had been in regular training for low-level eventing. Serum activity of AST (213 U/L) and CK (Figure 1) and blood lactate (0.5 mmol/L; Supplementary Table S1) were within normal limits prior to surgery (day 1). Premedication and induction and maintenance of anesthesia were considered routine (Table 1).
A segmental volvulus was reduced and a typhlotomy performed. The horse stood in recovery at 2 hours but was unable to remain standing. Intravenous fluid therapy, flunixin meglumine (1.1 mg/kg, IV), dexamethasone (0.1 mg/kg, IV), and 23% calcium gluconate (250 mL, IV) were administered. With assistance from a sling, the horse stood approximately 6.5 hours after the end of anesthesia, and blood lactate increased to 8.1 mmol/L (Supplementary Table S1). Ten hours later, blood lactate declined to 1.9 mmol/L and CK activity was 4,824 U/L (Figure 1). The horse was discharged to a rehabilitation facility on day 6. The horse did well with supportive care but became recumbent and was humanely euthanized on day 11 by barbiturate overdose. Necropsy was performed approximately 12 hours after euthanasia, and formalin-fixed, paraffin-embedded slides of adductor muscle were submitted to the NMDL.
Muscle histopathology
Acute myonecrosis characterized by vacuolated cytoplasm and loss of cross striations were evident in 50% of myofibers. Chronic myodegeneration was also evident, characterized by dense monocellular infiltrates, primarily histiocytes and a few lymphocytes (Figure 3). The majority of myofibers were depleted of glycogen, highlighted with the use of PAS stain. A few myofibers had residual subsarcolemmal glycogen or irregularly distributed glycogen in acutely necrotic fibers. A few regenerative fibers were apparent with the use of desmin immunolabeling.
Horse 4
A 7-year-old warmblood (specific breed not specified in record) gelding weighing approximately 560 kg with no history of myopathy was presented for evaluation (day 0) of a right forelimb lameness. The horse had been in regular training as a jumper but had started refusing jumps. Due to behavioral concerns, the horse was anesthetized for injection of biologic agents into the right bicipital bursa, injection of platelet-rich plasma into the right front check ligament, and shockwave therapy. Examination prior to anesthesia was within normal limits. Intravenous anesthesia was induced in a padded recovery stall, and the horse was positioned in left lateral recumbency (Table 1). After the 25-minute procedure, the horse attempted to stand but was unable to fully support its weight. Xylazine (0.4 mg/kg) and acepromazine (0.04 mg/kg) were administered to allow placement of a sling approximately 2.5 hours after the end of the procedure. After 1 to 2 hours, the horse was able to stand but could not fully bear weight on the left pelvic limb and continued to knuckle forward, raising concern for focal myoneuropathy. The horse remained standing overnight but was tachycardic and had pigmenturia, and the muscles over the back and hindquarters became palpably firm. Vitamin E (9 IU/kg, q 24 h), dimethyl sulfoxide, and dexamethasone (0.1 mg/kg, q 24 h) were administered, and acepromazine was Continued on day 1. Following the development of swelling over the right scapula, methocarbamol was started at 25 mg/kg PO twice daily. The horse was given xylazine (0.4 mg/kg) and a loading dose of butorphanol (0.01 mg/kg), followed by a 5-mg/h butorphanol constant rate infusion and IVF. Creatine kinase activity at that time was above the upper limit of detection of the analyzer (Figure 1), and AST activity was 1,988 U/L.
On day 2, serum activity of CK (Figure 1) and AST remained increased but pigmenturia improved. The horse initially appeared brighter but was persistently tachycardic and later became recumbent and was sweating profusely. Nasogastric intubation, abdominal palpation per rectum, and abdominal ultrasound were unremarkable. Peripheral lactate was 3.1 mmol/L (Supplementary Table S1). The horse stood but remained tachycardic with swelling of the gluteal muscles and had difficulty advancing the left pelvic limb. On days 5 to 7, CK and AST activity remained above the upper limit of detection. Dantrolene (2 mg/kg, PO, q 8 h) and regional laser therapy of the right biceps brachii were initiated on day 8 (Figure 1). The swelling of the gluteal muscles improved on day 9, but CK and AST activities remained high. On day 10, the horse became recumbent and was unable to rise and thus was humanely euthanized by barbiturate overdose and submitted for necropsy, which was performed approximately 24 hours later. Multiple areas of severe muscle pallor were evident in the hind limb adductors and forelimb triceps and biceps brachii (Figure 2). Formalin-fixed, paraffin-embedded slides of the semimembranosus were submitted to the NMDL.
