Clinical review : Treatment of heat stroke : should dantrolene be considered ? Rapid and efficient cooling is the most important therapeutic objective in patients with heat stroke -LRB- HS -RRB- . This article reviews the mechanism of action and rationale for the use of dantrolene as a potential supportive cooling method in the treatment of HS . Relevant studies were included to support discussion of the role of dantrolene for the treatment of HS . In some studies dantrolene was shown to accelerate cooling rate when administered after the development of exertional HS . Dantrolene was also found to be effective in reducing the extent of HS signs when given as pretreatment in an animal model . Accumulated data do not support the routine use of dantrolene as an adjuvant cooling technique in HS , but administration of this drug in severe cases , or in which no improvement is observed , appears rational . Further trials are needed in order to assess the true effectiveness of dantrolene in HS . Introduction Hyperthermia is defined as any core temperature rise to above the hypothalamic set-point at which heat-dissipating mechanisms are impaired . Normal core temperature values are in the 36.5 -- 37.5 °C range at rest and can rise to 40 °C during strenous exercise . Hyperthermia is usually caused by an imbalance between total heat -LRB- metabolic and environmental heat -RRB- accumulated and total heat lost from the body . Hyperthermia per se may be physiological and can be compensated for -LRB- as in the moderate elevation in core temperature that occurs in an exercising and otherwise asymptomatic individual -RRB- , or it may be pathophysiological but generally well tolerated . It may also be associated with adverse pathophysiological consequences such as inability to continue physical exertion -LRB- heat exhaustion -RRB- . At the extreme , hyperthermia represents a state in which the elevation in core temperature is either already accompanied by organ injury or is sufficient to produce such injury if left untreated . Several syndromes have been reported to be associated with extreme hyperthermia , including malignant hyperthermia -LRB- MH -RRB- , neuroleptic malignant syndrome -LRB- NMS -RRB- and heat stroke -LRB- HS -RRB- . The mainstay of treatment of these syndromes includes the administration of basic resuscitative measures together with simultaneous cooling aimed at reducing body temperature -LSB- 1,2 -RSB- . Cooling may be achieved by several methods , such as immersion in cold water and evaporation of water over the skin -LSB- 3-7 -RSB- . Because heat is primarily produced by hyperactivity of muscles in the various syndromes , dantrolene sodium , a muscle relaxant , has also been suggested to accelerate cooling -LSB- 8-10 -RSB- . In MH , dantrolene administration resulted in a rapid reduction in mortality rate , and therefore it is now considered as an essential part of treatment in this syndrome -LSB- 11-13 -RSB- . Dantrolene has also been recommended for the treatment of NMS -LSB- 14 -RSB- . To date , no drug has shown significant efficacy in improving the outcome of patients with HS . Experience with dantrolene use in HS is in its initial phases -LRB- Tables 1,2,3 -RRB- . In some studies a possible benefit from dantrolene treatment was reported , whereas in others it was not found to be effective -LSB- 15-22 -RSB- . We reviewed relevant studies concerning dantrolene use in HS in order to establish its role in the treatment of this condition . Studies included in this review were identified by means of a comprehensive Medline search , limited to the English language literature , using the following keywords : ` dantrolene ' and ` hyperthermia ' or ` heat ' . Each article identified was further examined for relevancy . Dantrolene Dantrolene sodium is a hydantoin derivative . It acts directly on muscle contractile elements , attenuating the amount of calcium released from the sarcoplasmic reticulum of skeletal muscle to the cytosol -LSB- 23-25 -RSB- . As a result , calcium dependent excitation -- contraction coupling and consequent muscle contraction are inhibited . The mean biological half-life of dantrolene in healthy volunteers or patients was reported to range from 6 to 9 hours , with extremes of 3 and 22 hours -LSB- 25-30 -RSB- . It is primarily metabolized in the liver , with 15 -- 25 % of the dose administered being excreted by the kidneys -LSB- 27,29,30 -RSB- . Dantrolene is marketed as Dantrium -LRB- Norwich Eaton Pharmaceuticals , Norwich , NY , USA -RRB- and can be administered intravenously -LRB- in solution with mannitol and sodium hydroxide -RRB- or orally . When dantrolene is used as an emergency therapy , such as in acute hyperthermic syndromes , it is unlikely to cause major adverse effects -LSB- 25 -RSB- . However , prolonged use may be associated with undesirable side effects that include weakness , drowsiness , diarrhea and malaise -LSB- 25 -RSB- . Hepatotoxicity , which can be irreversible , is also a major concern . The risk for hepatic injury appears to be about twofold greater in females , in patients receiving doses