Brown eyes drooping, Cronutt fell asleep quickly in his transport enclosure after receiving an intramuscular cocktail of midazolam, medetomidine, and butorphanol. Having arrived from Six Flags Discovery Kingdom in Vallejo, where he had been cared for as a special needs animal, the 8-year-old California sea lion was now in the parking lot of the SAGE Veterinary Center in Redwood City. It was October of 2020, and Cronutt was being prepared for a novel and potentially life-saving procedure.1, 2, 3
Cronutt was first rescued in 2017 while stranded on the coast of San Luis Obispo County. After several rescues and releases along the California coast, he was deemed un-releasable at The Marine Mammal Center (TMMC) in Sausalito due to poor appetite and multiple reappearances on land. He also had a grand mal seizure while at TMMC.2
Cronutt was transferred to Six Flags Discovery Kingdom in 2018 for longer-term care, where he continued to show epilepsy and dementia-like symptoms.3, 4 Months prior to the surgery, his condition further deteriorated. His worsening inattention and seizures—he had 11 the previous week—put him at risk for drowning. He was generally failing to thrive, and his appetite declined to the point his weight had dropped by 25 percent.3, 5 What was the root of Cronutt’s illness? Ingestion of domoic acid, a neurotoxin secreted by the algae Pseudo-nitzschia that accumulates in small fish and shellfish, had injured the sea lion’s brain.
Algal blooms have become common in California coastal waters over the past few decades due to warming from climate change. These blooms have led to a higher incidence of marine wildlife exposure to domoic acid. Reports of poisoning in sea lions were first noted in the 1990s, and have also been reported in seals, sea otters, and whales.6 It is currently estimated that hundreds of sea lions are sickened with domoic acid each year.2 Chronic exposure to domoic acid in sea lions often causes significant neurological symptoms and brain damage that resembles the pathology of humans with temporal lobe epilepsy. MRI imaging of animals exposed to domoic acid classically shows hippocampal degeneration. Unfortunately, the outcome is often death, which occurs in 60 percent of affected marine mammals.7 Cronutt’s procedure was a last effort to salvage a dismal situation.
Neurosurgeons from the University of California, San Francisco (UCSF) were now
planning to inject neural progenitor cells from a pig neonate into Cronutt’s left hippocampus, which was scarred and shrunken on MRI. UCSF neuroscientist Dr. Mariana Casalia, a member of Dr. Scott Baraban’s lab (https://barabanlab.ucsf.edu), helped develop the cellular therapy. The lab found that the transfer of the neural progenitor cells in epileptic mice decreased seizures, memory problems, and anxiety by 90 percent.4
Sea lions exposed to domoic acid interested Dr. Baraban’s group, as they ultimately aimed to apply the therapy to larger animal models. The research team, in coordination with UCSF physicians and the veterinarians and scientists at TMMC/Discovery Kingdom, had put years of work into customizing a targeting system for a sea lion brain, optimizing the procedure using a sea lion cadaver.4, 7 As Cronutt was no longer responding to medications—anti-epileptics, steroids, appetite stimulants—his longtime veterinarians Dr. Claire Simeone and Dr. Vanessa Hoard reached out to Dr. Baraban, who had previously been in contact with Six Flags about the experimental therapy and its possible utility in marine mammals.2 Dr. Baraban agreed to help, and in a matter of weeks, a team was assembled.
