Routine use of oxygen in the treatment of myocardial infarction: systematic review

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1 Systemati review See Editorial, p Medial Researh Institute of New Zealand, Wellington, New Zealand; 2 Capital and Coast Distrit Health Board, Wellington, New Zealand; 3 University of Otago Wellington, Wellington, New Zealand; 4 University of Southampton, Southampton, UK Correspondene to: Professor R Beasley, Medial Researh Institute of New Zealand, PO Box 10055, Wellington 6143, New Zealand; Rihard.Beasley@mrinz.a.nz Aepted 1 July 2008 Published Online First 15 August 2008 Routine use of oxygen in the treatment of myoardial infartion: systemati review M Wijesinghe, 1 K Perrin, 1 A Ranhord, 2 M Simmonds, 2 M Weatherall, 3 R Beasley 1,4 ABSTRACT Context: International guidelines reommend the routine use of oxygen therapy in the treatment of myoardial infartion (MI). Objetive: To undertake a systemati review and metaanalysis of randomised plaebo-ontrolled trials of oxygen therapy in MI. Data soures: Medline, Cohrane Database of Systemati Reviews, Cohrane Central Register of Controlled Trials, EMBASE and CINHAL. Study seletion: Randomised plaebo-ontrolled trials of oxygen therapy in MI. Data extration: The primary linial outome was mortality. Results: Two of 51 potential studies met the inlusion riteria. The one study with substantive linial outome data reported that in unompliated MI, high-flow oxygen was assoiated with a non-signifiant inreased risk of death (risk ratio 2.9, 95% CI 0.8 to 10.3, p = 0.08) and a greater serum aspartate aminotransferase level (differene 19.2 IU/ml, 95% CI 0 to 38.4, p = 0.05) than room air. Conlusion: The limited evidene that does exist suggests that the routine use of high-flow oxygen in unompliated MI may result in a greater infart size and possibly inrease the risk of mortality. Oxygen has been used in the treatment of myoardial infartion (MI) and aute oronary syndromes for over 100 years. 1 The rationale for its longstanding use is that it inreases oxygen delivery to the ishaemi myoardium, thereby reduing the size of the MI and improving linial outomes. Evidene in support of this approah is primarily derived from animal models, in whih the administration of 100% oxygen under normobari or hyperbari onditions during and/or after experimental oronary artery olusion redues the extent of myoardial nerosis in some, 2 6 but not all, studies However, onern has been expressed that the findings from animal studies may have poor generalisability to the linial situation in humans Furthermore, there is evidene that the routine use of high-flow oxygen in unompliated MI may not improve linial outomes and may potentially ause harm It is well established that arterial oxygen tension is a major determinant of oronary artery tone and that hyperoxia may result in a marked redution in oronary artery blood flow Other ardiovasular effets of high-flow oxygen therapy inlude a redution in ardia output and stroke volume and an inrease in systemi vasular resistane and blood pressure in patients with a MI Despite this onfliting evidene, ontemporaneous international guidelines reommend the routine use of supplemental oxygen in the treatment of MI. As the treatment of MI is at the forefront of evidene-based mediine, we sought to review the linial effiay and safety of the use of oxygen in this linial situation. A systemati review was undertaken to identify randomised plaebo-ontrolled trials of oxygen therapy in the treatment of aute MI with the intention of estimating differenes in linial outomes by meta-analysis. METHODS Searh strategy To identify all studies that investigated the effet of oxygen therapy in MI, a searh of studies ontaining the key words oxygen or myoardial infartion was onduted from Medline, Cohrane Database of Systemati Reviews, Cohrane Central Register of Controlled Trials, Embase and CINHAL to Marh The referene lists of all relevant studies were also examined. Partiular attention was given to searhing for studies before 1950, whih would not be inluded in the eletroni referene databases. Inlusion riteria Two people examined eah paper s title and abstrat and then the full paper if neessary. To be inluded in the review, studies had to be randomised, ontrolled, linial trials of oxygen therapy in MI that reported linial outome measures. Exlusion riteria Any studies investigating the use of oxygen for any linial indiation other than MI, suh as heart failure, were exluded. Non-randomised ontrolled trials, review artiles, editorials and letters were also exluded. Animal studies were exluded owing to the poor generalisability from laboratory animal models to patients beause of differenes in oronary anatomy, ollaterals, haemodynami responses and natural disease states suh as oronary artery disease Studies using hyperbari oxygen or intraoronary oxygen infusion were exluded as these therapeuti interventions are not ommonly used in linial pratie and the physiologial effets may differ from those of normobari highflow oxygen therapy. As a result, the findings of suh studies are not generalisable to onsideration of the effiay and safety of oxygen therapy in the treatment of MI. Data extration Extration of data was based on reported summary statistis (ounts, means and standard deviations) 198 Heart 2009;95: doi: /hrt

