Reperfusion and HBOT
I think of physiology when regarding medical conditions as a way to
illustrate the issue. Using this technique I picture that reperfusion
injury occurs in tissues not from restoration of oxygenated blood to
ischemic tissues but from restoration of poorly oxygenated blood, the plasma
of which floods the tissues adding to edema. If we think about the cellular
chemicals produced during the ischemic process we can understand they make
the cells susceptible to swelling, and a sudden inflow of fluid (the blood
plasma) then creates swollen, dysfunctional cells. Hyperbaric oxygenation
allows the cells to get the life-sustaining oxygen without the excess fluid,
the benefit without the downside. So as you read these articles see if you
agree with my illustration.
BMJ 1995;310:477-478 (25 February) Reperfusion injury after acute
myocardial infarction Evidence is accumulating that reperfusion may have
clinically important adverse effects The restoration of oxygenated blood to
ischaemic myocardium--reperfusion--halts the process leading to infarction.
Early reperfusion is the only way to prevent progression to myocardial
necrosis and thus to limit the size of the infarct. It may also, however,
injure the heart. This paradox has become clinically important with the
advent of thrombolytic treatment and primary coronary angioplasty for acute
myocardial infarction. Several studies have shown that there are three main
components of reperfusion injury: reperfusion arrhythmias, myocardial
stunning, and lethal myocyte injury. Sixty years ago Tennant and Wiggers
recognised that the reintroduction of blood flow could cause arrhythmias.1
In animal experiments arrhythmias may occur within seconds of the onset of
reflow.2 In humans reperfusion arrhythmias are commonly associated with
intracoronary thrombolytic treatment3 and primary coronary angioplasty.4 5
They may be less common after intravenous thrombolytic treatment,6 and in
these circumstances it has been proposed that they pose no additional threat
to life.7 The disparity may, however, be related to the rate of recanalisation. Yamazaki et al showed that in dogs sudden reperfusion was more likely to be associated with a high frequency of arrhythmias than was staged reperfusion.8 In a randomised clinical study comparing intravenous thrombolytic treatment with primary coronary angioplasty, ventricular fibrillation was significantly more common in the angioplasty group (6.7% v 2.0%).4 These studies provided angiographic proof of reperfusion--which was not available in several of the multicentre trials of thrombolysis.6 9 10 The duration of the preceding ischaemia is a second important determinant of vulnerability to arrhythmias after reperfusion. In another experiment on dogs Balke et al observed a peak of 67% in the frequency of ventricular fibrillation when reperfusion was achieved after 20-30 minutes of ischaemia, as opposed to 22% after 60 minutes.11 When thrombolytic treatment is given very early (and the intracoronary thrombus is fresh, less organised, and
easier to lyse) reperfusion arrhythmias may be expected to be more prominent. A recent study by the European Myocardial Infarction Project Group randomised 5469 patients to thrombolytic treatment before admission or to later treatment in hospital. Although mortality did not differ in the two groups, prehospital ventricular fibrillation occurred significantly more often in patients treated out of hospital.12 Severe reperfusion arrhythmias may not be common, but the fact that they are life threatening makes them clinically relevant and not dismissible.
Myocardial stunning, which is a delay in functional improvement, is a second
phenomenon that may occur after reperfusion. It seems to follow a time
course similar to that observed in experiments on animals.13 A study by
Schmidt et al on 264 patients found that the improvement of systolic
performance in the reperfused region was only modest after three days but
that considerably more recovery occurred between three days and six
months.14 Reviews by Bolli et al and Kloner have shown the clinical
relevance of myocardial stunning, which may delay recovery from cardiogenic
shock after reperfusion.15 16 Myocardial stunning would seem to be
reversible (given sufficient time), and it might therefore seem of little
clinical importance. Moreover, studies on animals have shown that stunning
may be corrected by inotropic agents.17
The danger, however, is that in
patients with acute left ventricular failure precipitated by myocardial
infarction who have undergone reperfusion treatment, poor ventricular
function due to stunning may be mistaken for permanent injury. Clinicians
need to know that this contractile dysfunction may be reversible provided
that inotropic (or mechanical) circulatory support is maintained--though we
still do not know how much support is needed or for how long. A final
complication is that large doses of inotropes not only increase myocardial
oxygen demand but are also arrhythmogenic--two actions that may cause
further haemodynamic decline.