Lovingly surrounding Cronutt was an 18-person team that included his caretakers from Six Flags Discovery Kingdom, members of Dr. Baraban’s research group, three UCSF neurosurgeons, and TMMC veterinarians who had cared for Cronutt in Marin. Also present was his anesthesia team: Dr. Fabian Okonski, a pediatric anesthesiologist at Lucile Packard Children’s Hospital at Stanford, and veterinarian Dr. Shawn Johnson from TMMC.1, 5 COVID-19 protocols meant that only a small number of people could be in the clinic’s operating room, so Cronutt was sedated in his enclosure gurney in the parking lot.5
Following the attachment of monitors and intubation with an 18.0-mm endotracheal tube, Cronutt was wheeled into the CT scan suite. During transport, it was noted that he was becoming profoundly bradycardic, with his heart rate dropping to 8, and his end-tidal carbon dioxide level declining to near zero, suggesting a very low cardiac output. This pattern of events was well known to Dr. Okonski and Dr. Johnson, as it is a common precursor to sudden death in pinnipeds (flipper-footed mammals) under anesthesia.1 In general, for reasons not entirely understood but perhaps related to the neural reflexes of deep diving, marine mammals historically have had a mortality of up to 8 percent under general anesthesia. In comparison, the mortality rate of other zoo and exotic animals under anesthesia averages 1 percent.1
Knowing there was limited time before a cardiac arrest occurred, Dr. Okonski urgently placed an ultrasound-guided internal jugular vein catheter for resuscitation. An ultrasound-guided arterial line was also placed, since blood pressure in these animals is often low during anesthesia, and oscillometric cuffs are not reliable on flippers.1 With aggressive chemical resuscitation, Cronutt’s status improved, and the 5-hour-long procedure, consisting of stereotactically guided cell injections into the hippocampus, was completed. Cronutt awoke smoothly and was recovered with help from his handlers. He stayed in a dry pen for 3 days post-operatively.3
Dr. Okonski has been involved at TMMC for about 8 years. He initially worked as a rescue volunteer for the center, but he started observing marine animal surgeries when the chief veterinarian heard that he was an anesthesiologist. Over time, he began to work alongside the veterinarians at TMMC. Dr. Okonski has been amazed by what the veterinarians and veterinarian anesthesiologists bring to the table: a thorough understanding of the effects of different drugs and the physiology and behavior of multiple species.1
Ultimately, Dr. Okonski believes that his work with veterinarians has been collaborative. Since becoming more involved in the care of marine mammals at TMMC, his team’s active hemodynamic management and aggressive resuscitation of seals and sea lions under anesthesia has decreased mortality significantly. Arterial line placement has become more common for any animal needing a prolonged general anesthetic at TMMC, and developing a non-invasive blood pressure measuring device that will work on flippers remains an ongoing project. Other projects currently underway include further evaluation of the pharmacodynamics and kinetics of various inotropes and pressors, characterizing structural heart defects in domoic acid toxicity using echocardiography, and improving pain control after major surgery in pinnipeds through regional anesthesia.1
While it is unlikely that Cronutt will ever be released due to his habituation to humans, he remains seizure-free more than a year since the treatment. His feeding and weight have returned to normal. His handlers report that he has become a more outgoing and playful sea lion and that he has befriended his sea lion neighbor, Missy. Additionally, he is learning new things, like how to tell left from right, which is indicative of intact memory formation, an important hippocampal function.5 While more transplants need to be performed in sea lions to understand the safety and efficacy of this kind of procedure, Cronutt’s outcome has been very positive. The hope over time is that neural regeneration using cellular therapies can eventually be translated to humans.
Over the past few decades, veterinarians have had a history of partnering with anesthesiologists from academic centers in the care of endangered and exotic animals. California hosts some of the nation’s most diverse fauna, and species conservation is a fundamental goal. Beyond conservation, it is also clear that every animal cared for has the potential to benefit veterinary and human medicine, as well as the global fund of knowledge in both basic and clinical sciences.