2 Systemati review for the intention-to-treat population. The primary outome variable was in-hospital mortality. Seondary outome variables were measures of infart size by ardia enzyme levels, ourrene of ventriular arrhythmia and opiate use. Where relevant, other linial outome variables reported in the linial trials were noted. The trial quality was assessed using the standard Jadad sore based on the adequay of randomisation, blinding and follow-up, with a maximum sore of five points. Data analysis As only two studies met the inlusion riteria and only one of these reported on the number of deaths in eah treatment group formal meta-analysis was not undertaken. In the two identified studies, point estimates and onfidene intervals were alulated for the main outome variables, using relative risk for ategorial variables and a t test for ontinuous variables. RESULTS Searh results Figure 1 shows the QUOROM statement for the searh, whih identified 51 potentially relevant artiles on the use of oxygen therapy in MI. From these, the 13 studies whih investigated the use of hyperbari or aqueous oxygen, six review artiles, one letter, four editorials and two systemati reviews were exluded. An additional 23 studies were exluded, inluding ase reports, ase series, rossover studies, ohort studies and non-randomised trials of oxygen therapy in MI. Two studies met the riteria for inlusion in the systemati review and are presented in detail here. Study 1 A study undertaken by Rawles and Kenmure. 34 This parallel-group, double-blind ontrolled trial of oxygen therapy in unompliated MI randomised 200 patients with suspeted MI to reeive either oxygen or ompressed air by Figure 1 QUOROM statement for the searh. means of a medium onentration mask at a flow rate of 6 l/min for 24 h. Both patients and medial staff were blinded to the treatment reeived. Patients were exluded if they had linial evidene of heart failure, hroni pulmonary disease or were breathless from any other ause, or if they had been transferred from other wards for the treatment of arrhythmias or had experiened a ardia arrest before admission or had ardiogeni shok. Forty-three patients in whom MI was not subsequently onfirmed were exluded from the analysis. The Jadad sore for this study was 5/5; however, there was no prespeified primary outome variable or power alulation. There were 9/80 (11.3%) deaths in the oxygen group and 3/77 (3.9%) in the air group, relative risk of death 2.9 (95% CI 0.8 to 10.3, p = 0.08). The maximum serum aspartate aminotransferase level was used as a surrogate for infart size, with mean (SD) values of 99.9 (63.1) and 80.7 (56.8) IU/ml in the oxygen and air groups respetively; differene 19.2 IU/ml (95% CI 0 to 38.4, p = 0.05). Ventriular tahyardia ourred in 11/80 (13.8%) and 5/77 (6.5%) of the oxygen and air groups, relative risk 2.1 (0.8 to 5.8, p = 0.13). Opiate use ourred in 57/80 (71.3%) and 52/77 (67.5%) of the oxygen and air groups, relative risk 1.1 (0.9 to 1.3, p = 0.61). The authors onluded that there was suggestive evidene of a deleterious effet of oxygen and that there seems to be little plae for routine oxygen administration to all patients with aute myoardial infartion. Study 2 A study undertaken by Wilson and Channer. 35 This parallel-group, non-blinded ontrolled study of oxygen therapy in MI was reported in onjuntion with a postal survey on the use of pulse oximetry and supplemental oxygen in oronary are units in England. In the linial study, 50 patients with MI who had reeived thrombolysis with streptokinase within 6 h, were randomised to 4 l/min of oxygen or room air via fae mask for 24 h. However, results are only reported for 42 of the partiipants and one subjet who died within the 24 h period of the study was exluded. The study was not blinded in regard to oxygen therapy. However, one of the aims of this study was to determine the ability of dotors to diagnose hypoxaemia linially and, as a result, the oximetry reordings were blinded to both patient and dotor. Patients with entral yanosis, pulmonary disease requiring oxygen independent of ardia status, those in whom blood gases showed a PaCO kpa and patients with left ventriular failure requiring inotropi support were exluded from the trial. All patients were monitored with a pulse oximeter and Holter ECG monitoring ontinuously for the 24 h period of the study. The Jadad sore was 5/5; however, there was no prespeified primary outome variable or power alulation. The purpose of the study was to doument the ourrene of hypoxaemia and to measure the effet of supplemental oxygen on hypoxaemia rather than to ompare outomes measured by infart size or mortality. The authors did not state in whih randomised group the death ourred and as a result, we were not able to alulate the risk of death for oxygen therapy. No surrogate measurement of infart size was presented. Ventriular tahyardia ourred in 5/22 (22.7%) and 5/20 (25.0%) of the oxygen and air groups, relative risk 0.9 (0.3 to 2.7, p = 0.86). Opiate use ourred in 16/22 (72.7%) and 18/20 (90.0%) of the oxygen and air groups, relative risk 0.8 (0.6 to 1.1, p = 0.15). Of interest 1/22 (4.5%) partiipants who reeived oxygen had an episode of oxygen saturation below 80% ompared with 7/20 Heart 2009;95: doi: /hrt