Muscle histopathology
Both acute necrosis and chronic muscle degeneration were evident. Some myofibers appeared swollen and hypereosinophilic with fragmentation and vacuolation (Figure 2). Throughout the right hind adductors, there was variable moderate to severe myofiber atrophy with edema and infiltration by small to moderate numbers of histiocytes with fewer lymphocytes and plasma cells. In the left hind semimembranosus, atrophic myofibers had centralized nuclei that were occasionally multiple and rowing typical of regeneration. There was proliferation of fibrocytes in areas of myocyte loss. Complete glycogen depletion was evident in all muscle fibers (Figure 3).
Additional histopathology
Moderate subacute myocardial atrophy and degeneration with fibrosis in the myocardium were also noted.
Horse 5
An 11-year-old Hanoverian mare weighing 703 kg never stood despite sling assistance after surgery to remove osteochondral fragments from the left metatarsophalangeal joint. Prior to anesthesia, the mare had been in regular work (type unknown). Anesthesia was uneventful (Figure 1). While in the recovery stall, CK activity was increased and marked hypocalcemia (iCa, 0.89 mmol/L), azotemia (creatinine, 6.6 mg/dL), and hyperlactatemia (12.4 mmol/L) were present (Figure 1). The horse was placed in an emergency sling for the next several hours; however, lactate increased to 21 mmol/L, muscle fasciculations developed, and the horse made no coordinated efforts to stand. The horse was humanely euthanized by barbiturate overdose, and necropsy was performed the same day. Genetic testing for myosin-heavy chain myopathy and PSSM1 were negative. Formalin-fixed, paraffin-embedded slides of the semimembranosus were submitted to the NMDL.
Muscle histopathology
Typical of acute myodegeneration, skeletal muscle (unspecified muscle groups) showed multifocal swelling of myofibers with vacuolated cytoplasm and mild perimysial edema. There were no histiocytes or lymphocytes in the sample (Figure 3). Immunohistochemical labeling for desmin was unremarkable. Complete glycogen depletion was apparent in all muscle fibers.
Additional histopathology
Postmortem examination identified lesions in the lateral cuneate nucleus of the brainstem, including moderate to severe neuronal loss, spheroid formation, chromatolysis, and mild gliosis consistent with equine degenerative myeloencephalopathy/equine neuroaxonal dystrophy. The kidneys revealed acute tubular degeneration with myoglobinuric casts. The cardiac interstitium was multifocally expanded by loose fibrous connective tissue.
Horse 6
An 18-year-old warmblood (specific breed not specified) gelding weighing 637 kg was presented for colic. Prior to the colic episode, the horse was in regular dressage training. Preanesthetic bloodwork showed normal serum activity of AST (212 U/L), CK (Figure 1), and blood lactate (Supplementary Table S1). A gastrosplenic ligament rent with incarcerated jejunum was identified, and a 15-foot jejunal resection and anastomosis was performed. Anesthesia was uneventful, though the horse required sling assistance to stand. The following morning, CK activity was above the upper limit of detection of the analyzer (Figure 1) and AST activity was 966 U/L. The horse appeared bright and comfortable but later that day began displaying signs of colic, became recumbent, and was unable to stand. Blood lactate (12 mmol/L), serum AST (1,140 U/L), and CK activities (Figure 1) were markedly increased. Humane euthanasia was elected and necropsy declined. Samples of the semimembranosus and semitendinosus were submitted in formalin for histopathology to the NMDL.
Muscle histopathology
A few scattered fibers in the semimembranosus had vacuolated cytoplasm typical of acute myonecrosis. Unlike the other cases, a moderate number of mature myofibers had centrally displaced nuclei indicative of regeneration (Figure 3). There was no evidence of histiocytes or lymphocytes. Immunohistochemical labeling for desmin was unremarkable. A mild to moderate amount of glycogen depletion was noted in intact fibers. Complete depletion was only evident in degenerating fibers.
Horse 7
A 10-year-old Oldenburg gelding presented for colic. Prior to surgery, serum activity of CK (Figure 1) and AST (400 U/L) was mildly increased. A 720° torsion of the large colon was corrected. Twelve hours after anesthesia, the horse developed severe rhabdomyolysis and became recumbent and unable to stand. The horse was euthanized by barbiturate overdose, and a formalin-fixed muscle biopsy was obtained 12 hours after euthanasia and submitted to the NMDL.
Muscle histopathology
The semimembranosus contained scattered myofibers with vacuolated cytoplasm typical of acute myonecrosis. Immunohistochemical labeling for desmin was unremarkable. All fibers were completely depleted of glycogen (Figure 3).
