Oxygen Therapy Reperfuse, but Remain Poorly Ventilated Tension (Pao2) and Sao2 Are 10–13 Kpa and 94–98%, Respectively

CME: CLINICAL PRACTICE AND ITS BASIS

effect (decreased CO2 buffering by oxyhaemoglobin) all contribute to hyper- Respiratory medicine capnia, but the greatest effect is likely to relate to worsened ventilation-perfusion mismatch. Deoxygenated pulmonary Edited by Craig Davidson MD FRCP, arterial blood is diverted away from areas Consultant in Respiratory and Intensive Care Medicine, of diseased lung because alveolar hypoxia St Thomas’ Hospital, London due to poor ventilation causes vasoconstriction and thus decreased local perfusion (ie hypoxic pulmonary vasoconstriction). If high-flow oxygen is The normal ranges of arterial oxygen applied, these alveoli re-oxygenate and Oxygen therapy reperfuse, but remain poorly ventilated tension (PaO2) and SaO2 are 10–13 kPa and 94–98%, respectively. It is apparent and fail to clear CO2. In reasonably that DO cannot be significantly healthy lungs, regional failure to clear Luke S Howard MA DPhil MRCP, Consultant 2 CO can be compensated by an overall Chest Physician, Department of Respiratory enhanced by increasing PaO2 above 16 2 Medicine, Hammersmith Hospital, Imperial kPa, where haemoglobin is 100% satu- increase in ventilation, but impaired res- College Healthcare NHS Trust rated and the amount of oxygen dis- piratory mechanics prohibit this in solved in the plasma is small. This COPD. Other adverse effects of hyperoxia Clin Med 2009;9:156–9 manoeuvre will maximise CaO2 but may relate to effects on the cardiovascular not always optimise DO2. system and the production of reactive Oxygen delivery (DO ) is arguably the oxygen species (discussed in detail else- 2 Oxygen ‘toxicity’ most critical requirement for the mainte- where5). Table 1 summarises some of the nance of normal organ function and can There are many reasons why maximising concepts, with selected references.

be illustrated by Equation 1: SaO2 may firstly not optimise DO2 and Hyperbaric oxygen therapy for stroke and secondly may impact adversely on other intracoronary hyperoxaemic reperfusion DO = CaO × cardiac output 2 2 aspects of a patient’s physiology. The for myocardial infarction (MI) are cur-

where CaO2 is total oxygen content, best-known example of this occurs rently being explored. It is possible that made up largely of oxygen bound to during acute exacerbations of chronic the significant rise in oxygen tension in haemoglobin and, to a much smaller obstructive pulmonary disease (COPD). infarcted tissue may outweigh the physio-

degree, oxygen dissolved in plasma. DO2 Here PaO2 above 10 kPa is associated logical changes and oxidative stress, but therefore depends not only on the degree with respiratory acidosis and worse out- these data are awaited. Studies of supra- 3,4 of oxygenation of the blood but also on comes. Decreased hypoxic drive, physiological DO2 in critical illness have cardiovascular function and haemo- absorption atelectasis and the Haldane so far failed to show benefit.10 globin concentration. Despite its impor- tance, it is not the most tightly regulated physiological parameter for metabolism and gas exchange. This is well illustrated Table 1. The adverse effects of hyperoxia achieved with normobaric oxygen. by a study of repeated venesection Organ/System Effect of hyperoxia resulting in isovolaemic anaemia (5 g/dl) in healthy humans.1 While cardiac Pulmonary • Absorption atelectasis output rose, it was insufficient to main- • Release of hypoxic pulmonary vasoconstriction, leading to worsened ventilation/perfusion matching tain DO2 but because of the steep slope of the oxyhaemoglobin dissociation • Decreased ventilation Pulmonary capillary leak – oxygen toxicity curve at the tissue level, the fall in DO2 • was offset by increased oxygen extrac- Cardiovascular • Coronary vasoconstriction tion, indicated by a reduction in mixed • Increased systemic vascular resistance (increasing cardiac work) venous oxygen (SvO2). Decreased cardiac output (decreasing O delivery) • 2 SvO2 is therefore a much better indi- Reperfusion injury post-myocardial infarction6 cator of oxygen delivery than arterial sat- • • Worsened outcomes post-neonatal resuscitation7 uration (SaO2), and is one of the targets Neurological Neuronal injury post-cardiac arrest in adults8 in resuscitation in sepsis. SaO2 is readily • measurable and helpful in resuscitation, • Increased mortality following minor/moderate stroke9 although attention should be paid to Haematological Decreased CO buffering by haemoglobin (Haldane effect) • 2 integrated physiological function.2