The third phenomenon associated with
reperfusion is lethal myocyte injury, but uncertainty continues about its
clinical relevance--or indeed whether it occurs at all. One view is that
reperfusion only accelerates the destruction of already irreversibly damaged
cells.18 Reperfusion has been shown to induce contraction band necrosis,
resulting in a weakened myocardium, which in turn may lead to cardiac
rupture.
Data from the second and third international studies of infarct
survival (ISIS 2 and 3) and the study by the Gruppo Italiano per lo Studio
della Streptochinasi nell'Infarto Miocardico (GISSI) showed a small--but
consistent --excess of deaths on the first day only.6 9 10 This excess
occurred in the first six hours and was largely due to cardiac rupture and
cardiogenic shock, not bleeding or stroke. After the first day the benefits
of thrombolytic treatment were similar regardless of age or time to presentation. The increased incidence of early cardiac rupture may be due
not to reperfusion itself but to the modality of reperfusion. When reperfusion is induced by thrombolysis the treatment may cause intramyocardial haemorrhage, which may predispose to cardiac rupture.19 Furthermore, though thrombolytic treatment has been shown to reduce the size of the infarct and mortality, improvements in left ventricular function have been less striking. The reasons for this discrepancy have been a source of debate, and the traditionally accepted relation between patency of the coronary artery, myocardial salvage, and ventricular function has been questioned. Restoration of the patency of vessels may not in itself be sufficient to restore myocardial contractile function in all patients. These findings imply that there is a trade off between the early problems of
thrombolytic treatment and the longer term benefits. They may also represent
a previously hidden manifestation of reperfusion injury. The clinical evidence strongly suggests that the components of reperfusion injury identified in the laboratory are of practical importance. Myocardial reperfusion may not benefit all patients and may actually be harmful to some. Components of reperfusion injury may occur not only in isolation but also in combination--when more profound consequences might be expected. The exact mechanisms of reperfusion injury are uncertain, but they probably include cellular overload of calcium, osmotic cell swelling, and myocyte or microvascular damage from cytotoxic free radicals derived from oxygen. The evidence for this last mechanism comes from interventional studies designed to show whether agents targeting the formation of free radicals might protect against reperfusion injury.20
Direct evidence of the presence of free radicals has now been provided by electron paramagnetic resonance spectroscopy and spin trapping techniques in coronary venous effluent blood,
before and after primary angioplasty reperfusion.21 Nevertheless, confirming
the presence of free radicals does not in itself indicate that reperfusion injury has occurred or that free radicals are the only mediators of reperfusion injury. Further clinical studies are needed to examine closely the relation between free radical generation and various components of myocardial reperfusion injury. Only when these data are available can the potential benefits of adjuvant pharmacological agents in modulating the extent of tissue injury be determined by randomised clinical trials. Senior registrar in cardiology Royal Brompton National Heart and Lung Hospital, London SW3 6NP Professor of cellular pathophysiology Department of Medicine, Royal Liverpool University Hospital, Liverpool L69 3BX
Consultant cardiologist Department of Cardiology, Cardiothoracic Centre,
Liverpool L14 3PE Ever D Grech, Malcolm J Jackson, David R Ramsdale
References: 1.Tennant R, Wiggers CJ. The effect of coronary occlusion on
myocardial interaction. Am J Physiol 1935;12:351-61. 2.Manning AS, Hearse
DJ. Reperfusion-induced arrhythmia: mechanisms and prevention. J Mol Cell
Cardiol 1984;16:497-518. [Medline] 3.Goldberg S, Greenspon AJ, Urban PL,
Muza B, Berger B, Walinsky P, et al. Reperfusion arrhythmia: a marker of
restoration of antegrade flow during intracoronary thrombolysis for acute
myocardial infarction. Am Heart J 1983;105:26-32. [Medline] 4.Grines CL,
Browne KF, Marco J, Rothbaum D, Stone GW, O'Keefe J, et al. A comparison of
immediate angioplasty with thrombolytic therapy for acute myocardial
infarction. N Engl J Med 1993;328:673-9. [Medline] 5.Grech ED, Ramsdale DR.