Discussion
This case series highlights features of severe generalized PAM in 7 warmblood horses that lacked the typical risk factors for PAM. Whereas most healthy horses stand a median of 37 ± 13 minutes after anesthesia and horses with colic 54 ± 21 minutes, horses in the current report were either unable to stand or took 180 to 390 minutes to stand, despite remaining stable while under anesthesia.32 Serum CK activity (3 of 3) and blood lactate concentrations (3 of 3) were normal prior to surgery and rose markedly (CK, 7 of 7; lactate, 5 of 5) as PAM developed (Figure 1; Supplementary Table S1). Three horses were unable to remain standing in the recovery stall, prompting euthanasia, whereas 4 horses appeared to recover from PAM and then developed recurrence 5 to 11 days later. Muscle histopathology confirmed the presence of acute myonecrosis (6 of 7) and acute-on-chronic myodegeneration of several days’ duration in recurring cases (3 of 7). The only survivor had no apparent histopathologic changes 15 days after anesthesia. Complete glycogen depletion was evident with the use of PAS stains of acute samples from 5 of 6 horses. We propose that development and recurrence of rhabdomyolysis as horses recover from anesthesia could reflect a disruption in muscle homeostasis created by hypoxia/reperfusion injury, a hypermetabolic event, and ongoing oxidative stress.
While some studies have identified an association between increased body weight and poor anesthetic recovery scores, a specific association between body weight and PAM is unclear. When cases of PAM have been quantified, they are often grouped with postanesthetic myelopathy or neuropathy, making it challenging to interpret how body weight affects the risk of horses developing PAM specifically.3,6,9,22–24 A significant impact of body weight and PAM has been documented in draft breeds, with weights for warmblood breeds falling between those of draft and light breed horses such as Thoroughbreds and Standardbreds.22 Body weight may have contributed to PAM in our cases; however, we consider it unlikely to be the sole contributing factor for PAM.
Body position, specifically lateral recumbency, is significantly associated with increased risk for developing PAM.4,10 Adequate perfusion pressure appears to be important for overcoming the detrimental effects of high intracompartmental pressure in dependent muscles and hydrostatic pressure in nondependent muscles that limit blood flow to at-risk muscles.33 Horses anesthetized in lateral recumbency are predisposed to rhabdomyolysis of the triceps, masseters, and gluteal muscles, whereas horses anesthetized in dorsal recumbency develop myositis in the epaxial and gluteal muscles.10,34–39 Given that the rhabdomyolysis in our report was generalized and 5 of 7 horses were positioned in dorsal recumbency, positioning was not considered the inciting cause of PAM in this report.
Prolonged anesthesia, hypoxemia, ischemia, and MAP < 70 mm Hg are proposed risk factors for PAM.4,9–11,34 While likely still relevant, many of these risk factors are based on older studies in which horses were anesthetized with halothane and hypotension was treated less aggressively than in current practice, making it difficult to extrapolate to the present study.10,12 While prolonged anesthesia is associated with poor recoveries, the association between prolonged anesthesia and PAM is not a consistent finding.3,5,7,10,11,40 Several large-scale studies showed the duration of anesthesia that increased the risk of PAM varied from 90 to nearly 180 minutes, though other studies found no significant association between PAM and the duration of anesthesia.4,5,7,10,41 The anesthetic times for horses in our study were within published durations for similar procedures with a mean duration of 146 minutes, and thus it is unlikely that prolonged anesthesia contributed to PAM in the horses in our study.40
One possible contributor to PAM in the warmbloods in our study was triggering of a hypermetabolic event in recovery. While mild increases in lactate have been reported in healthy horses and colic cases upon standing in recovery, lactate rarely reaches the high levels seen in the cases here. In a study32 comparing healthy horses undergoing general anesthesia for elective MRI and horses undergoing emergency exploratory celiotomy for colic, elective cases had a median lactate of 1.6 mmol/L immediately after recovery and colic cases had a median lactate of 5.0 mmol/L. Blood lactate prior to surgery in the 3 colic cases described here was normal (< 2 mmol/L); however, in recovery, lactate increased to 11.8 ± 6.8 mmol/L. While it is possible that hyperlactatemia in our colic cases was impacted by metabolic perturbations from colic, even horse 5, which underwent metatarsophalangeal surgery and never stood, had lactate as high as 12 and 21 mmol/L in recovery, suggesting that profound anaerobic glycolysis occurred. Therefore, we believe that fulminant anaerobic glycolysis was associated with the development of PAM.42 Skeletal muscles, particularly fast twitch fibers abundant in equine locomotor muscles, are exquisitely sensitive to ischemia reperfusion injury; thus, it is possible that muscle ischemia and reperfusion injury contributed to the noted metabolic changes.43,44
Glycogen depletion and the inability to produce sufficient ATP for muscle function has been shown to be the most important determinant of the ultimate extent of skeletal muscle ischemic necrosis.37 One known cause of surging anaerobic glycolysis and muscle necrosis is MH caused by mutations in the sarcoplasmic reticulum calcium release channel (RYR1).45 Blood lactate concentrations of 18 mmol/L, a 30% decline in muscle glycogen, and a 50% decline in muscle ATP concentrations occur after 30 minutes of halothane anesthesia in pigs with the porcine MH mutation.46 In Quarter Horses, MH is caused by a C7360 RYR1, but this mutation has not been reported in warmbloods and genetic testing was negative in horse 1.27 Further, in contrast to MH, anaerobic glycolysis occurred after anesthesia and increases in body temperature were not noted in the horses in our study.45 It is possible that more minor alterations in RYR1 function occurred in our horses than that producing fulminant MH.
