artificial oxygen carriers aim at improving oxygen transport and 		   oxygen unloading to the tissue .
artificial oxygen carriers may thus be used as 		   an alternative to allogeneic blood transfusions or to improve tissue 		   oxygenation and function of organs with marginal oxygen supply .
the present 		   article describes the currently evaluated perfluorocarbon emulsions , in order 		   to summarize their efficacy , discuss potential side effects and illustrate 		   potential future applications .
perfluorochemicals are chemically inert synthetic molecules that 		   consist primarily of carbon and fluorine atoms , and are clear , colourless 		   liquids .
they have the ability to physically dissolve significant quantities of 		   many gases including oxygen and carbon dioxide .
perfluorochemicals thus 		   have to be emulsified for intravenous use . with sophisticated technology , it is 		   possible to generate a stable perfluorocarbon emulsion with exceptionally small 		   particles ( median diameter < 0.2 m ) .
first - generation perfluorocarbon emulsions as well as russian or 		   chinese products have been described in a previous review .
western development of second - generation perfluorocarbon 		   emulsions has focused on linear perfluorocarbon molecules such as 		   perfluorooctyl bromide ( c8f17br , also referred to as perflubron ) , 		   perfluorodecyl bromide ( c10f21br ) and perfluorodichlorooctane ( c8f16cl2 ) . using solely 3.6%w / v egg yolk phospholipid ,
alliance 		   pharmaceutical corporation ( san diego , california , usa ) developed a 		   concentrated ( 60% w / v ) and stable perfluorocarbon emulsion , oxygent , which is 		   composed of 58% w / v perfluorooctyl bromide and 2% w / v perfluorodecyl bromide , 		   with an average particle size of 0.16 - 0.18 m diameter . 		  
hemagen / perfluorocarbon ( st louis , missouri , usa ) developed another 		   concentrated ( 40% v / v ) perfluorocarbon emulsion , oxyfluor , using 		   perfluorodichlorooctane , egg yolk phospholipid and triglycerid with an average 		   particle size of 0.22 - 0.25 m diameter .  
after intravenous administration , the droplets of the perfluorocarbon 		   emulsion are taken up by the reticuloendothelial system ( res ) .
intravascular half life is 		   dose - dependent , and for oxygent was found to be 9.4  2.2 h for a dose of 		   1.8 g / kg . after the initial uptake of the 		   perfluorocarbon emulsion into the res the droplets are slowly broken down , and 		   the perfluorocarbon molecules are taken up in the blood again ( bound to blood 		   lipids ) and transported to the lungs , where the unaltered perfluorocarbon 		   molecules are finally excreted via exhalation . at present no metabolism of 		   fluorocarbon molecules is known in humans .
the 		   results of most of these studies are not published in the scientific 		   literature , but they form the basis for regulatory authorities to allow 		   clinical testing .
common side effects such as delayed febrile reaction and 		   flu - like symptoms seem to be related to the normal activity of phagocytic cells 		   of the res .
the magnitude of these side effects depend on the particle size of 		   the emulsion .
smaller particles ( 0.1 - 0.2 m diameter ) appear to be less 		   detectable for the res than larger particles ( > 0.2 m diameter ) and 		   cause only mild temperature increases and mild flu - like symptoms in relatively 		   few individuals . once in the res , excretion depends on vapor pressure and lipid 		   solubility of flourocarbons .
elimination half - time is 3 - 4 days for 		   perfluorooctyl bromide and 8 days for perfluorodichlorooctane .
because 		   flourocarbon molecules are inert to biochemical degradation , they diffuse back 		   into the blood where they dissolve in plasma lipids .
these lipids transport the 		   perfluorocarbon molecules to the lungs where they are excreted by 		   exhalation . at higher doses ( 1.7 g / kg oxyfluor , 1.8 g / kg oxygent ) a transient 		   decrease in platelet count
was observed 2 - 3 days after dosing , with recovery by 		   7 - 14 days . with oxygent , 		  
however , the decrease in platelet count was mild ( 10 - 20 % ) and no drug - related 		   effects on platelet function were observed .
furthermore , plasmatic coagulation 		   was not compromised and template bleeding time was not prolonged by 1.8 g / kg 		   oxygent .