over 300 mg/day and in those treated for over 60 days -LSB- 31 -RSB- . In addition , dantrolene sodium solution is highly alkaline -LRB- pH 9.6 -RRB- , and intravenous injection may cause extravasation and tissue necrosis -LSB- 25 -RSB- . Heat stroke and ` thermic stress syndrome ' HS is a life-threatening illness characterized by an elevation in core body temperature to above 40 °C with central nervous system -LRB- CNS -RRB- dysfunction that results in delirium , convulsions , or coma -LSB- 32,33 -RSB- in the absence of any other cause of CNS dysfunction , and skin dryness . The affected individual may suffer from a characteristic multiple organ clinical and pathological syndrome caused by temperature-induced tissue damage -LSB- 1,34 -RSB- . HS results from exposure to a high environmental temperature , in which case it is called ` classic ' heat stroke -LRB- CHS ; or ` nonexertional ' HS -RRB- , or from strenuous exercise , in which case it is called ` exertional ' heat stroke -LRB- EHS -RRB- -LSB- 34-36 -RSB- . CHS is usually seen in the very young or elderly and in poor socioeconomic settings with limited access to air conditioning . EHS is seen more commonly in exercising individuals , for instance soldiers in army training . Further reviews on HS are available -LSB- 32-36 -RSB- . Epidemiological incidence data for HS is imprecise because of varying definitions of heat-related death and under-diagnosis -LSB- 35 -RSB- . One study conducted in urban USA found a variation from 17.6 to 26.5 cases per 100,000 capita . Data from Saudi Arabia show a seasonal incidence pattern , ranging from 22 to 250 cases per 100,000 capita . The crude mortality rate in Saudi Arabia has been estimated at 50 % . Treatment consists of immediate cooling and support of organ system function . Some authors believe that HS , as well as MH and other hyperthermic syndromes , are different manifestations of a broader underlying condition called ` thermic stress syndrome ' -LSB- 9,10,15,17,37 -RSB- . This common malady , which is triggered by different mechanisms , is characterized by an extreme elevation in body temperature and CNS dysfunction , which may be complicated by bleeding diathesis , elevated serum enzymes levels and renal failure . Because dantrolene was found to be effective in the treatment of MH and NMS , its usage has also been recommended for the treatment of HS -LSB- 8-10,15 -RSB- . Dantrolene use in heat stroke Two reports from the early 1980s demonstrated a beneficial effect from using dantrolene in HS . Lydiatt and Hill -LSB- 15 -RSB- reported on a patient with EHS who responded favourably to dantrolene -LRB- 4 mg/kg intravenously -RRB- after sympthomatic therapy had failed . In a case report , Denborough -LSB- 8 -RSB- reported that intravenous dantrolene -LRB- 20 mg bolus -RRB- therapy produced rapid recovery in a young soldier suffering from EHS after a march . In a controlled study , the adjuvant effects of dantrolene in comparison with passive cooling were investigated in a canine model of CHS -LSB- 16 -RSB- . Intravenous administration of dantrolene -LRB- 5 mg/kg -RRB- did not significantly improve cooling rates , haemodynamic parameters , pathological changes , or clinical outcome when compared with passive cooling . Channa and coworkers -LSB- 17 -RSB- conducted a study in which 20 EHS patients were randomly assigned to two groups with only one group receiving dantrolene -LRB- 2.45 mg/kg intravenously -RRB- . Patients in both groups were cooled either using the Makkah body cooling unit or by ` conventional methods ' , namely spraying of tap water over the patients while fanning . Cooling rates were found to be significantly higher in the dantrolene group . All patients survived and there was no difference in the incidence of neurological sequelae between the groups . The effects of dantrolene were also evaluated in 53 patients suffering from CHS -LSB- 21 -RSB- . All patients were treated by using a body cooling unit in which atomized water was sprayed over the victim while they were fanned with hot air . In addition , treatment with either dantrolene -LRB- 2 mg/kg -RRB- or placebo was given intravenously after blind , randomized selection . Dantrolene administration did not result in any enhancement of the cooling rate , and there was no significant difference in the number of hospital stays between the two groups . It should be noted that in this study both treatment groups achieved satisfactory cooling in under 1 hour . Therefore , a possible positive effect of dantrolene in extreme cases of HS , in which cooling times might be longer , can not be ruled out . It should further be noted that in this study Bouchama and coworkers -LSB- 21 -RSB- treated their patients with dantrolene and mannitol simultaneously . Thus , it could not be concluded whether the reported positive effects were attributed to dantrolene or to mannitol . Mannitol may be beneficial in the setting of HS because of its effect on expanding the intravascular volume and reducing tissue injury after ischemia by scavenging oxygen free radicals -LSB- 38,39 -RSB- . In order to address