FRCA Notes

Oxygen Toxicity

This is a fascinating clinical topic. My concern is we will find in years to come that we've been inadvertently poisoning our perioperative and acutely unwell patients with gratuitious use of supplementary oxygen.

The curriculum basis for this topic is suspect, but "describes the correct prescribing of oxygen", knowing the "effect of oxygen therapy on control of breathing" and understanding "classes of drugs acting on the respiratory system including oxygen" seems to cover it.

From an exam point of view, hyperoxia featured as a CRQ in 2022 (60% pass rate), with knowledge of pathophysiology and clinical features reportedly lacking.

Resources

  • Hyperoxia describes any situation where cells/tissues/organs are exposed to oxygen at a higher-than-normal partial pressure
    • I.e. a PaO2 greater than normal for that patient's age whilst breathing room air

  • Hyperoxia can be classified as:
    1. Normobaric i.e. at 1atm pressure
    2. Hyperbaric i.e. although FiO2 may be 0.21 or even lower, PaO2 is greater than normal

Generation of reactive oxygen species

  • During cellular metabolism, oxygen is reduced to water by the transport of electrons along the mitochondria enzyme chain, and the movement of protons across the mitochondrial membrane
  • Not all electrons & protons form water, however, as there is a degree of 'leakage' from the electron transport chain
  • Other molecules are thus generated: reactive oxygen species (ROS; a.k.a. oxygen free radicals)
    • Approximately 2% of mitochondrial oxygen forms ROS

  • The most abundant of these ROS are:
    • The superoxide ion: O2.-
    • Hydrogen peroxide: H2O2

  • These already intrinsically toxic molecules react via the Fenton reaction (Jesus Christ Fenton!) to produce even more damaging ROS molecules:
    • The extremely unstable hydroxyl radical: OH., which reacts with pretty much anything
    • The high-energy, short-lived singlet oxygen: 1O2

Biological effects of reactive oxygen species

  • In all cells there is a balance between oxidant and anti-oxidant molecular activity; its redox state
  • ROS do have some beneficial effects, such as:
    • Regulation of phagocytes
    • Facilitating the death of unwelcome micro-organisms

  • ROS have a number of harmful effects, however:
    • Damaging DNA or RNA, or impairing DNA repair
    • Affecting gene transcription
    • Lipid peroxidation, which damages cell membranes
    • Interfere with protein function by direct oxidation of amino acids
    • Oxidative deactivation of enzymes

  • There may be non-radical mediated injury from oxygen too, in particular oxygen-mediated inhibition of glutamic acid decarboxylase
    • This reduces CNS GABA levels and thus contributes to seizures

Anti-oxidants

  • Anti-oxidants can both prevent ROS formation and scavenge ROS molecules, inactivating them
  • Hyperoxia increases ROS formation to the extent that they overwhelm the antioxidant mechanisms' capacity
  • Cellular oxidative stress ensues
  • Examples of antioxidants include:
    • Superoxide dismuthase (SOD)
    • Catalase
    • Vitamin C
    • Vitamin E
    • Beta carotene
    • GSH Peroxidase

Respiratory

  • Normobaric hyperoxia causes predominantly respiratory system changes, such as:
    • Abolishes hypoxoc pulmonary vasoconstriction within a few minutes
    • Increases alveolar dead space and may cause hypercapnoea
    • Excessive drying (i.e. non-humid) of inspired gas and the negative sequelae of this
    • Absorption atelectasis due to rapid oxygen absorption from alveoli
    • Exposure to FiO2 >0.6 for ≥24hrs leads to damage of the respiratory epithelium of the tracheobronchial tree i.e. tracheobronchitis and mucositis
    • Long-term use may cause bronchopulmonary dysplasia (neonates), interstitial pulmonary fibrosis (if previous bleomycin therapy) or exacerbate ARDS (paraquat consumption)

  • Respiratory oxygen toxicity (the Lorrain Smith effect) manifests as a smorgasbord of clinical features:
    • Retrosternal burning, heaviness or tightness
    • Chest pain (pleuritic)
    • Cough
    • Dyspnoea
    • Reduced vital capacity
    • Tachypnoea
    • Paradoxical hypoxaemia
    • Acute lung injury