in addition , there 		   was no complement activation ; no suppression of 		   humoral or cell - mediated immune function ; no haemodynamic effects or 		   vasoconstriction ; no changes in liver , lung or renal function ; and no 		   clinically relevant effects on blood chemistry .
oxygen transport characteristics of perfluorocarbon emulsions are 		   fundamentally different from those of blood ( fig .
in contrast , 		   perfluorocarbon emulsions are characterized by a linear relationship between 		   oxygen partial pressure and oxygen content .
elevated arterial oxygen partial 		   pressures are thus beneficial to maximize the oxygen transport capacity of 		   perfluorocarbon emulsions . 		
ventilation with 100% oxygen may raise concerns regarding oxygen 		   toxicity . during relatively short exposure times ( < 8 h )
, however , no evidence 		   of oxygen toxicity was detected   and the earliest 		   signs of oxygen toxicity were observed only after 18h .  
red blood cells are flexible , disk - shaped cells approximately 7 - 8 m in diameter and are packed with highly concentrated hemoglobin . in 		   arterioles
red cells fill most of the vessel diameter with a relatively small 		   plasma phase near the vessel wall where smaller cells such as platelets ( 1 m in diameter ) and small particles concentrate ( near - wall particle 		   excess phenomenon ) . in the capillaries
the distance between red blood cells 		   increases , producing significant intercellular plasma gaps , and capillaries are 		   found that are perfused by plasma only . due to the small size ( < 0.2 m in diameter ) perfluorocarbon 		   emulsion particles mainly flow in the peripheral plasma layer in larger vessels 		   . in the microcirculation , 		  
perfluorocarbon emulsion particles perfuse even the tiniest capillaries 		   ( 4 - 5 m in diameter ) , where no red blood cells may flow under certain 		   conditions .
it is precisely this area in which perfluorocarbon emulsions exert 		   their greatest effects , because they augment local oxygen delivery much more 		   than would be expected from the increase in oxygen content in the arterial 		   blood ( large vessel with red blood cells ) .
another 		   important aspect that determines the efficacy of perfluorocarbon emulsions is 		   the fact that all oxygen carried by the perfluorocarbon is in the dissolved 		   state , resulting in a higher oxygen partial pressures in the microcirculation 		   and thereby augmenting the driving pressure for the diffusion of dissolved 		   oxygen into the tissue .
a perflubron emulsion ( oxygent ) was assessed in a variety of 		   haemodilution studies .
keipert et al 		   applied perflubron emulsion in dogs after acute normovolemic haemodilution 		   ( anh ) at a haematocrit of 10% . with the application of oxygent , cardiac output 		   tended to increase and a massive rise in mixed venous oxygen partial pressure 		   and mixed venous saturation was observed .
the percentage of metabolized oxygen 		   that originated from endogenous haemoglobin decreased with the application of 		   oxygent , indicating that the oxygen transported by oxygent is preferentially 		   metabolized , due to its excellent oxygen unloading characteristics .
an increase in mixed venous oxygen partial pressure indicates 		   improvement in global oxygenation status , rather 		   than shunting of oxygen from arterioles directly into venules ( i.e. oxygen 		   bypassing the microcirculation ) .
this view is substantiated by a study that 		   demonstrated an increase of oxygen consumption in a maximally working , in - situ 		   gastrocnemius muscle preparation in anesthetized and haemodiluted dogs after 		   oxygent administration .
it is also substantiated by 		   the fact that increases in mixed venous oxygen partial pressure are generally 		   associated with an oxygent - dependent improvement in tissue oxygenation , as 		   demonstrated in the heart , brain , muscle , gut and liver .
furthermore , holman et 		   al   tested oxygent in severely haemodiluted 		   dogs undergoing cardiopulmonary bypass .
dogs treated with increasing doses of 		   oxygent survived cardiopulmonary bypass progressively better than did control 		   animals .
oxygent may also be beneficial as an adjunct to resuscitation . in a 		   porcine model of near fatal haemorrhage ,
infusion of oxygenated oxygent into the aortic arch also 		   improved outcome in another resuscitation model .
mixed venous oxygen partial pressure was higher in oxygent - treated 		   animals after anh to a haemoglobin of 7 g / dl than in control animals , and measures of left 		   ventricular systolic and diastolic contractile function were found to be 		   improved after oxygent administration at a haemoglobin level of 3 g / dl .