this question , Zuckerman and coworkers -LSB- 19 -RSB- designed a randomized controlled study in which heat stroked piglets were treated by one of the following four methods : passive cooling , ` conventional cooling ' -LRB- intravenous fluid resuscitation , sponging with tap water , mechanical fanning and ice gastric lavage -RRB- , conventional cooling along with dantrolene , and conventional cooling along with mannitol . Although dantrolene significantly shortened the cooling time when compared with conventional cooling , it did not shorten the cooling time when compared with mannitol . Moreover , it was shown that dantrolene did not improve cardiovascular parameters when administered in addition to conventional methods . Tayeb and Marzouki -LSB- 20 -RSB- investigated whether dantrolene might be advantageous in prophylaxis against HS in exercising sheep . They found that pretreatment with dantrolene -LRB- 3 mg/kg and 1.5 mg/kg intravenously -RRB- caused a significant reduction in body temperature , and decreased the extent of HS signs as well as some of the induced changes in enzymes and hormones . These effects were more significant in the group receiving dantrolene 3 mg/kg than in the group receiving 1.5 mg/kg . The dantrolene group also exhibited a trend toward reduced mortality from HS -LRB- 0/12 -RRB- in comparison with the group that did not receive dantrolene treatment -LRB- 2/6 -RRB- . Using a rat model of EHS and CHS , Moran and coworkers -LSB- 18 -RSB- studied the efficacy of dantrolene both as a prophylactic agent and as a therapeutic drug . Administration of high doses of dantrolene -LRB- 140 mg/kg intravenously -RRB- before heat stress delayed the development of HS in the sedentary animals . Estimated temperatures were lower in the exercising rats that received Dantrolene pretreatment , but this was most reasonably attributed to the limited physical capacity induced by dantrolene . When dantrolene , at the same dose , was administered after the development of HS , it significantly improved the cooling rate in the exercising rats -- an effect that was not seen in the sedentary group . Discussion The rationale for the use of dantrolene in HS emerged from the overlap in the systemic manifestations of HS and other hyperthermic syndromes , particularly MH . However , some researchers claimed that , although hyperthermia was characteristic of both MH and HS , these syndromes represent two clinical entities with different heat generating cellular mechanisms . Although MH is characterized by muscular rigidity , which causes active heat production , HS usually manifests in the form of flaccidity , and heat production does not continue uncontrolled -LSB- 17,40 -RSB- . Therefore , dantrolene , which uncouples the excitation -- contraction sequence heat generating mechanism , may not be beneficial in the treatment of HS . Moreover , MH is a genetically transmitted disease , which is triggered by several depolarizing muscle relaxants or volatile anaesthetic agents -LSB- 41,42 -RSB- . In comparison , to the best of our knowledge , no genetic predisposition has been definitely incriminated in the typical HS patient . However , several reports suggest a possible link between HS and MH . Tobin and coworkers -LSB- 43 -RSB- reported a case of fatal HS in a patient who experienced MH 8 years earlier and speculated whether other HS victims are MH susceptible . An abnormal caffeine -- halothene contracture test , which is considered indicative for MH susceptibility , was found in more than 40 % of individuals who survived EHS , whereas less than 1 % of the general population exhibited this response -LSB- 44 -RSB- . It is important to note that adequate recovery time must be given before performing such tests after a bout of rhabdomyolysis . Muscle function takes considerable time to recover and , inferentially at least , so does muscle metabolism . Therefore , care must be taken before relying on post-HS muscle contracture tests . A possible underlying myopathy in EHS patients was demonstrated by Bendahan and coworkers -LSB- 45 -RSB- , who found abnormal muscle energetics in such patients by using a 31P magnetic resonance spectroscopy . Therefore , there is some evidence to suggest that a subset of individuals with HS may also be predisposed to MH . Theoretically , this subset of individuals might continue to have a relatively high level of heat production even after collapse . They may also be at increased risk for EHS because an attenuated muscular efficiency can increase muscular caloric production at the same absolute work intensity . The fact that some individuals with HS might have a contribution of MH-type pathophysiology might also explain why there has been anecdotal evidence suggesting a possible benefit from dantrolene in selected cases . The above studies indicate that the cooling rate was the only parameter among those evaluated that improved when dantrolene was administered after the development of HS -LSB- 17-19 -RSB- . However , this effect was not demonstrated in all studies . The diversity of results may be accounted for by the