title: Isoflurane anesthetic hypersensitivity and progressive respiratory depression in a mouse model with isolated mitochondrial complex I deficiency.
abstract: BACKGROUND
  Children with mitochondrial disorders are frequently anesthetized for a wide range of operations. These disorders may interfere with the response to surgery and anesthesia. We examined anesthetic sensitivity to and respiratory effects of isoflurane in the Ndufs4 knockout (KO) mouse model. These mice exhibit an isolated mitochondrial complex I (CI) deficiency of the respiratory chain, and they also display clinical signs and symptoms resembling those of patients with mitochondrial CI disease.
  
  
  METHODS
  We investigated seven Ndufs4(-/-) knockout (KO), five Ndufs4(+/-) heterozygous (HZ) and five Ndufs4(+/+) wild type (WT) mice between 22 and 25 days and again between 31 and 34 days post-natal. Animals were placed inside an airtight box, breathing spontaneously while isoflurane was administered in increasing concentrations. Minimum alveolar concentration (MAC) was determined with the bracketing study design, using the response to electrical stimulation to the hind paw.
  
  
  RESULTS
  MAC for isoflurane was significantly lower in KO mice than in HZ and WT mice: 0.81% ± 0.01 vs 1.55 ± 0.05% and 1.55 ± 0.13%, respectively, at 22-25 days, and 0.65 ± 0.05%, 1.65 ± 0.08% and 1.68 ± 0.08% at 31-34 days. The KO mice showed severe respiratory depression at lower isoflurane concentrations than the WT and HZ mice.
  
  
  CONCLUSIONS
  We observed an increased isoflurane anesthetic sensitivity and severe respiratory depression in the KO mice. The respiratory depression during anesthesia was strongly progressive with age. Since the pathophysiological consequences from complex I deficiency are mainly reflected in the central nervous system and our mouse model involves progressive encephalopathy, further investigation of isoflurane effects on brain mitochondrial function is warranted.
authors: Department of Anesthesiology, Radboud University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors: Suzanne
authors: S
authors: Roelofs
authors: Ganesh R
authors: GR
authors: Manjeri
authors: Peter H
authors: PH
authors: Willems
authors: Gert Jan
authors: GJ
authors: Scheffer
authors: Jan A
authors: JA
authors: Smeitink
authors: Jacques J
authors: JJ
authors: Driessen
mesh_terms: D000758:Anesthesia / Q000379:methods; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics; D005260:Female; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000503:physiopathology*; D012131:Respiratory Insufficiency / Q000503:physiopathology*
chemical_list: D000777:Anesthetics; C534449:Ndufs4 protein, mouse; D007530:Isoflurane; D042967:Electron Transport Complex I