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04 April 2014 No. 10 HYPEROXIA J. Invernizzi Moderator: L. Pillay Discipline of Anaesthetics CONTENTS HYPEROXIA ......................................................................................................... 4 PATHOPHYSIOLOGY .......................................................................................... 4 Oxygen Delivery ................................................................................................ 4 Reactive Oxygen Species ................................................................................. 7 OXYGEN USE IN HOSPITALS ............................................................................. 8 Oxygen Use in Resuscitation ........................................................................... 8 OXYGEN USE PERI-OPERATIVELY ................................................................. 12 PROPOSED CHANGES TO CURRENT PRACTICE .......................................... 15 REFERENCES.................................................................................................... 17 Page 2 of 21 INTRODUCTION The role of oxygen in the development and sustenance of life on earth is a hugely complicated and diverse topic. The formation of an oxygen rich atmosphere and the emergence of oxygen-dependant organisms are topics that encompass a lot of the physical, philosophical and theological questions at the root of our existence and are well beyond the scope of this lecture. It is sufficed to say that a continuous supply of oxygen, a by-product of photosynthesis, is required by all aerobic organisms in order to maintain cellular metabolism (1, 2). All life on earth is based on reduction-oxidation reactions (reduction to store energy and oxidation to release it). As an element, Oxygen is voracious electronacceptor. It can therefore react with most elements in a variety of manners ranging from rapid and violent, as is seen in explosions and fires, to slow and ceaselessly as is seen when metal rusts. In aerobic organisms, oxygen is reduced to water as the final step of the electron transport chain within the mitochondria, part of an overall process which encompasses the oxidation of glucose and other substrates to carbon dioxide(2). Fig. 1: Electron Transport Chain (3) Oxygen is probably the most widely used drug within the hospital setting, with a large proportion of patients receiving oxygen at some point during their admission. Very few patients receiving anaesthesia, presenting with cardiac or respiratory pathologies, or undergoing intensive care will not be given oxygen at some stage. When considering also the number of patients that will receive oxygen during transport to hospital by the emergency care practitioners, the scale of oxygen use becomes apparent. Page 3 of 21 HYPEROXIA Definition: A higher than normal oxygen tension, such as that produced by breathing air or oxygen at greater than atmospheric pressures (4) PATHOPHYSIOLOGY Oxygen Delivery Supplemental oxygen is often administered with various presumptions. Firstly, it is recognised that avoidance of hypoxia is one of the core goals in patient care. However this is often achieved on the premise that excess oxygen is not harmful (2) . Furthermore it is also often presumed that the amount of oxygen available to tissues in various parts of the body is directly proportional to the concentration of oxygen supplied to the patient. In simple terms, a high concentration of administered oxygen results in a high amount of oxygen available at tissue level. Unfortunately while this is true in certain circumstances, the amount of oxygen available at tissue level depends both on arterial oxygen content as well as the perfusion of the tissues, as is demonstrated in the often quoted oxygen delivery equation: Fig. 2: Oxygen Delivery Equation (5) Page 4 of 21 What is not widely considered is that hyperoxia causes vasoconstriction in the cardiac, cerebral, renal and other key vasculatures both directly and via hyperoxia-induced hypocapnia (6). This can result in a situation whereby perfusion decreases more than arterial oxygen content increases, resulting in an overall decrease in regional oxygen delivery and subsequently relative hypoxia at a tissue level (6). This seemingly paradoxical situation can then easily be overlooked as tissue hypoxia is prescribed to the underlying disease process, with few people recognising the administration of supplementary oxygen as a contributory factor. This process can be better understood when examining the oxygen delivery equation in more detail, and fully appreciating the effects of the various factors on the overall delivery of oxygen: Arterial Oxygen Content (7) Assuming the patient is not hypoxic and that the haemoglobin is fully saturated, CaO2 increases only 0.003ml/l per mmHg rise in PaO2. This equates to roughly only a 7.5% rise in CaO2 between a PaO2 of 100mmHg compared to a PaO2 of 600mmHg. However, when looking at research done on the brain for instance, cerebral blood flow decreases between 11 and 33% in hyperoxic conditions (8, 9). This would result in an overall decrease in the delivery of oxygen to tissues despite (and in deed because of) the higher FiO2. This effect is also not confined to the brain, with similar results being demonstrated in the renal (10) and cardiac (11, 12) systems, as