models investigated . When dantrolene was administered in an exercising model , it was found to be more effective than in a CHS model . This is not surprising because dantrolene inhibits muscle contraction , which does not play a role in the pathophysiology of CHS . Collectively , most of the studies suggest that dantrolene is not beneficial in reducing mortality rate when it is given for the treatment of HS . However , survival rates in EHS currently approach 95 % , and the studies were not large enough to exhibit a reduced mortality -LSB- 1,46 -RSB- . Moreover , some reports suggest that dantrolene may even prevent death in cases of severe HS -LSB- 15,17 -RSB- . For example , one patient in the study conducted by Channa and coworkers -LSB- 17 -RSB- who received dantrolene made a complete recovery in spite of an initial core temperature of 44 °C . An EHS patient described by Lydiatt and Hill -LSB- 15 -RSB- had a rectal temperature of 42 °C for more than 30 min and responded only to dantrolene . Noteworthy , the authors did not state the upper recording limit of their thermometer . If a clinical thermometer has an upper limit of 42 °C , then it will record 42 °C when the actual temperature is 46 °C . Despite successful cooling for 30 min , the thermometer still shows 42 °C even though the temperature has been reduced by 4 °C . Taking dantrolene at this instant will lead to an impressive , albeit misinterpreted , result . Some researchers indicated that the relative ineffectiveness of dantrolene in some of the studies may be related to an inadequate dose -LSB- 21,47 -RSB- . Dantrolene was administered in doses of 2 -- 5 mg/kg , which were selected according to recommended protocols with regard to the use of this agent in MH . However , the optimal dose of dantrolene in MH is still questionable . Although Britt -LSB- 48 -RSB- reported a complete recovery from MH when dantrolene was used at a dose of 6 mg/kg , others -LSB- 31 -RSB- postulated that an increased dose of dantrolene may be associated with hepatotoxicity . The risk for hepatotoxicity is even more concrete in HS patients because the liver is commonly injured in HS and increasing the dose of dantrolene may worsen this hepatic damage . Nevertheless , hepatotoxicity has never been reported in HS victims who received dantrolene . Despite the absence of outcome-based data , it might nevertheless be pathophysiologically rational to try dantrolene in selected cases . Dantrolene may be beneficial where there is evidence of ongoing excessive heat production , such as in cases of HS that are accompanied by muscular rigidity . In these cases , the apparent HS may be misdiagnosed , and the patient may actually be suffering from MH or NMS . Finally , dantrolene might also have a role to play in limiting muscle injury and its consequences in rhabdomyolysis by impairing calcium release from the sarcoplasmic reticulum -LSB- 49,50 -RSB- . Loss of calcium homeostasis in muscle cells may be associated with muscle injury resulting from impairment in mitochondrial respiration and ATP production , activation of phospholipase A2 with production of leukotrienes and prostaglandins , increased production of free radicals , and activation of calcium-activated proteases -LSB- 49 -RSB- . Although there is no evidence that dantrolene reduces the extent of muscle injury in EHS , it was found to protect against muscle injury associated with exercise in several studies -LSB- 51-54 -RSB- . Dantrolene pretreatment reduced the severity of HS signs in an exercising animal model . This effect may be attributed to decreased muscular production of metabolic heat or to an unknown modulation of neurotransmitter release -LSB- 20 -RSB- . However , the effect of dantrolene on muscle contracture may result in limited physical capacity . Furthermore , the administration of dantrolene before HS is more theoretical than real because the incidence of EHS is negligible in comparison with the number of individuals who are engaged in physical activity and/or are exposed to heat strain . Conclusion Therapy with the accepted MH prophylactic dose of 2 -- 5 mg/kg resulted in a possible benefit from dantrolene treatment in HS in some studies , whereas in others it was not found to be effective . The limited literature does not support the routine use of dantrolene as an adjuvant cooling technique in the setting of HS . Nevertheless , because dantrolene does appear to increase cooling rate , furthur studies are advised for dantrolene use in severe cases or cases in which no improvement is observed with other cooling methods . Wider trials are still needed to evaluate the efficacy of dantrolene in reducing mortality , thereby justifying its use in HS . Noteworthy , dantrolene should not be used as a single cooling method , and its administration should only be in addition to the well established ` conventional methods ' . Competing interests None declared . Abbreviations CHS = classic heat stroke ; CNS = central nervous system ; EHS = exertional heat stroke ; HS = heat stroke ; MH = malignant hyperthermia ; NMS = neuroleptic malignant syndrome .