this might be explained by an augmented oxygen delivery 		   through very narrow capillaries where oxygent particles may penetrate better 		   than the relatively large red blood cells , and thereby improve local tissue 		   oxygenation more than red blood cells .
these studies 		   thus indicate that oxygent indeed transports and unloads oxygen into the areas 		   where it is needed most .
anh 		   to a haemoglobin concentration of approximately 9 g / dl was performed . during surgery
oxygent ( 0.9 g / kg ) was administered when a 		   blood transfusion was deemed necessary by the anaesthesiologist , which occurred 		   at a haemoglobin concentration of approximately 8 g / dl .
mixed venous oxygen 		   tension and mixed venous oxygen saturation both increased significantly after 		   oxygent administration , and cardiac output was stable .
although only relatively 		   little oxygen was transported by perflubron emulsion ( approximately 1% ) , 5% of 		   the metabolized oxygen was transported by oxygent , again indicating that 		   oxygent - transported oxygen is preferentially metabolized .
recently , the results of two large prospective randomized multicenter 		   studies on the use of oxygent in orthopaedic and genitourinary surgery were 		   presented . in the 		   orthopaedic study
, 147 patients undergoing hip 		   replacement and spine surgery were haemodiluted preoperatively to a hemoglobin 		   level of 9 g / dl .
after the patients had reached a predefined transfusion 		   trigger , they were randomized into four groups : standard of care ( retransfusion 		   of 450 ml autologous blood at an unchanged fractional inspired oxygen of 0.4 ) ; 		   oxygent ( 0.9 or 1.8 g / kg ) with colloid to a total 450 ml with ventilation with an 		   fractional inspired oxygen of 1.0 ; and infusion of 450 ml colloid with 		   ventilation with an fractional inspired oxygen of 1.0 .
oxygent ( 1.8 g / kg ) was 		   most successful in reversing transfusion triggers in 97% of patients , as 		   compared with 60% in the control group .
the duration of transfusion trigger 		   reversal in the oxygent 1.8 g / kg group was significantly longer ( 80 min ) than in 		   the control and colloid groups ( 55 and 30 min , respectively ) . in the study that 		   including 109 patients undergoing genitourinary surgery , similar results were achieved .
thus , physiologic 		   transfusion triggers may be treated at least as successfully with oxygent as 		   with autologous blood of colloids .
this illustrates the remarkable potency of 		   oxygent to deliver readily available oxygen to those areas in the body in which 		   the extra oxygen is needed most .
optimal use of perfluorocarbon emulsions in the future may consist of 		   a combination of anh preoperatively with application of an artificial oxygen 		   carrier such as a perfluorocarbon emulsion during the operation , a procedure 		   termed ' augmented anh ' [ roth dj , keipert pe , 		   faithfull ns , zuck tf , riess jg : facilitated oxygen delivery in conjunction 		   with hemodilution .
us patent # 5,451,205 ( issued september 19 , 1995 ) and 		   european patent # ep 0627 913 b1 ( issued april 4 , 1998 ) ] ( fig .
augmented anh is a concept in which patients undergo anh to 		   relatively low haemoglobin levels preoperatively . during the operation , when 		   the haemoglobin concentration decreases further due to surgical blood loss and 		   concomitant colloid or crystalloid replacement , perfluorocarbon emulsions in 		   conjunction with 100% oxygen ventilation
is administered to enhance oxygen 		   delivery and improve tissue oxygenation . as a consequence ,
lower levels of 		   haemoglobin concentration can be safely tolerated . towards the end of the 		   operation ,
this will 		   result in a relatively high haemoglobin concentration in the postoperative 		   period and oxygen delivery will again be provided by endogenous haemoglobin
. 		   therefore , greatly elevated arterial partial oxygen tension values are not 		   necessary in the postoperative period and the relatively short half - life of 		   perfluorocarbon emulsions ( < 24 h ) will not compromise their success in 		   reducing allogeneic blood transfusion requirement ( fig .