well as in organs such as the eye and skin (13, 14) . Normobaric hyperoxia has been shown to decrease coronary blood flow by 8-29% in patients with coronary artery disease or chronic heart failure resulting in a similar overall effect in the heart as in the brain (11, 12). Page 5 of 21 Fig. 3: Oxygen Haemoglobin Dissociation Curve(15) The precise mechanism mediating hyperoxic vasoconstriction is still under debate. Proposed mechanisms include the inhibition of vasodilators such as prostaglandins and nitric oxide by reactive oxidative species (10, 16), an increased production of vasoconstrictive substances such as endothelin-1 (13), and the activation of brainstem respiratory neurons (17). The theory of hyperoxia-induced-hypocapnia, or “reverse Haldane effect” also needs to be examined. Oxygenated haemoglobin binds less CO2 (the Haldane effect), therefore in the face of hyperoxia, in order to maintain CO2 transport, bicarbonate and dissolved CO2 (PCO2) levels need to increase. This rise in PCO2 in turn stimulates chemoreceptors in the brainstem (indirectly via raised H+ levels), which result in an increase in the respiratory rate. This response often exceeds the rise in PCO2 resulting in a hyperoxic-induced-hypocapnia, which in turn can lead to vasoconstriction in CO2-responsice vascular beds (18, 19). Regardless of the mechanism however, both hyperoxia and hypocapnia have both independently been shown to result in vasoconstriction (9). Page 6 of 21 Fig. 4: Effects of hyperoxia on minute-ventilation, ETCO2 levels and cerebral blood flow Typical effects of hyperoxia on minute ventilation (V̇e), end-tidal Pco2 (PETCO2), and middle cerebral artery velocity (MCAV), an index of cerebral blood flow, in one of five normal subjects. Correction of the hyperoxia-induced hypocapnia by addition of CO2 to the inspired gas (normocapnic hyperoxia) returned middle cerebral artery velocity back toward control.(18) Reactive Oxygen Species Reactive oxygen species (ROS) are oxygen molecules that contain an unpaired electron and are considerably more reactive than their paired-electron counterparts. They are produced in the mitochondria during partial metabolism of oxygen, and include the superoxide anion (O2-), hydrogen peroxide (H2O2) and the hydroxyl radical (OH-). Excess ROS are metabolised by the cell via various enzyme systems including glutathione perioxidases, lactoperioxidases, superoxide dismutases, and various catalases. Extracellularly, uric acid fulfils the role as the biggest free radical scavenger (20). Although responsible for many deleterious effects if their production exceeds their breakdown by the cell, they are also used by the cell in various ways. It has long been recognised that ROS are utilised by phagocytic cells as part of their host defences. Recently however, they have also been recognised to have a role in a myriad of other functions such as cell signalling, apoptosis, the expression or suppression of genes, the activation of intracellular cascades such as those involving mitogen activated protein kinases, and platelet aggregation (21). In excess however, ROS can result in damage to DNA, oxidation of polyunsaturated fatty acids (lipid peroxidation), oxidation of cellular amino acids as well as inactivation of various enzymes via oxidation of cofactors. This damage is in turn implicated in ageing, atherosclerosis, carcinogenesis, ototoxicity and cardiovascular disease (20). Page 7 of 21 Defence against hyperoxic damage associated with the ever-increasing atmospheric oxygen levels is thought to be behind the endosymbiotic integration of primitive bacteria into early organisms as they evolved. These bacterium, which evolved into mitochondria, provided a dual service of metabolising ROS (protecting the rest of the cell), while at the same time facilitating cellular respiration and the formation of energy, paving the way to the evolution of multicellular organisms (1). It is thought that it is the combination of an impaired delivery of oxygen at tissue level, as well as the reactive oxidative species produced by an excess of oxygen that results in the various poor clinical outcomes associated with hyperoxia (6). OXYGEN USE IN HOSPITALS Supplemental oxygen is used in three main scenarios in the hospital setting. In resuscitation, peri-operative care and critical care. Oxygen Use in Resuscitation Neonate Approximately 10% of newborns require assistance to start breathing at birth with around 1% of these requiring full resuscitation (22). In 2010 the new International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science guidelines on neonatal resuscitation were published following a review of the available literature. These guidelines in turn form the basis for the American Heart association, European resuscitation Council and International Liaison Committee on Resuscitation’s guidelines respectively (23). A number of significant changes were made to the 2005 guidelines. These included that for babies born at term, resuscitation should begin with air rather than 100% oxygen, administration of supplemental oxygen should be a blend of oxygen and air, and the concentration of oxygen delivered should be guided by oximetry. These recommendations were based upon studies that had shown that while resuscitation with 100% oxygen conferred no advantage to the child, an increase time until