Termination of reperfusion arrhythmias by coronary artery occlusion. Br
Heart J 1994;72:94-5. [Abstract] 6.ISIS-2 Collaborative Group. Randomised
trial of intravenous streptokinase, oral aspirin, both or neither among 17
187 cases of suspected acute myocardial infarction: ISIS-2. Lancet
1988;ii:349-60. 7.Lie JT. Cardiovascular controversies. The reasons why
clinical cardiologists disregard reperfusion arrhythmias. Cardiovascular Res
1993;27:1906. 8.Yamazaki S, Fujibayashi Y, Rajagopalan RE, Meerbaum S,
Corday E. Effects of staged versus sudden reperfusion after acute coronary
occlusion in the dog. J Am Coll Cardiol 1986;7:564-72. [Medline] 9.Gruppo
Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI).
Effectiveness of intravenous thrombolytic treatment in acute myocardial
infarction. Lancet 1986;i:397-402. 10.ISIS-3 (Third International Study of
Infarct Survival) Collaboratiave Group. ISIS-3: a randomised comparison of
streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin
plus heparin vs aspirin alone among 41299 cases of suspected acute
myocardial infarction. Lancet 1992;339:753-70. [Medline] 11.Balke CW,
Kaplinski E, Michelson EL, Naito M, Dreifus LS. Reperfusion ventricular
tachyarrhythmias: correlation with antecedent coronary artery occlusion
tachyarrhythmias and duration of myocardial ischemia. Am Heart J
1981;101:449-56. [Medline] 12.European Myocardial Infarction Project Group.
Prehospital thrombolytic therapy in patients with suspected acute myocardial
infarction. N Engl J Med 1993;329:383-9. [Medline] 13.Ellis SG, Henschke CI,
Sandor T, Wynne J, Braunwald E, Kloner RA. Time course of functional and
biochemical recovery of myocardium salvaged by reperfusion. Am J Coll
Cardiol 1983;1:1047-55. 14.Schmidt WG, Sheehan FH, von Essen R, Vebis R,
Effert S. Evolution of left ventricular function after intracoronary thrombolysis for acute myocardial infarction. Am J Cardiol 1989;63:497-502. [Medline] 15.Bolli R, Hartley CJ, Rabinovitz RS. Clinical relevance of
"myocardial stunning." Cardiovasc Drugs Ther 1991;5:877- 0. 16.Kloner RA.
Does reperfusion injury exist in humans? J Am Coll Cardiol 1993;21:537-45. ]
17.Ellis SE, Wynne J, Braunwald E, Henschke CI, Sandor T, Kloner RA.
Response of reperfusionsalvaged, stunned myocardium to inotropic-stimulation. Am Heart J 1984;107:9-13. 18.Hearse DJ. Reperfusion of the ischemic myocardium. J Mol Cell Cardiol 1977;9:605-16. [Medline] 19.Waller BF, Rothbaum DA, Pinkerton CA, Cowley MJ, Linnemeier TJ, Orr C, et al. Status of the myocardium and infarct-related coronary artery in 19 necropsy patients with acute recanalization using pharmacologic (streptokinase, r-tissue plasminogen activator), mechanical (percutaneous transluminal coronary angioplasty), or combined types of reperfusion
therapy. J Am Coll Cardiol 1987;9:785-801. [Medline] 20.Bolli R. Oxygen-derived free radicals and myocardial reperfusion injury: an overview. Cardiovasc Drugs Ther 1991;5(suppl 2):249-68. 21.Grech ED, Dodd NJF, Bellamy CM, Faragher EB, Morrison WL, Ramsdale DR. Detection of circulating free radicals following angioplasty reperfusion for acute myocardial infarction. Circulation 1993;88:I-157.
BMJ 1994;309:1582-1583 (10 December) Hyperbaric oxygen in crush syndrome
Editor --Andrew D Shaw and colleagues emphasise the urgent need for
orthopaedic referral for the underlying problem of the compartment syndrome
--namely, impending muscle necrosis.1 They do not mention the role of
adjuvant hyperbaric oxygen in this condition. Pathophysiologically, in the
compartment syndromes ischaemia and oedema create a vicious circle in which
hypoxia plays a central part. Partially viable tissues may recover if hypoxia is relieved. Treatment with hyperbaric oxygen can increase tissue oxygen tensions to values higher than those achieved by any other method. 100% Oxygen at 304 kPa (3 atmospheres absolute) can produce arterial oxygen tensions of up to about 250 kPa) by direct solution in plasma.2 The resultant diffusion gradient into tissues is also clearly increased. Red cells become more deformable at such pressures, facilitating transport through constricted microcirculation. Hyperbaric oxygen also produces
arteriolar vasoconstriction. While this effect might seem undesirable, the
hyperoxygenation itself counteracts any short term decrease in blood flow.