Emergency oxygen use in adults Even when saturations are being 2 Oxygen only when needed to achieve monitored, it may be appropriate normal oxygen saturations, given the Guidelines as other contributors to DO2 absence of proven benefit of aiming Recent guidelines for emergency oxygen (Equation 1) may not yet be known. higher and of concerns over the in adults have been developed under the Furthermore, it can provide a physiological and potentially toxic auspices of the British Thoracic Society margin of safety in the event of effects of hyperoxia. (BTS) in association with 21 UK soci- worsening gas exchange. However, The latter is the position taken by the 5 eties. In determining emergency oxygen this margin of safety may also mask committee. Notably, in the areas reviewed policy, the committee felt two diametri- deterioration11 since saturations will in Table 1, guidelines from other societies cally opposed philosophical positions fall only when the alveolar-arterial recommend administering oxygen to could be assumed due to the paucity of gradient is large or the patients with stroke12 and MI13,14 only in evidence: PaO2/fractional concentration of the event of hypoxaemia. 1 Plentiful oxygen. Maximising SaO2 oxygen in inspired gas (FiO2) ratio Consequently, the guidelines (Fig 1) with high-concentration oxygen falls below 100. Other clinical recognise the necessity for HCO in crit- (HCO) is advisable in many features may flag deterioration, but ical illness, but in other situations recom- situations, particularly in critical patients who need increasing oxygen mend that oxygen is given only if illness when monitoring is to maintain saturations may trigger saturations fall below the normal range unavailable (eg at the roadside). warning systems earlier. (94–98%).5 Aligned with the Surviving Sepsis Campaign,15 the guidelines

emphasise that maximised SaO2 is not synonymous with optimised DO2 and that vascular filling, haematocrit and Is the patient cardiac output also need appropriate critically ill*? adjustment. Exception is made, however, for patients at risk of hypercapnic respiratory

Yes – treat with No reservoir or bag-valve mask Key Points

Optimisation of oxygen delivery Is the patient at risk of requires more than oxygen therapy hypercapnic respiratory and attention should be paid to failure? vascular filling, haematocrit and cardiac output

High-concentration oxygen may cause worse outcomes through physiological effects and reactive No – is SpO 2 Yes – aim for SpO 88–92% oxygen species <85%? 2 or level on alert card Emergency oxygen should be pending ABG prescribed to a target saturation (88–92% in those at risk of No – aim for hypercapnic respiratory failure, 94–98% in those not at risk), SpO2 94–98% except in critical illness Start with 24% or 28% Venturi mask Oxygen therapy at home should be assessed, prescribed and followed Start with nasal cannulae up by a specialised oxygen service, (2–6 l/min) or usually led by a respiratory face mask physician in secondary care (5–10 l/min) In active patients, ambulatory oxygen *Critical illness is defined as cardiopulmonary arrest, shock, major trauma and head injury, near- should be prescribed to maintain drowning, anaphylaxis, major pulmonary haemorrhage, carbon monoxide poisoning, status saturations above 90% epilepticus and other life-threatening emergencies. KEY WORDS: chronic obstructive Fig 1. Initial algorithm for inhospital prescription of oxygen. ABG = arterial blood pulmonary disease, hypercapnia, 5 gas; SpO2 = peripheral oxygen saturation. hypoxaemia, oxygen, saturation

failure, typically patients with COPD, but HCO, alveolar CO2 (PACO2) will rise. trend to worse outcomes in the former also with neuromuscular and chest wall When PIO2 is reduced to baseline, alve- group. It is beyond the scope of this disorders. The recommended SaO2 is olar PO2 (PAO2) will therefore be lower article to enumerate all the reasons why 88–92%, based on observations that PaO2 than previously (until the CO2 body this trial cannot be used to justify HCO of 7.3–10 kPa is associated with the stores are blown off). Consequently, in COPD exacerbations. One compelling 3 lowest incidence of acidosis. Patients arterial PaO2 will be lower than prior to factor, though, is that in neither group known to be at risk of hypercapnic respi- HCO. It can be considered conceptually was PaO2 allowed to rise significantly. It ratory failure should be given an alert as CO2 occupying more ‘space’ in the was therefore a trial comparing two levels card with a prespecified saturation target alveolus. Thus, if an at-risk patient has of controlled oxygen. Furthermore, with range, usually 88–92%, although for been given HCO, oxygen should be with- regard to the effect of the degree of some this may be lower. Arterial blood drawn gradually, stepping down through hypercapnic acidosis present in their gases should guide further management fixed-concentration Venturi masks. population on the oxygen dissociation