3 Systemati review (35.0%) of the partiipants who reeived air, relative risk 0.1 (95% CI 0.02 to 1.0, p = 0.01). DISCUSSION This systemati review and meta-analysis identified only two randomised plaebo-ontrolled trials of high-flow oxygen therapy in the first 24 h after an unompliated MI, with substantive linial outome data provided in only one study. 28 Point estimates from the study with substantive reporting identified that high onentration oxygen resulted in a threefold inreased mortality rate and greater infart size, as measured by serum ardia enzyme rise in patients with unompliated MI. Confidene intervals were wide and this study laked statistial power to detet linially important differenes in other linial outomes. As a result we onlude that there is an absene of evidene to support the routine presription of high-flow oxygen therapy in patients with unompliated MI. A pessimisti view of the available evidene is that the use of supplementary oxygen may ause harm when routinely used in this situation. Inluded studies As the evidene of potential harm from this systemati review is primarily derived from the Rawles and Kenmure study, 34 it is neessary to onsider its methodology and findings in some detail. The study was well designed with a Jadad sore of 5, the high-flow oxygen and air regimens were administered double blind with the ylinders shrouded, and an intention-to-treat analysis was performed. Patients had unompliated MI and as a result, the findings do not related to MI ompliated by heart failure, ardiogeni shok or arrhythmias. Furthermore, there does not appear to have been routine use of b blokers, thrombolysis, perutaneous oronary intervention, or aspirin therapy in this trial and thus the findings may not be generalisable to urrent pratie. The 25% greater ardia enzyme release was suggestive of a greater infart size due to the high onentration oxygen therapy. The threefold inrease in deaths in the oxygen treatment group an be onsidered from a number of perspetives. First, the study was not powered to determine a differene in mortality, with the primary aim to determine the effet of oxygen on the size of the infartion, inidene of arrhythmias and the use of analgesis. This is refleted in the wide onfidene intervals onsistent with either harm or benefit. Taking the upper limit, the number needed to ause a death might have been as small as 6.5 for oxygen therapy. These findings provide no support for the view that oxygen therapy was either benefiial or safe, whih would be neessary to justify its use as a routine therapeuti intervention. In ontrast, this study suggests that the routine use of high-flow oxygen in unompliated MI may result in a greater infart size and, possibly, inrease the risk of mortality. The other study inluded in the systemati review 35 did not report, and in any ase laked statistial power to investigate, our nominated primary outome of death. The seondary outomes of ventriular tahyardia ourrene and use of opiates were not different between the two groups, despite a higher prevalene of severe hypoxaemia in the group reeiving air. These findings are onsistent with previous studies that reported no relationship between hypoxia and ishaemia in oronary artery disease, but ontrasted with another study that demonstrated a temporal relationship between noturnal hypoxaemia and both ST-segment depression and arrhythmia after a MI. 38 Potential mehanisms This interpretation of potential harm with high onentration oxygen therapy is onsistent with its known haemodynami effets. In patients with MI, hyperoxia redues ardia output and stroke volume and inreases the mean arterial pressure and systemi vasular resistane If the baseline arterial oxygen saturations are.90%, high onentration oxygen does not inrease oxygen transport, as the redutions in ardia output are in exess of the inrease in oxygen ontent. 26 The adverse haemodynami responses are greatest in patients with MI not ompliated by heart failure or ardiogeni shok. 39 More importantly, there is also substantive evidene that arterial oxygen tension is a major determinant of oronary artery regulatory tone, and that high onentration oxygen therapy resulting in hyperoxia redues oronary artery blood flow, although an inrease in ollateral blood flow to the ishaemi myoardium has been reported in an animal model. 