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Pigs are extensively used for biomedical research as animal models given their similarities to humans including size, arterial capacity, and cutaneous structure. While their size also allows for the use of clinically available anesthesia equipment (for example, endotracheal tubes and ventilators), anecdotes exist with respect to stress reactions after exposure to volatile anesthetics. Over 3 mo at our institution, 11 pigs (Sus scrofa domesticus) exposed to isoflurane anesthesia during 2 research protocols were euthanized after exhibiting clinical signs of malignant hyperthermia, including hyperthermia, hypercapnia, skeletal muscle rigidity, dyspnea, tachycardia, and hypotension. This group was composed of intact Yorkshire/Landrace crosses (68 to 91 kg) purchased from a research breeder. While malignant hyperthermia is caused by a mutation in ryanodine receptor 1 (RYR1), another unnamed porcine stress syndrome is caused by a dystrophin defect. We analyzed the incidence of the RYR1 mutation and a dystrophin variant in 9 of the originally clinically affected pigs and in 56 subsequent pigs. All animals tested negative for the RYR1 mutation, while the dystrophin variant was found in 2 out of 7 clinical (28.6%) and 22 out of 46 (47.8%) subsequently tested female pigs. Creatine kinase, indicative of muscle damage, was slightly elevated at baseline in dystrophin variant-positive carriers, albeit not significantly. However, for the original clinically affected pigs, the increase in body temperature while under anesthesia was significantly greater in dystrophin variant-positive carriers (7.9 ± 0.8 °C) compared with noncarriers (5.2 ± 0.6 °C, P = 0.046). Taken together, we describe the suspected involvement of a dystrophin variant as one of the genetic etiologies in an unnamed condition that has been anecdotally experienced by pig researchers but not reported. We propose naming this condition volatile anesthesia porcine stress syndrome (VAPSS), which is an umbrella term that includes multiple genetic origins, the most well-known of which is malignant hyperthermia stress syndrome in pigs. Identifying other etiologies for VAPSS has implications for genetic and clinical screening to improve welfare in pigs bred for biomedical research and agricultural purposes.

Keywords: BMD, Becker muscular dystrophy; DMD, Duchenne muscular dystrophy; FFPE, formalin, fixed paraffin, embedded; MH, malignant hyperthermia; PSS, porcine stress syndrome; PRRSV, porcine reproductive and respiratory syndrome virus; RYR1, ryanodine receptor 1; TIVA, total intravenous anesthesia; USUHS, Uniformed Services University of the Health Sciences; VAPSS, volatile anesthesia porcine stress syndrome
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Copyright: © American Association for Laboratory Animal Science
<bold>Figure 1.</bold>
Figure 1.

Dystrophin genotyping by PCR-RFLP. The dystrophin (DMD) variant (p.Arg1953Trp, rs196952080) was genotyped using AciI digest and visualized (reverse image) in 1.5% agarose gels with ethidium bromide. The full-size PCR product is 310 bp, and digested fragments are 75 bp and 235 bp. Lane M, 100-bp molecular weight ladder; lane 1, tryptophan T-allele, affected; lanes 2, 3, and 6, C/T heterozygotes; lanes 4 and 5, arginine C-allele, normal. Full, uncropped blot is given.


<bold>Figure 2.</bold>
Figure 2.

A subject under isoflurane anesthesia displaying signs of skeletal muscle rigidity after exposure to volatile anesthetics. Note the extension of the forelimbs and hindlimbs despite attempts to stabilize the limbs with ropes.


<bold>Figure 3.</bold>
Figure 3.

Electrocardiogram of affected patient under 1% to 1.5% isoflurane anesthesia. (A) Baseline recording taken 30 min into study (top) and (B) recording taken roughly 23 h later. Note the increased frequency, blunted QRS complex, and exaggerated T wave after anesthesia.


<bold>Figure 4.</bold>
Figure 4.

Body temperature (top row) and heart rate (bottom row) for animals under isoflurane anesthesia (A) without and (B) with the use of IV dantrolene, (C) as well as those only receiving total intravenous anesthesia (TIVA). Dantrolene was administered at the arrows indicated. Note progressive hyperthermia and tachycardia for all subjects with the exception of one dantrolene subject that stabilized from hours 8 to 16 (boxes in B). This progressive increase in body temperature and heart rate is not seen with TIVA (C).


<bold>Figure 5.</bold>
Figure 5.

Laboratory values for dystrophin-positive carriers (black bars) compared with noncarriers (gray bars). There was an effect of anesthesia/time on all measures, including (A) creatine kinase, (B) body temperature, (C) heart rate, (D) lactate, and (E) pH. (C) However, only heart rate was significantly elevated in carriers compared with noncarriers. *P < 0.05; n = 17 and 27 for carriers and noncarriers, respectively. BL, baseline; TOD, time of death.


Contributor Notes

Corresponding author. Email: james.corrigan@usuhs.edu
These authors contributed equally to this study.
Received: Jul 12, 2024
Accepted: Nov 25, 2024