Oxidative stress occurs with reperfusion injury, and prolonged oxidative stress due to antioxidant deficiencies could have altered the function of the RYR1 by heightening sensitivity to Ca2+ activation.47,48 A surge of beta-adrenergic hormones, which may have occurred in PAM horses housed in hospitals, transported long distances, or that were fractious, could have triggered excessive calcium release from the sarcoplasmic reticulum and the development of rhabdomyolysis in days following anesthesia.49 Notably, delayed-onset PAM was also reported in a fractious 13-year-old Thoroughbred undergoing 40 minutes of IV anesthesia.50 Complete glycogen depletion was noted at PAM recurrence in horses 1, 3, and 4 from 5 to 11 days after anesthesia. Muscle glycogen is slow to replete in horses, taking up to 72 hours in horses on full feed.51 Hyporexia could have contributed to a lack of glycogen repletion in these horses, but a second occurrence of a hypermetabolic event could not be ruled out, as blood lactate measurements were not taken at this time.
It is possible that the warmbloods in our study had an underlying predisposing myopathy. In a study6 of complications from MRI procedures, 8 of 10 horses with PAM, including 2 fatalities, were warmbloods. Out of 1,349 horses anesthetized in a study52 examining the effect of an air mattress on anesthetic recovery, 12 (0.9%) developed PAM, 9 of which were Dutch Warmbloods. However, the breed distribution of the entire study group was not described for comparison.52 Chronic underlying myopathy such as MH, hyperkalemic periodic paralysis, PSSM1, and recurrent exertional rhabdomyolysis (RER) can predispose horses to anesthetic complications.10,14 Only 1 warmblood in our case series (horse 6) had histopathologic changes suggestive of underlying RER, but there was no history or clinical signs of the condition. Horses susceptible to RER usually only exhibit clinical signs when fit and in a high-stress training environment; thus, it is possible that this horse, which had minimal glycogen depletion, could have had a chronic myopathy such as RER as a predisposing factor.11,53 The 6 remaining cases had no evidence of chronic myopathy. It is possible that the horses in our study had an unknown genetic predisposition to PAM. Unfortunately, pedigrees were not available from owners due to the tragic outcome of anesthesia in these horses. Further studies evaluating a familial basis for PAM in warmblood breeds are warranted.
Pain management and provision of IV fluids are tenets of managing rhabdomyolysis in horses. If oxidative stress plays a role in reperfusion injury to muscles affected by PAM, provision of antioxidants could be important. Dimethyl sulfoxide; vitamin E, a potent antioxidant in cellular membranes; and Coenzyme Q10, a potent fat-soluble antioxidant present in the highest concentrations in the inner mitochondrial membrane, are commercially available for horses.54,55 Dantrolene is another therapeutic that might benefit horses that develop PAM because increasing myoplasmic calcium concentrations are the final common pathway for most forms of rhabdomyolysis.47 Dantrolene impedes calcium release from the sarcoplasmic reticulum and has been used to both prevent and treat rhabdomyolysis.56,57 The recommended dantrolene dose is 2 mg/kg, and absorption is optimal when given to fed horses. Two horses in our case series received 2 mg of dantrolene/kg PO: horse 1 received dantrolene the evening prior to euthanasia from recumbency and horse 2 on day 9 after anesthesia. Horse 2 showed a marked improvement in comfort level and a dramatic decrease in CK after initiation of therapy, though it is unknown whether these changes resulted directly from dantrolene. In a small crossover study58 comparing the effects of premedicating 6 horses with dantrolene (6 mg/kg via nasogastric tube) 1 hour prior to anesthesia, serum CK activity was monitored under anesthesia and for 12 hours after anesthesia and was lower in horses that received dantrolene, though the difference was not significant. This dose of dantrolene is not recommended because it increases serum potassium and lowers MAP under anesthesia.58 With the high fatality rate of PAM in warmblood horses and the risk of recurrence of rhabdomyolysis, provision of antioxidants and rapid initiation of dantrolene therapy could potentially address ischemia reperfusion injury.