40 The magnitude of the redution in oronary blood flow with hyperoxia may be substantial in patients with oronary artery disease. This has been illustrated by two studies whih used the measurement of intraoronary Doppler flow in subjets with stable oronary artery disease. Breathing 100% oxygen by fae mask for min dereased oronary blood flow by 20 30% in assoiation with a 23 40% inrease in oronary resistane. Oxygen breathing eliited these hanges without affeting the diameter of the large onduit oronary arteries. These findings indiate that hyperoxia is a potent vasoonstritor stimulus to the oronary irulation, funtioning at the level of the mirovasular resistane vessels. These effets are likely to be seondary to an effet on oronary endothelial funtion, with the aelerated oxidative degradation of oronary endothelium-derived nitri oxide by reative oxygen speies. Another potential mehanism is that hyperoxia resulting from high onentration oxygen therapy may exaerbate reperfusion injury to the heart owing to the inreased prodution of oxygen-free radials. 41 This may be partiularly relevant to the urrent therapeuti goal in patients with STsegment elevation myoardial infartion of ahieving urgent reperfusion of the ishaemi myoardium by restoration of oronary blood flow by thrombolysis or perutaneous oronary intervention. 42 Methodologial onerns The main methodologial onern is whether all available studies were inluded in the systemati review. We onsider that it is likely that we have identified all eligible randomised ontrolled trials beause of the omprehensive nature of the searh, inluding non-english language publiations and the extensive review of published manusripts, systemati reviews and guidelines. Although eletroni databases do not referene studies before 1950 we are onfident that our searh strategy identified almost all potential studies during this period owing to our omprehensive review of published papers. Four studies were identified in the systemati review that indiated benefit with the use of oxygen in angina or MI, but did not meet our inlusion riteria. Three studies reported benefit with oxygen therapy in paing-indued angina 43 and exerise-indued angina, although similar benefits ould not be demonstrated in later studies The other study was that of Madias et al, 48 who suggested that the administration of 200 Heart 2009;95: doi: /hrt

4 Systemati review oxygen therapy to patients experiening a MI may redue ishaemi injury, based on preordial ST-segment mapping. Unfortunately, the lak of a randomised ontrol design, standardisation of the duration of oxygen therapy, or blinding in the ST measurements, limited the signifiane of these findings. The major evidene for the benefit of oxygen therapy in MI omes from studies of experimental oronary olusion in animal models. Some 2 6 but not all 7 10 of these studies have reported that high onentration oxygen therapy under normobari or hyperbari onditions redues the size of the MI. However, the extrapolation of these findings to the linial setting is unertain, partiularly beause of differenes in oronary anatomy and ollaterals, whih are muh more extensive in animal models suh as the dog Furthermore, experimental animals had normal oronary vessels and myoardial funtion, whereas most patients with MI have diffuse oronary obstrutive lesions and myoardial damage. Likewise, the findings from animal studies of hyperbari oxygen are not generalisable to the use of oxygen therapy under normobari onditions in MI. This restrition also applies to human studies of hyperbari oxygen, 49 or intraoronary infusion of aqueous oxygen 50 in MI. Guidelines Major international guidelines have taken the pragmati approah of reommending routine oxygen therapy in the treatment of unompliated MI, whih is onsistent with widespread linial pratie. If the Amerian Heart Assoiation is taken as an example, 32 it states that it is reasonable to administer supplementary oxygen to all patients with unompliated ST-segment elevation myoardial infartion during the first 6 hours as level C evidene. However, it is aknowledged in the aompanying text that it is not known whether this therapy limits myoardial damage or redues morbidity or mortality. The two studies referened in support of oxygen therapy are the animal study of experimental oronary artery olusion 2 and the human preordial ECG mapping study 48 disussed above. We respetfully suggest that these reommendations are not supported by the balane of evidene and at best an be onsidered level I (insuffiient evidene) or at worst level C evidene of harm. The reommendations of the New Zealand Branh of the Cardia Soiety of Australia and New Zealand may be preferred, 42 in whih it is reommended that oxygen should be administered to keep the saturations around 96% as level D evidene. Hypoxaemia may ommonly our in MI and oxygen therapy may be indiated to relieve hypoxaemia identified by oximetry monitoring in this situation. CONCLUSIONS We onlude by suggesting that there is insuffiient evidene to support the routine use of high-flow oxygen in the treatment of unompliated MI. 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