first breath was exhibited. This recommendation was further supported by 2 large meta-analyses which both demonstrated decreased mortality in infants resuscitated with air instead of 100% oxygen (24, 25). In preterm infants blended oxygen may be required, however the guidelines caution against both hypoxia and hyperoxia in the infant, and suggest that if no blended oxygen is available then air should be used for resuscitation in preterm infants as well (22). Page 8 of 21 Other studies have demonstrated other deleterious effects of 100% oxygen in neonates. These include amongst others: - Myocardial and renal injury (26) - Oxidative stress persisting for at least 4 weeks after birth (27) - Higher risk of childhood leukaemia and cancer(28, 29) Furthermore, animal studies have demonstrated potential harm to other systems including the neurologic, respiratory and central nervous system (23). Adult Oxygen is currently used in three main scenarios for adult resuscitation: 1) To treat established hypoxaemia 2) To prevent potential hypoxaemia in an ill patient 3) To alleviate dyspnoea Only the use of oxygen to treat established hypoxaemia is evidence based, the other two indications are not. There is no evidence to suggest that administration of oxygen to an ill patient without hypoxaemia will be of any benefit to them, nor that oxygen supply to a breathless normoxaemic patient will relieve the breathlessness (30). If the potential for hypoxaemia exists then monitoring of the patient should rather be instituted (31). As a result of the wanton application of oxygen in the acute care setting, hyperoxia can be as common as hypoxia (32). Unfortunately the practice of administration of oxygen by healthcare practitioners varies widely, with many strongly held beliefs but a relative paucity of randomised control trials providing evidence on the matter. In 2008 the British Thoracic Society (BTS) established a working group to address this problem, which resulted in the formulation of an evidence-based guideline for emergency oxygen use in the UK (33). Some recommendations of the BTS are: Assessment: - High concentration oxygen should be administered immediately to all critically ill patients. - SPO2 should be monitored in all breathless or critically ill patients - SPO2 monitoring should be available in all locations that emergency oxygen is used Prescription: - Oxygen delivery should be prescribed and written on drug chart with target saturation noted. - Oxygen should be prescribed to achieve a target of 94-98% for most acutely ill patients (including cardiac patients) or 88-92% for those at risk of hypercapnic respiratory failure (Chronic obstructive airways disease, cystic fibrosis, restrictive lung disorders, morbid obesity). Page 9 of 21 Discontinuation: - Oxygen should be weaned once target saturations are achieved, and crossed off the drug chart once therapy is discontinued. Fig. 5: British Thoracic Society oxygen administration guidelines (33) Page 10 of 21 Acute Coronary Syndromes Oxygen for treatment of ACS (acute coronary syndromes) was formally suggested as early as the 1930’s (34). Since then it has become a mainstay of treatment with the M.O.N.A. (morphine, oxygen, nitrates, aspirin) acronym being taught to most med school graduates despite there only ever having been low-grade evidence (level C) for its use in uncomplicated ST-elevation myocardial infarction (35). While the effects of hypoxia on cardiac tissue are well understood, increasingly studies are beginning to consistently show the detrimental effects of hyperoxia on cardiac function, with decreased coronary blood flow, increased coronary resistance and decreased myocardial oxygen consumption being demonstrated in both normal patients and patients with cardiac pathology when exogenous oxygen is administered in the absence of hypoxemia (11, 12, 36-39). A Cochrane review in 2013 attempted to resolve the debate. It found twice the increase in mortality in patients with acute myocardial infarction (AMI) who received oxygen as opposed to air, however was limited by the lack of research that directly addressed this topic (only four small randomised controlled trials). A large randomised controlled trial, the AVOID (Air vs. Oxygen in Myocardial Infarction) study, is currently underway in Australia and will hopefully provide more clarity on this matter (40). Currently American Heart Association recommendations include administration of oxygen in AMI if there is dyspnoea and hypoxaemia as shown on pulse oximetry, or if there are signs of heart failure. Oxygen should then be administered to titrate to a SPO2 of greater or equal to 94%. Cardiac arrest provides an even more contentious topic. During cardiopulmonary resuscitation, delivery of 100% oxygen remains recommended protocol with hypoxia being the predominant state in most resuscitations. There is however compelling evidence from animal studies to suggest that hyperoxia may result in worse outcomes due to ischaemic/reperfusion injury (41). This has been corroborated by a large clinical review (over 6000 patients) which demonstrated a significantly increased in-hospital mortality rate in hyperoxic patients following cardiac arrest compared to normoxic patients (OR 1.8, 95%CI 1.5-2.2) even when controlling for possible confounders such as age, preadmission functional status, comorbid conditions, vital