Cardiovascular

  • Coronary vasoconstriction
  • Hyperoxia associated with increased infarct size in uncomplicated MI (NEJM, 2017 )

CNS

  • CNS toxicity (the Paul-Bert effect) is the predominant feature of hyperbaric hyperoxia
  • CNS vasoconstriction can occur with consequent reductions in CBF
    • This effect appears to be exacerbated in brain injury/TBI
  • This can manifest as non-specific symptoms reminiscent of a terrible hangover:
    • Nausea
    • Headache
    • Dizziness
    • Visual disturbance
    • Irritability
    • Disorientation
    • Muscle twitching
  • Eventually seizures occur

Ophthalmic

  • Reversible constriction of peripheral vision
  • Cataract formation
  • Progressive myopia
  • Retrolental fibroplasia (premature infants)

  • Carbon monoxide poisoning
    • High inspired oxygen concentrations reduce the half-life of CO (300min to 90min)
    • This can further reduced to 20min by using 3atm hyperbaric oxygen

  • Pneumothorax
    • Lowers PaN2 in blood, reducing the total partial pressure of dissolved gases in blood thus increasing the rate of diffusion of nitrogen from pneumothorax into the blood
    • BTS guidance advocates 100% oxygen in patients with COPD who require hospital admission because of pneumothorax which does not require drainage
    • Also pneumocephalus and pneumomediastinum

  • Cluster headaches
  • Hyperbaric oxygen chamber for:
    • Anaerobic wound infections
    • Diving-associated nitrogen toxicity a.k.a. the bends

General measures

  • As per a 2009 NPSA Report, we should be treating oxygen like any other drug
  • This means titrating supplementary oxygen to saturations 92 - 96% (or 94 - 98%) and monitoring it appropriately to avoid either hyperoxia or hypoxia
    • The exception is a known history of bleomycin therapy, when 85 - 88% is acceptable

Perioperative care

  • There's conflicting or weak evidence about the beneficial impact of high inspired oxygen concentrations in the perioperative period on:
    • PONV
    • Surgical site infections (JAMA, 2009; BJA, 2019)
    • Anastomotic integrity
    • Post-operative pulmonary infections
  • Indeed, higher inspired oxygen concentrations may be associated with a greater degree of perioperative oxidative stress (BJA, 2020)

  • Post-operatively the most common reason for oxygen administration is alongside an opioid PCA
    • Hyperoxia has been found to have an additive effect on opioid-induced respiratory depression in healthy volunteers on a remifentanil infusion
    • Those on 50% oxygen (compared with air) showed a steeper reduction in minute ventilation, an increase in end-tidal CO2 and a higher incidence of apnoeic episodes
    • Current guidelines suggest oxygen should be used to correct rather than prevent hypoxia

  • Some of the adverse physiological effects of hyperoxia are less relevant under GA e.g. with artificial ventilation in place atelectasis can be treated with recruitment manoeuvres
  • Yet outside of short periods of time under anaesthesia when 100% oxygen is suitable (e.g. pre-oxygenation), a more rational approach to oxygen administration to avoid both hyperoxia and hypoxia seems sensible

  • If the above content is only tenuously relevant for the FRCA, then the below would certainly seem beyond the call of anaesthetic duty; it is placed here for interest only

  • The PILOT study showed those given a lower (88% - 92%) saturations target did not differ from those given higher (92% - 96% or 96% - 100%) targets with respect to the number of ventilator free days, in-hospital mortality or a number of other adverse clinical events (NEJM, 2022)

  • A study of oxygenation post-ROSC found those given a 9 - 10kPa target had the same rates of coma, severe disability or death as those given a 12 - 14kPa target (NEJM, 2022)

  • ICU-ROX demonstrated no difference in ventilator-free days or 180-day mortality when lower saturations thresholds were used (NEJM, 2020)

  • The single centre, underpowered, early-terminated OXYGEN-ICU study showed a mortality benefit from conservative oxygen targets compared to unrestricted oxygenation (JAMA, 2016)