Original article
Jain IH, Zazzeron L, Goli R, Alexa K, Schatzman-Bone S, Dhillon H, Goldberger O, Peng J, Shalem O, Sanjana NE, Zhang F, Goessling W, Zapol WM, Mootha VK. Hypoxia as a therapy for mitochondrial disease. Science 2016;352:54–61. PMID: 26917594
In a recent PAAD, Myron recalled the oft ridiculed consultant’s adage to “avoid hypoxia and hypotension” and wondered who these consultants recommend hypoxia and hypotension for? As someone who has devoted some of my research career to studying hypoxia, spends time at high altitude, and often remarks that one of the problems with living at sea level is that there is just too much oxygen down there, I mentioned to him that there actually are a whole group of patients for whom hypoxia is not only possibly beneficial but can actually be therapeutic,and sent him a fascinating paper about it. Of course, my reward was to be tasked with writing another PAAD. This one is from the journal Science.
The group of patients that I am talking about, of course, are those with mitochondrial diseases. The most common class of inborn errors of metabolism, mitochondropathies span a large spectrum of genetic mutations with protean clinical manifestations across many organ systems, including the central and peripheral nervous system, muscular system, cardiac, GI, hepatic, endocrine and renal systems.1-3 Some children with these diseases have frequent visits to the operating room, and because nearly every anesthetic drug affects mitochondrial function and the electron transport chain, these children require special consideration for anesthesia. Because of the very pronounced inhibitory effect that propofol exerts on Complex I of the electron transport chain, it is generally recommended that propofol be avoided in these patients, and low concentrations of sevoflurane be used instead.1-3 Indeed, patients (and animal models) with Complex I defects have been shown to be exquisitely sensitive to sevoflurane and require only a fraction of the usual MAC. In addition to these recommendations, avoiding hyperoxia is thought to be important, and the experimental evidence for this is truly fascinating. Today’s PAAD describes some recent research on the role of oxygen in the pathogenesis of these disease states and how hypoxia might be employed in their therapy and management. This has implications on our anesthetic management, as supplemental oxygen use is ubiquitous perioperatively and we often pay only cursory attention to the concentration at which it is administered.
Leigh Disease is one of the prototypic mitochondropathies and has a uniformly poor prognosis. It occurs in about 1:40,000 live births, presents in infancy (after an apparently normal neonatal course) with metabolic crisis including acidosis, neuropsychomotor and developmental regression, failure to thrive, and in the most severely affected individuals, death from metabolic and respiratory failure in the first few years of life. A mouse model, in which one of the Complex I subunits (Nduf4) is knocked out, shows a very similar clinical and pathological course to human Leigh Disease, with pups appearing normal at birth but soon developing growth retardation, neurological and motor regression and early death. If raised in an oxygen enriched environment, the progression of the clinical symptoms, pathological findings and age of death are dramatically accelerated. But as this paper from the laboratories of Vamsi Mootha and Warren Zapol showed, a hypoxic environment (FiO2 = 0.11, producing an SpO2 of 89% and PaO2 of 45 torr) can prevent the development of expression of the syndrome if begun before the onset of symptoms.4-6 Not only were the clinical manifestations prevented, but both MRI imaging and histopathological examination showed that hypoxia prevented the pathognomonic CNS lesions. Even more remarkably, if hypoxia is introduced part way into the clinical course when the degenerative symptoms were manifest, it can actually reverse the neurological deterioration, improve weight gain and quadruple longevity. Cardiomyopathy, a common finding in Leigh syndrome, was incompletely prevented by hypoxic breathing; mild LV dysfunction was still seen in many of these mice as they aged. In contrast, none of the normoxic knockout mice even survived long enough for cardiomyopathy to develop. The investigators also demonstrated a dose-response relationship of hypoxia therapy, as it were. Intermittent hypoxia, where the animals breathed hypoxic gas for only 10 hours a day, was ineffective at preventing the development of disease. So was a moderate level of hypoxia (FiO2=0.17, producing an SpO2 of 61%, and the equivalent of living in the foothills west of Denver at 1800m).4, 5 Only the more profound and uninterrupted hypoxic breathing conditions were beneficial. Nevertheless, the investigators note that unlike the animal model, human infants with less severe manifestations of Leigh Disease may have more intermittent episodes of metabolic and neurological deterioration rather than a rapid relentless downhill course, and they speculate that it is possible that intermittent hypoxia might be effective in that setting.
To my knowledge there have not been any human trials of hypoxia in Leigh or any other mitochondropathy, and the use of hypoxia as a therapeutic modality in humans remains theoretical. I and others believe, however, that because oxidative stress may be an inducer of disease exacerbations it is prudent to avoid the use of supplemental oxygen in patients with a mitochondrial disorder, particularly ones involving Complex I.
The implications of this reach beyond mitochondrial disease. The neurodegenerative effects of general anesthetics seen in experimental models appear to be mediated by oxidative stress induced mitochondrial apoptosis. Although there is considerable controversy about whether those animal model findings have relevance to the clinical anesthetic care of children, could excessive oxygen exposure during anesthesia potentiate any oxidative stress induced by the anesthetics - and the anesthetic increase the oxidative stress induced by hyperoxia?
References:
1. Hsieh VC, Niezgoda J, Sedensky MM, Hoppel CL, Morgan PG. Anesthetic Hypersensitivity in a Case-Controlled Series of Patients With Mitochondrial Disease. Anesthesia and analgesia. Oct 1 2021;133(4):924-932. doi:10.1213/ane.0000000000005430
2. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. Sep 2015;17(9):689-701. doi:10.1038/gim.2014.177
3. Niezgoda J, Morgan PG. Anesthetic considerations in patients with mitochondrial defects. Paediatric anaesthesia. Sep 2013;23(9):785-93. doi:10.1111/pan.12158
4. Ferrari M, Jain IH, Goldberger O, et al. Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome. Proc Natl Acad Sci U S A. May 23 2017;114(21):E4241-e4250. doi:10.1073/pnas.1621511114
5. Grange RMH, Sharma R, Shah H, et al. Hypoxia ameliorates brain hyperoxia and NAD(+) deficiency in a murine model of Leigh syndrome. Mol Genet Metab. May 2021;133(1):83-93. doi:10.1016/j.ymgme.2021.03.005
6. Jain IH, Zazzeron L, Goli R, et al. Hypoxia as a therapy for mitochondrial disease. Science. Apr 1 2016;352(6281):54-61. doi:10.1126/science.aad9642