Dr. Fred Mihm, for example, is an anesthesiologist at Stanford who has helped anesthetize lions, tigers, giraffes, elephants, and gorillas at the San Francisco Zoo. In 2004, he helped provide anesthesia for an extensive medical checkup for Koko, the gorilla famous for her ability to communicate with sign language.8
At the San Diego Zoo, Dr. Stan Perkins and Dr. Mark Greenberg of the University of California, San Diego (UCSD) have assisted with similar exotic animals, such as the giant pandas before their departure in 2019. Dr. Greenberg cared for the first great ape to undergo open-heart surgery in 1994, setting up a makeshift ICU at the zoo when post-operative complications arose.9
Dr. Paul Ponganis, a cardiac anesthesiologist trained at Stanford who now works at the Scripps Institution of Oceanography, is world-renowned for his work studying the diving physiology and behavior of Emperor penguins with fellow Scripps biologists in Antarctica. He has authored hundreds of publications, looking at questions such as how a penguin can stay underwater in a low oxygen and blood flow state for an extended time (10-20 minutes), or how they are able to collapse and reinflate their lungs after deep dives. Understanding this physiology could lead to better treatments for shock and stroke patients, who suffer damage when their brains and other organs are deprived of oxygen, or for premature infants with respiratory distress syndrome, who suboptimally ventilate their alveoli.10
These are several examples of the work with animals being undertaken by anesthesiologists in California. The collaboration between anesthesiologists, veterinarians, and other scientists clearly offers new insights into the physiology and treatment of complex mammals. In addition, the hope is that a partnership can translate into strategies to improve the care of human patients. Participating in veterinary anesthesia can help hone the technical skills needed to gain intravenous or arterial access in humans, improve the process of anesthetizing unruly and uncooperative patients, reveal insights into working in unfavorable or resource-deficient environments, and promote an open-minded approach to problem solving that is more physiology-based and less species-centric.
As for Cronutt, his medical team and handlers believe the therapeutic breakthrough has given him a second chance at life.
References
1. Phone Interview of Dr. Fabian Okonski. November 2020.
2. Richtel, M. Brain. Surgery for a ‘Sweet Boy’: Saving Cronutt the Sea Lion. The New York Times. https://www.nytimes.com/2020/10/08/science/sea-lion-epilepsy-surgery-cronutt.html. Published October 8, 2020.
3. Simeone, Claire A. et al. Xenotransplantation of Porcine Progenitor Cells in an Epileptic California Sea Lion (Zalophus Californianus): Illustrative Case. Journal of Neurosurgery, 21 Mar. 2022. https://doi.org/https://doi.org/10.3171/CASE21417.
4. Weiler, Nicholas. How a UCSF team is giving Cronutt the sea lion a second chance with neuroscience. University of California, San Francisco. https://www.universityofcalifornia.edu/news/how-ucsf-scientists-are-saving-cronutt-sea-lion-neuroscience. Published October 16, 2020.
5. Mullin, Emily. Pig Brain Cells May Have Cured a Sea Lion’s Epilepsy – Are Humans next? Science, National Geographic, 7 Jan. 2022. https://www.nationalgeographic.com/science/article/pig-brain-cells-may-have-cured-a-sea-lions-epilepsyare-humans-next.
6. Scholin, Christopher A. et al. Mortality of Sea Lions along the Central California Coast Linked to a Toxic Diatom Bloom. Nature, vol. 403, no. 6765, 2000, pp. 80–84. https://doi.org/10.1038/47481.
7. Wells, Janet. Cellular Transplant Therapy Pioneered by UCSF Reverses Sea Lion’s
Epilepsy. Human Interest, UCSF Magazine, 2021. https://magazine.ucsf.edu/cellular-transplant
-therapy-pioneered-ucsf-reverses-sea-lions-epilepsy.
8 Baker, M. When Koko the gorilla needs a checkup, Stanford docs swing into action. Stanford University. https://news.stanford.edu/news/2004/august18/med-koko-818.html. Published August 18, 2004.
9. Greenberg, M. et al. Surgical repair of an atrial septal defect in a juvenile Sumatran orangutan (Pongo pygmaeus sumatraensis). J Zoo Wildl Med. 1999 Jun;30(2):256-61. PMID: 10484142.
10. Miller, Mary. If It’s November, This Must Be Antarctica. Alumni Profile – Stanford Medicine Magazine – Stanford University School of Medicine, 2002. https://sm.stanford.edu/archive/stanmed/2002fall/md-antarctica.html.
Special thanks to Dr. Fabian Okonski and Dr. Harrison Chow for their support in writing this essay, Dr. Jane Moon for editorial assistance, and to Dianne Cameron of Six Flags Discovery Kingdom for the photographs of Cronutt.