signs, and other physiological indices (42). This same study also evaluated post-resuscitation PaO2 levels in ICU patients and found that for every post resuscitation increase of 100mmHg in PaO2, there was an associated 24% increase in relative risk of death (42). A further large review (43) has subsequently questioned various aspects of the methodology utilised in obtaining these results, however this study too contained flaws in methodology and as yet no large randomised control trial has been performed to corroborate the results of either review. Page 11 of 21 Chronic Obstructive Airways Disease (COPD) The risks of high concentration oxygen supplementation in COPD have long been acknowledged. The use of high concentration oxygen in these patients may result in hypercapnic ventilatory failure due to various mechanisms including the Haldane effect, ventilation perfusion mismatching (due to loss of hypoxic pulmonary autoregulation), atelectasis and inhibition of the patient’s hypoxic drive(17). This has resulted in the recommendation for COPD patients of supplemental oxygen being limited to 28%. Despite this, many COPD patients receive higher concentrations of oxygen both pre-hospital and in-hospital. This has been shown in numerous randomised controlled trials to adversely affect patient outcomes including acidosis, hypercapnia and overall mortality (32). Other Resuscitation scenarios Hyperoxaemia has also been shown to adversely affect outcomes when used in the acute treatment of many other conditions. These include congestive heart failure where a decreased cardiac output, increased systemic vascular resistance, increased left ventricular end diastolic pressures and increased isovolumic relaxation times have been shown (12, 37, 44), and stroke where an increased stroke severity score and overall mortality has been demonstrated (45, 46). The American Heart Association has advised against the use of supplemental oxygen in normoxaemic acute stroke patients in their guidelines for stroke management in accordance with this research (47). OXYGEN USE PERI-OPERATIVELY Infection Rates Several studies have been published that suggest a correlation between the use of high intraoperative oxygen concentrations (FiO2) and decreased surgical site infections. A recent meta-analysis provided mixed results on the topic concluding that although there was no overall benefit, benefit was seen in the subgroups of colorectal surgery and general anaesthesia (48). The PROXI trial however, the largest randomised control trial to tackle this issue, failed to demonstrate any reduction in surgical site infection with the use of an 80% FiO2 compared to a 30% FiO2 for laparotomies for various indications of at least 2 hours duration in the 1400 patients included in the trial (49). Wound Healing High levels of oxygen have for many years been argued to increase the rate of surgical and traumatic wound healing. Unfortunately the evidence directly addressing this topic is poor and conflicting. A recent Cochrane review (2013) concluded that due to the lack of evidence, further randomised controlled trials on the topic were required (50). Page 12 of 21 Pulmonary Atelectasis Pulmonary atelectasis is a well-recognised sequlae of general anaesthesia being present in 90% of patients regardless of whether they are spontaneously breathing or paralysed (51). Atelectasis in turn increases shunt, increases pulmonary vascular resistance, decreases compliance, may contribute to perioperative hypoxaemia, and may increase the chance of post-operative pneumonia (52, 53). One of the mechanisms of atelectasis occurs when the patient is ventilated with 100% oxygen. The nitrogen in the alveoli is washed out and replaced by oxygen, which in turn is quickly absorbed into the pulmonary vasculature, not leaving enough gas in the alveoli to maintain patency. Atelectasis, especially in the presence of pre-existing lung disease or limited cardio-pulmonary reserve may in turn have a significant impact on perioperative outcomes (54). Recommendations to avoid perioperative atelectasis include preoxygenation with an FiO2 of 0.8 in low airway-risk patients, or recruitment for 10 seconds following preoxygenation with an FiO2 of 1.0 in higher risk patients (53). Intraoperatively the use of PEEP (positive end expiratory pressure), and ventilation during anaesthesia utilising only a moderate fraction of inspired oxygen (FiO2 e.g. 0.30.4) is recommended (51). Fig. 6: CT in obese patients undergoing anaesthesia Page 13 of 21 (55) O2 Use in Critical Care The problem of tissue hypoxia is central to the management of most patients in the critical care setting. The current paradigm of critical care emphasises the avoidance of tissue hypoxia over any risk associated with hyperoxia. Careful evaluation is needed however to avoid the harmful effects of high concentrations of FiO2 and invasive mechanical ventilation associated with the repeated attempts to achieve normoxaemia in patients that may have a persistently low level of arterial oxygenation despite the efforts to restore it to normal (56). Furthermore, there has been little survival benefit shown in restoring normoxaemia in critical care patients (57, 58). Unfortunately little is known about the benefit vs. harm ratio between the strategies to increase arterial oxygenation compared to the risks of