Subsequent reduction in transcapillary flow of fluid and increased capillary
resorption of extravascular fluid rapidly decrease tissue oedema. The fall in intracompartmental pressure that follows is clearly beneficial, specifically in the compartment syndrome.3 Animal models suggest a particularly effective role for hyperbaric oxygen in the compartment syndrome complicated by haemorrhagic hypotension.4 In the compartment syndrome hyperbaric oxygen should be given as adjuvant treatment with general resuscitation and surgery. We agree with Shaw and colleagues that surgical decompression should be considered urgently. Hyperbaric oxygen is conventionally given after surgery, using 243 kPa (2.4 atmospheres absolute) 100% oxygen for 90 minutes three times daily for the first day and twicedaily thereafter.5 In cases of surgical delay for any reason and in cases in which the decision is taken not to operate, hyperbaric oxygen should be used
immediately if it is available; this may also assist in distinguishing viable from nonviable tissue at subsequent surgery.
BMJ 1999;319:1083-1084 ( 23 October ) Editorials Hyperbaric oxygen in
carbon monoxide poisoning Conflicting evidence that it works There is
little dispute that carbon monoxide poisoning is common: in the United
States it produces an estimated 40 000 emergency department visits each
year,1 and the accompanying editorial outlines the difficulties in
diagnosing poisoning caused by this "silent killer." There is disagreement,
however, about how best to treat carbon monoxide poisoning, and in
particular about the role of hyperbaric oxygen. Carbon monoxide is produced
endogenously in small amounts and as a byproduct of incomplete combustion.
It is colourless, odourless, and undetectable by human senses. It binds to
haemoglobin, displacing oxygen; causes a leftward shift of the
oxyhaemoglobin dissociation curve; binds to many intracellular proteins; and
may interfere with ATP production at the cytochrome level.2 It can also
activate neutrophils pathologically, leading to a reperfusion injury
manifested by lipid peroxidation.3 Low levels of carbon monoxide produce
evidence of oxidative stress.4
Recently, apoptosis in brain tissue has been
observed after carbon monoxide poisoning.5 Supplemental oxygen was found
helpful in treating carbon monoxide poisoning in 1868,6 and hyperbaric oxygen was first used for clinical poisoning in 1942.7 The theoretical
benefits of hyperbaric oxygen include a faster reduction in carboxyhaemoglobin levels, increased intracellular delivery of oxygen, and reduced neutrophil activation and adherence, thereby reducing lipid peroxidation.8 Despite anecdotal reports on the beneficial effects of hyperbaric oxygen for acute carbon monoxide poisoning,8 its role in such poisoning has been questioned. 9 10 Four randomised clinical trials have studied the issue in humans. Raphael et al treated non-comatose acutely
poisoned patients with hyperbaric or normobaric oxygen and found no difference in subjective outcome at one month.11 In a small trial in conscious patients Ducasse observed that hyperbaric oxygen preserved vascular responsiveness to acetazolamide and that treated patients had better quantitative electroencephalograms than those treated with normobaric oxygen.12 Thom et al randomised conscious poisoned patients to hyperbaric or normobaric oxygen and found no delayed neurological sequelae in those receiving hyperbaric oxygen.13 Only limited inferences can be drawn from these trials, however, because of methodological problems, including lack of blinding,11-13 possible ineffective hyperbaric oxygen dosing,11 delays in giving hyperbaric oxygen,11 inconsistent and incomplete follow up, 11 13 lack of functional (neuropsychological) outcome measures, 11 12 and failure
to enrol unconscious patients.11-13
A recent Australian double blind
randomised trial addresses some of these limitations.10 Scheinkestel et al
showed that hyperbaric oxygen did not improve cognitive outcome in acute
carbon monoxide poisoning, including in severe poisoning; indeed, they found that it might worsen outcome, in that more of the severely poisoned patients in the hyperbaric oxygen group had a poor outcome at completion of
treatment. Most of their 191 patients (73%) had severe poisoning and most
had attempted suicide (76%). Concomitant depression and use of psychoactive drugs might have influenced the results. The delay before most patients received hyperbaric oxygen (about seven hours) might have reduced its effectiveness.8 Scheinkestel et al used high concentrations of oxygen
continuously in both groups for three days, and more in patients who remained abnormal at three days. This dose of normobaric oxygen is generally not used in carbon monoxide poisoning, so the controls might not have represent a true control group for testing whether hyperbaric oxygen
improves or worsens outcome. Cluster randomisation was necessary for
practical purposes, but this might have caused differences between the two
arms of the trial.