as soon as they are available. curve (the Bohr effect), target PaO2 Overzealous withdrawal of HCO may Criticisms of the guidelines values of 6.6 kPa and 9 kPa theoretically do more harm than good through translate to saturations of 74% and 89%,

rebound hypoxaemia. This can be best Following these guidelines, there is likely respectively. While, on average, the PaO2 understood through use of the alveolar to be further argument about the risk of levels were higher than this, the higher

gas equation (Equation 2): giving high or low levels of oxygen to target PaO2 was actually much closer to patients with COPD. Critics of the lower the BTS recommendations. PAO PIO – PACO /RER 2 2 2 saturation policy often quote a ran- A criticism often levelled at the con- where RER is the respiratory exchange domised pilot study of COPD exacerba- trolled oxygen protagonist is that the

ratio of O2 consumption to CO2 produc- tions in which PaO2 was titrated to sickest patients require higher concentration. When the partial pressure of 6.6 kPa in one group and 9 kPa in the tion oxygen and for this reason there is 16 inspired oxygen (PIO2) is increased with other. There was a non-significant an association with worse respiratory

Has the patient chronic hypoxaemia*?

Yes – assess and prescribe LTOT to achieve No – consider ambulatory oxygen if breathless

PaO2 >8 kpa and follow up patient and desaturates below 90% on walk test

If patient wants ambulatory oxygen, assess Prescribe O2 flow rate required to keep SpO2 activity level >90% on exercise

Low activity group – prescribe O at same 2 Active group rate as LTOT

Conditions considered suitable for LTOT and ambulatory O2: Conditions considered suitable for LTOT only: COPD Bronchiectasis Severe chronic asthma Pulmonary malignancy Interstitial lung disease Chronic heart failure Cystic fibrosis Pulmonary vascular disease

*PaO2 <7.3 kPa (or 8 kPa in presence of secondary polycythaemia and/or clinical or echocardiographic evidence of pulmonary hypertension) in the absence of an exacerbation of chronic lung disease in the previous five weeks.

Fig 2. Algorithm for prescription of long-term oxygen therapy (LTOT) and ambulatory oxygen. COPD = chronic obstructive

pulmonary disease; PaO2 = arterial oxygen tension; SpO2 = peripheral oxygen saturation.