, it is important not to compromise 		   blood coagulation during the surgical procedure , otherwise blood loss might be enhanced and thus allogeneic 		   blood savings limited .
therefore , a careful selection of colloids is necessary 		   to avoid blood coagulation becoming compromised .
apart from the use of perfluorocarbon emulsions to reduce allogeneic 		   blood transfusions in surgery , there are numerous other potential future 		   indications based on their potential to augment tissue oxygenation .
such future 		   indications will probably include treatment and prevention of cerebral 		   ischaemia , stroke , cardiopulmonary bypass - related cerebral adverse events , 		   spinal cord ischaemia , myocardial ischaemia due to acute infarction , 		   percutaneous coronary angioplasty , acute limb ischaemia , emergency surgery and 		   trauma as long as no allogeneic blood is available , 		   and decompression sickness .
other applications include the use of 		   perfluorocarbon emulsions to augment tumour oxygenation to render them more 		   sensitive to radiation and chemotherapy , to prevent or treat sequelae of air 		   embolism , and finally to improve organ preservation for subsequent organ 		   transplantation ( referenced in ) .
perfluorocarbon emulsion and blood - based oxygen transport : oxygen 				 dissociation curve of native human blood ( blood ) and a perfluorocarbon ( pfc ) 				 emulsion .
note that 5 volume % ( 5 vol% ) of oxygen can be offloaded by blood as 				 well as by a pfc emulsion . with a pfc emulsion , higher
note also that pfc emulsion - transported oxygen is 				 more completely offloaded than blood - transported oxygen , resulting in an 				 approximate oxygen extraction ( o2-ex . ) ratio of 90% for the pfc emulsion , as 				 compared with approximately 25% for blood , assuming a normal mixed venous 				 partial oxygen tension of approximately 40 mmhg .
c o2 , oxygen content ; po2 , 				 partial oxygen tension . modified according to looker et al   and keipert et al ) .
the concept of augmented acute normovolemic haemodilution ( a - anh ) 				 is divided into three periods ( a - c ) .
( a ) preoperative anh with conventional 				 volume replacement without the use of an artificial oxygen carrier such as a 				 perfluorocarbon emulsion .
preoperative anh targets relatively low hemoglobin 				 levels , close to the individual transfusion trigger .
( b ) during surgery when 				 the haemoglobin concentration is expected to fall further due to surgical blood 				 loss , a perfluorocarbon emulsion will be used to augment oxygen - offloading 				 capacity to the body .
note that total oxygen offloading capacity from combined 				 haemoglobin - based and perfluorocarbon emulsion - based oxygen transport is 				 maintained during surgery at the level reached after preoperative anh ( ie above 				 the individual transfusion trigger , despite low haemoglobin concentrations 				 towards the end of surgery).(c ) postoperative retransfusion ( postop .
rt ) of anh 				 blood increases the haemoglobin concentration above the individual transfusion 				 trigger . therefore
, the decreasing contribution of pfc emulsion - based oxygen 				 transport will not adversely affect overall oxygenation of the organism .
 perfluorocarbon emulsions are being clinically evaluated as 			  artificial oxygen carriers to reduce allogeneic blood transfusions or to 			  improve tissue oxygenation . 
 perfluorocarbon emulsions are efficacious in animal 			  experiments , and in humans they are well tolerated and at least as successful 			  to reverse physiologic transfusion triggers than autologous blood . 			  
 perfluorocarbon emulsions may be used in the future in the concept of augmented 			  acute normovolaemic haemodilution . in this concept 
 relatively low preoperative 			  haemoglobin levels are targeted during preoperative normovolaemic haemodilution 			  and a perfluorocarbon emulsion is given to augment oxygen delivery during 			  surgery when low endogenous haemoglobin levels are expected . the autologous 			  blood is subsequently retransfused in the postoperative period when the 			  patient 's oxygenation is provided primarily by the endogenous 			  haemoglobin . 
 additional uses of perfluorocarbon emulsions will include 			  treatments of diseases with compromised tissue oxygenation such as cerebral or 			  myocardial ischaemia , air embolism and emergency or trauma surgery as long as 			  no allogeneic blood is available . 
Introduction
Background of perfluorocarbon emulsions
Safety profile
Oxygen transport
Preclinical efficacy of second-generation perfluorocarbon			 emulsions
Clinical efficacy of second-generation perfluorocarbon emulsions
Future uses of perfluorocarbon emulsions
Figures and Tables