All patients were admitted to hospital, and Scheinkestel
et al's report would have been strengthened if it had included detailed
outcome information at hospital discharge. Also the study is weakened by the
fact that one month follow up was low (46%). Nevertheless, this study
reminds us of how damaging carbon monoxide poisoning can be: hospital
mortality was 3%, and neuropsychological sequelae were present in 71% of
patients at hospital discharge, and 62% at one month.
Even with hyperbaric
oxygen, neuropsychological sequelae occur,14 and without hyperbaric oxygen, including in severe carbon monoxide poisoning, a normal functional recovery is possible.15 Unfortunately, no marker exists that will predict which patients will develop neurocognitive sequelae. In carbon monoxide poisoning treatment of many of the pathological processes that occur is probably time dependent, and if patients are not treated promptly with hyperbaric oxygen one can reason that hyperbaric oxygen might be ineffective. However, the time window for hyperbaric oxygen in human carbon monoxide poisoning is unknown. Thom has shown in rats that lipid peroxidation can be prevented if hyperbaric oxygen is used within 90 minutes of carbon monoxide exposure.16 Obviously, prevention of carbon monoxide poisoning remains paramount.
Households with attached garages or with any flame source should have regular inspections of their furnaces as well as carbon monoxide alarms.
Those people who do suffer acute carbon monoxide poisoning deserve, at the minimum, several hours of high concentrations of oxygen (preferably 100% oxygen) and follow up after the poisoning. And if cognitive and affective problems are detected after carbon monoxide poisoning these patients should be referred to neuropsychologists and occasionally psychiatrists. However, although both 100% normobaric oxygen and hyperbaric oxygen are accepted treatments for carbon monoxide poisoning, it remains unclear on present evidence whether hyperbaric oxygen offers a substantial advantage in clinical poisoning. For now clinicians must balance the costs and risks of transport of hyperbaric treatment against its theoretical benefits. We still need a well designed, multicentre, prospective, randomised controlled trial to answer the question of when, if at all, to refer patients with acute carbon monoxide poisoning. Lindell K Weaver, medical director, hyperbaric medicine. LDS Hospital, University of Utah School of Medicine, Salt Lake City, Utah 84143, USA Acknowledgments The carbon monoxide research conducted by LKW's department has been funded by the Deseret Foundation, LDS Hospital, and he has received honorariums to speak on carbon monoxide poisoning. 1. Hampson NB. Emergency department visits for carbon monoxide poisoning in the pacific northwest. J Emerg Med 1998; 16: 695-698[Medline]. 2. Piantadosi CA. Toxicity of carbon monoxide: hemoglobin vs histotoxic mechanisms. In: Penney DG, ed. Carbon monoxide. Boca Raton: CRC Press,
1996:163-186. 3. Thom SR. Carbon monoxide mediated brain lipid peroxidation in the rat. J Appl Physiol 1990; 68: 997-1003[Medline]. 4. Thom SR, Ischiropoulos H. Mechanism of oxidative stress from low levels of carbon
monoxide.