158 Clinical Medicine Vol 9 No 2 April 2009 © Royal College of Physicians, 2009. All rights reserved. CME Respiratory medicine failure. Against this a study from this group there will be patients on 9 Rønning OM, Guldvog B. Should stroke Norwich showed that when a policy of LTOT and some not, but who victims routinely receive supplemental giving 28% oxygen from the outset is desaturate on exercise. Both oxygen? A quasi-randomized controlled trial. Stroke 1999;30:2033–7. instituted, there is no clear increase in subgroups should be assessed by six- 10 Velmahos GC, Demetriades D, Shoemaker complications or significant hypox- minute or shuttle-walk testing to WC et al. Endpoints of resuscitation of aemia.17 In addition, far fewer patients titrate the optimal flow rate and to critically injured patients: normal or present with respiratory acidosis. assess the objective improvement in supranormal? A prospective randomized exercise capacity. trial. Ann Surg 2000;232:409–18. 11 Downs JB. Has oxygen administration Oxygen at home Ambulatory therapy is not indicated in delayed appropriate respiratory care? chronic heart failure, but desaturation Fallacies regarding oxygen therapy. Respir In 2006, a new policy for the prescription identifies coexistent pulmonary vascular Care 2003;48:611–20. of home oxygen, to include long-term, disease and patients may benefit in this 12 Royal College of Physicians. National ambulatory and short-burst treatments, clinical guideline for stroke, 2nd edn. instance. London: RCP, 2004. was introduced by the Department of Short-burst therapy provided by cylin- 13 Arntz HR, Bossaert L, Filippatos GS; Health based on a report by the Royal ders kept in the home and used as European Resuscitation Council. European College of Physicians in 1999.18 The two required for the relief of breathlessness, Resuscitation Council guidelines for key components of the policy were to: may also be prescribed. A recent review, resuscitation 2005. Section 5. Initial management of acute coronary syndromes. • rationalise oxygen providers, with however, suggested little gain to patients Review. Resuscitation 2005;67(Suppl 1): groups of primary care trusts with COPD and there is little clear guid- S87–96. assigning contracts to one of four ance on who will benefit.19 It remains 14 Scottish Intercollegiate Guidelines Network. companies, and largely a clinical decision for the relief of Acute coronary syndromes. A national clinical breathlessness, but other palliative care guideline. Guideline No 93, 2007. • move the responsibility of oxygen www.sign.ac.uk/pdf/sign93.pdf assessment, prescription and follow approaches should also be considered. 15 Dellinger RP, Levy MM, Carlet JM et al. up largely to secondary care, with Surviving Sepsis Campaign: international patients assessed by a service guidelines for management of severe sepsis References and septic shock: 2008. Intensive Care Med directed by a respiratory physician. 2008;34:17–60. There is a requirement for a detailed 1 Weiskopf RB, Viele MK, Feiner J et al. 16 Gomersall CD, Joynt GM, Freebairn RC, prescription, consent form and Human cardiovascular and metabolic Lai CK, Oh TE. Oxygen therapy for record form by the service. response to acute, severe isovolemic hypercapnic patients with chronic anemia. JAMA 1998;279:217–21. obstructive pulmonary disease and acute 2 Mak V. Respiratory failure: two forgotten respiratory failure: a randomized, Long-term oxygen therapy concepts. Clin Med 2001;1:290–1. controlled pilot study. Crit Care Med 2002; 3 Plant PK, Owen JL, Elliott MW. One year 30:113–6. The criteria for long-term oxygen therapy period prevalence study of respiratory 17 Durrington HJ, Flubacher M, Ramsey CF, (LTOT) for COPD have been extended to acidosis in acute exacerbations of COPD: Howard LSGE, Harrison BDW. Initial implications for the provision of non- oxygen management in patients with an other long-term conditions (Fig 2). If invasive ventilation and oxygen nocturnal hypoventilation is suspected, exacerbation of chronic obstructive administration. Thorax 2000;55:550–4. pulmonary disease. QJM 2005;98:499–504. formal assessment by a respiratory physi- 4 Plant PK, Owen JL, Elliott MW. Non- 18 Royal College of Physicians. Domiciliary cian is necessary as non-invasive ventila- invasive ventilation in acute exacerbations oxygen therapy services. Clinical guidelines tion will be more appropriate in of chronic obstructive pulmonary disease: and advice for prescribers. Report of a long term survival and predictors of in- Working Party of the Royal College of conditions such as neuromuscular and hospital outcome. Thorax 2001;56:708–12. chest wall diseases, rather than oxygen. Physicians. London: RCP, 1999. 5 O’Driscoll BR, Howard LS, Davison AG. www.rcplondon.ac.uk/pubs/brochure. There is now greater access to ambulatory BTS guideline for emergency oxygen use in aspx?e=78 oxygen, but evidence suggests that, when adult patients. Thorax 2008;63(Suppl 6): 19 O’Driscoll BR. Short burst oxygen therapy it is prescribed, many patients use it vi1–68. in patients with COPD. Monaldi Arch Chest 6 Rawles JM, Kenmure AC. Controlled trial Dis 2008;69:70–4. rarely. A diary card should be provided of oxygen in uncomplicated myocardial with the first two-month supply to deter- infarction. BMJ 1976;1:1121–3. mine need for continuation. 7 Davis PG, Tan A, O’Donnell CP, Schultze Patients being assessed for ambulatory A. Resuscitation of newborn infants with oxygen are subdivided into two groups: 100% oxygen or air: a systematic review and meta-analysis. Lancet 2004;364: • low activity: those who are usually 1329–33. immobile and need oxygen for 8 Kuisma M, Boyd J, Voipio V et al. leaving the home. They will need the Comparison of 30 and the 100% inspired same oxygen flow rate as their LTOT oxygen concentrations during early post- resuscitation period: a randomised • active: those likely to benefit from controlled pilot study. Resuscitation 2006; increased exercise capacity. Within 69:199–206.