The major limitations of this case series were the small number of horses, inconsistencies in monitoring and management of cases in the perianesthetic period, and variability in treatment and the specific muscles sampled at postmortem examinations. Unfortunately, due to the retrospective nature of these cases, there were some data missing from each case, limiting the number of conclusions that could be drawn from some variables. Referring veterinarians were contacted to fill in missing details, but in some cases, such as horse 7, the attending veterinarian was unavailable. While skeletal muscle was evaluated from each horse, the muscle was not always obtained immediately at euthanasia and the specific muscle sampled was not always specified in the report. Furthermore, some glycogen depletion could have occurred during the time that passed between euthanasia and postmortem sampling. Glycogen continues to be metabolized after death at a rate varying with storage temperature. At 5 °C, the temperature of most coolers, a 10% decline in glycogen is reported 10 hours after death in bovine studies, and when storage occurs at 15 to 25 °C, a 50% decline occurs at 10 hours.59 Our control samples indicated that glycogen is clearly evident in muscle at postmortem sampling 16 hours after death and residual glycogen is evident 24 hours after death. Because horses in our study were kept in storage coolers and muscle samples obtained within several to 24 hours after death, delayed sampling of muscle was not likely the main explanation for glycogen depletion. Glycogen depletion could vary depending on the muscle samples at postmortem. Ideally, muscle such as the adductors commonly affected in PAM would be sampled immediately after death from PAM horses and placed in formalin to accurately determine glycogen content at the time of death. Lastly, intake forms at most veterinary hospitals accept “warmblood” as a listed breed rather than a specific type of warmblood breed. Because the specific warmblood type was not reported for 2 horses in our study and pedigrees were not obtained, specific breed-related predispositions could not be investigated due to the small number of horses in this case series.
In conclusion, this study describes 7 cases of severe, delayed, and often fatal PAM in warmblood horses that remained stable while under anesthesia and lacked the majority of risk factors typically associated with poor anesthetic recoveries. The horses had no history of myopathy, and only 1 horse had a suspected and chronic myopathy based on histopathology. While the initial record review performed for this study identified 13 cases of PAM, 5 of the non-warmblood animals were draft horses or draft horse crosses, which are already well-known to be predisposed to PAM, and > 50% (7 of 13) were warmblood horses. While the specific cause of PAM in our cases cannot be elucidated, our findings suggest that hypermetabolic events as evidenced by increased lactate are a risk factor for developing PAM. Clinicians should be aware that warmblood breeds may have a predisposition toward PAM and should consider informing clients of this risk prior to anesthesia and also ensure that a thorough patient history is obtained prior to anesthesia. Special attention should be paid to maintenance of normotension, positioning, and appropriate padding during anesthesia. While these recommendations should apply to all horses, it is prudent that extra care be taken with warmblood horses. In the postanesthetic period, clinical signs, muscle enzyme activity, and lactate should be monitored closely to allow for prompt initiation of therapy for rhabdomyolysis. We suggest monitoring for up to 2 weeks to ensure that horses with delayed onset of rhabdomyolysis are identified. Therapy with dantrolene is recommended if these signs develop. These findings warrant larger epidemiological studies of warmblood horses undergoing anesthesia.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
None reported.
Disclosures
Dr. Valberg runs the Valberg Neuromuscular Diagnostic Laboratory and receives remuneration for processing and reporting on muscle biopsy submissions. Dr. Valberg receives royalties for genetic tests for type 1 polysaccharide storage myopathy. All other authors have nothing to disclose.
No AI-assisted technologies were used in the generation of this manuscript
Funding
The authors have nothing to disclose.
ORCID
K. Hepworth-Warren https://orcid.org/0000-0002-1322-5079
M. Tsoi https://orcid.org/0000-0002-7937-1597)
D. Goldsmith https://orcid.org/0000-0002-5619-4540
C. Noll https://orcid.org/0000-0001-7573-7865)
T. Pinn-Woodcock (https://orcid.org/0000-0003-0946-1893,
A. S. Dias Moreira https://orcid.org/0000-0002-5460-9765
K. A. Dembek (https://orcid.org/0000-0002-8499-5054
S. Valberg https://orcid.org/0000-0001-5978-7010
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