Health Effects Institute 1997; 80: 1-19[Medline]. 5. Piantadosi
CA, Zhang J, Levin ED, Folz RJ, Schmechel DE. Apoptosis and delayed neuronal damage after carbon monoxide poisoning in the rat. Exp Neurol 1997; 147: 103-104[Medline]. 6. Linas AJ. [Meeting of July 17, 1868.] Bulletins et Memoires de la Societe de Therapeutique. 1868; 2: 32-37. 7. End E, Long CW. Oxygen under pressure in carbon monoxide poisoning. J Ind Hyg Toxicol 1942; 24: 302-306. 8. Carbon monoxide poisoning. In: Hampson NB, chairman. Hyperbaric oxygen therapy: a committee report. Bethesda, Maryland: Undersea and Hyperbaric Medical Society, 1999:9-12. 9. Tibbles PM, Perrotta PL. Treatment of carbon monoxide poisoning: a critical review of human outcome studies comparing normobaric oxygen with hyperbaric oxygen. Ann Emerg Med 1994; 24: 269-276[Medline]. 10. Scheinkestel CD, Bailey M, Myles PS, Jones K, Cooper DJ, Millar IL, et al. Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomized controlled clinical trial. Med J Australia 1999; 170: 203-210[Medline]. 11. Raphael JD, Elkharrat D, Jars-Guincestre MC. Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet 1989; 2: 414-419[Medline]. 12. Ducasse JL, Celsis P, Marc-Vergnes JP. Non-comatose patients with acute carbon monoxide poisoning: hyperbaric or normobaric oxygenation? Undersea Hyperbaric Med 1995; 22: 9-15[Medline]. 13. Thom SR, Taber RL, Mendiguren II, Clark JM, Hardy KR, Fisher AB. Delayed neurologic sequelae after carbon monoxide poisoning: Prevention by treatment with hyperbaric oxygen. Ann Emerg Med 1995; 24: 474-480. 14. Weaver LK. Carbon monoxide poisoning. In: Guntupalli KK, Hanania NA, eds. Environmental emergencies. Critical care clinics. Philadelphia: Saunders, 1999:297-317. 15. Weaver LK, Hopkins RO, Larson-Lohr V. Neuropsychologic and functional recovery from severe carbon monoxide poisoning without hyperbaric oxygen therapy. Ann Emerg Med 1996;
27: 736-740[Medline]. 16. Thom SR. Antagonism of carbon monoxide-mediated brain lipid peroxidation by hyperbaric oxygen. Toxicol Appl Physiol 1990; 105: 340-344.
BMJ 1994;309:1513 (3 December) Hyperbaric oxygen treatment for crush injury EDITOR,--Andrew D Shaw and colleagues draw attention to the self
perpetuating process of oedema and ischaemia after crush injury and the need to break this cycle.1 In ischaemia, failure of oxygen delivery is at the
root of the problem. The cycle can be interrupted by giving oxygen at a high
dose, provided that it is used early. In the United States crush injury is a
recognised indication for hyperbaric oxygen treatment, which is paid for by
insurers when given for this indication. This was discussed in an editorial
in 1993.2 Although it has been hypothesised that additional oxygen may
worsen reperfusion injury, the reverse has proved to be the case. In an
experimental study Nylander et al found that a single 45 minute session of
hyperbaric oxygen significantly reduced postischaemic oedema and that the
effect lasted 48 hours.3 Zamboni et al found that hyperbaric oxygen
abolished neutrophil adhesion and minimised oedema after four hours of total ischaemia in rat gracilis muscle.4 They are now using hyperbaric oxygen routinely in the reimplantation of extremities and report complete muscle survival and minimal soft tissue oedema with ischaemia times of up to 12 hours. Crush injury is often accompanied by hypotension and fat embolism causing cerebral oedema, which can also benefit from hyperbaric oxygen treatment.5 P B James Senior lecturer in occupational medicine, Wolfson Hyperbaric Medicine Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY. References: 1.Shaw AD, Sjolin SV, McQueen MM. Crush syndrome following unconsciousness: need for urgent orthopaedic referral. BMJ 1994;309:857-9. (1 October.) [Full Text] 2.Kindwall EP. Hyperbaric oxygen. BMJ 1993;307:515-6. [Medline] 3.Nylander G, Lewis D, Nordstrom H, Larsson J. Reduction of postischemic edema with hyperbaric oxygen. Plast Reconstr Surg 1985;76:596-600. [Medline] 4.Zamboni WA, Roth AC, Russell RC, Graham B, Suchy H, Kucan JO. Morphological analysis of the microcirculation during reperfusion of ischaemic skeletal muscle and the effect of hyperbaric oxygen. Plast Reconstr Surg 1993;91:1110-21. [Medline] 5.Sukoff MH, Ragatz RE. Hyperbaric oxygenation for the treatment of acute cerebral edema. Neurosurgery 1982;10:29-38.
Reprinted with Permission