relative arterial hypoxaemia. This is further more complicated when trying to assess the benefit or risk of smaller deviations from normal, as well as taking into account the various underlying pathologies as well as inter-patient variability in response. Some assistance in the management of hypoxia can be gained from analysis of factors such as the arterial-alveolar oxygen partial pressure gradient: P(A-a)O2 This enables a quick evaluation as to whether or not the cause of the hypoxia is likely to respond to an increase in the FiO2. A normal gradient in the face of arterial hypoxaemia will likely respond well to increasing the FiO2, while a markedly raised gradient likely will not (56). Recent changes in the consideration of hypoxia in critical care patients have emphasised the time-course of the onset of the hypoxia in the management of the patient. The rationale behind this is that hypoxia of an acute or sub-acute onset such as upper airway obstruction or pneumonia, will most likely result in physiological responses that are aimed towards the immediate augmentation of oxygen delivery (increased ventilation, cardiac output), while hypoxia that is more chronic in onset may result in more of an adaption at the cellular level (56). Cellular hypoxia results in an exponential rise in the hetrodimeric protein, hypoxiainducible-factor 1 (HIF-1). This transcription factor in turn results in the upregulation of erythropoietin, vasogenic mediators and angiogenic factors, as well as stimulating the production of glycolytic enzymes which allow the continuation of energy production in oxygen-poor environments. Importantly HIF-1 also depresses mitochondrial oxygen consumption and improves the efficiency of mitochondrial ATP production via mitochondrial biogenesis deactivation and down-regulation of mitochondrial uncoupling (59, 60). These considerations in turn should be used to help determine the target arterial oxygenation levels, and ventilator strategies for the patient (56). Prolonged administrations of high concentrations of oxygen have long been recognised as having adverse consequences in the critical care setting. Page 14 of 21 One of the main affected sites is the lung, with high FiO2’s resulting in damage to pulmonary tissue resembling the Acute Respiratory Distress Syndrome (ARDS) clinical picture. This damage is proportional to the FiO2 and the duration of exposure (61, 62), and independent of the mechanical effects of ventilation (63). Oxygen toxicity has been shown to result in decreased mucocilliary transport (64), atelectasis, inflammation, pulmonary oedema and interstitial fibrosis (62). PROPOSED CHANGES TO CURRENT PRACTICE: Currently much of the evidence of the deleterious effects of hyperoxia is based on research which is still in its early stage. This combined with the fact that while we may want to avoid the extremes of hypoxia and hyperoxia on either side, the risks of smaller deviations from normoxia are largely still unknown, makes changes to current practice hard to formulate. Two stratagems have so far been proposed, “precise control of arterial oxygenation” and “permissive hypoxaemia” (2, 56). “Precise Control of Arterial Oxygenation” This involves targeting the PaO2 or SaO2 to individualised values, taking into account age, pathology, co-morbidities, chronicity of disease and clinical setting. Values outside a tightly defined range would be avoided in order to minimise the deleterious effects of both hypoxaemia and hyperoxaemia. This may be simplified by formulating ranges for cohorts of patients, such as post-operative, acute myocardial infarction etc. This approach essentially involves managing oxygen application to patients the same as we manage most other aspects of patient care such as the blood glucose level in diabetics, drug prescriptions, intravenous fluids or temperature control (2, 56). The prescription of a patient specific oxygen range is in-keeping with most of the current guidelines which deal with the application of supplementary oxygen (22, 33, 47), however its usefulness is limited by a poor knowledge and understanding of the correct application of oxygen therapy by many junior doctors and nurses (65). Page 15 of 21 “Permissive Hypoxaemia” In critically ill patients, the hypoxia observed may be of sub-acute or chronic duration. This in turn may be resulting in physiological adaptation at a cellular level. It is hypothesised that these patients may benefit from targeting a lower arterial oxygen level than would normally be accepted due to the increased resilience to hypoxia that the adaptation provides, combined with the decreased harm associated with chasing a normoxaemic level. This strategy at the moment is still hypothetical as more work needs to be done in order to identify oxygenation levels, biomarkers and patient cohorts that will allow its safe and effective implementation (2, 56). Fig. 7: Permissive Hypoxaemia (66) Page 16 of 21 REFERENCES 1. Lane N. Oxygen: The Molecule that Made the World. Oxford: Oxford University Press; 2003. 2. Martin DS, Grocott MP. III. Oxygen therapy in anaesthesia: the yin and yang of O2. British journal of anaesthesia. 2013 Dec;111(6):867-71. PubMed PMID: 24233308. Epub 2013/11/16. eng. 3. Muskopf S. Cellular Respiration: Biologycorner.com; 2014 [cited 2014 04/03/2014]. 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