O O O O O B I O O B O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B I O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O B O O B O O O B O O O O O B O O O B O O O O O B O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O B O O O O B O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B I I O O O B I O O O O B O O O O O O O

cooling
dantrolene
exertional heat stroke
heat stroke
hyperthermia
temperature


Physical

fitness

fatigue

and

quality

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life

after

liver

transplantation

Fatigue

is

often

experienced

after

liver

transplantation

The

aims

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this

cross-sectional

study

were

to

assess

physical

fitness

-LRB-

cardiorespiratory

fitness

neuromuscular

fitness

body

composition

-RRB-

in

liver

transplant

recipients

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to

explore

whether

physical

fitness

is

related

to

severity

of

fatigue

In

addition

we

explored

the

relationship

between

physical

fitness

and

health-related

quality

of

life

Included

were

patients

years

after

transplantation

-LRB-

aged

years

-RRB-

with

varying

severity

of

fatigue

Peak

oxygen

uptake

during

cycle

ergometry

walk

distance

isokinetic

muscle

strength

of

the

knee

extensors

body

mass

index

waist

circumference

skinfold

thickness

severity

of

fatigue

and

health-related

quality

of

life

were

measured

Cardiorespiratory

fitness

in

the

liver

transplant

recipients

was

on

average

lower

than

normative

values

-LRB-

P

-RRB-

Furthermore

the

prevalence

of

obesity

seemed

to

be

higher

than

in

the

general

population

-LRB-

vs.

-RRB-

We

found

no

deficit

in

neuromuscular

fitness

Cardiorespiratory

fitness

was

the

only

fitness

component

that

was

related

with

severity

of

fatigue

-LRB-

rs

to

rs

P

-RRB-

Particularly

cardiorespiratory

fitness

was

related

with

several

aspects

of

health-related

quality

of

life

-LRB-

rs

to

rs

P

-RRB-

Results

of

our

study

imply

that

cardiorespiratory

fitness

and

body

composition

are

impaired

in

liver

transplant

recipients

and

that

fitness

is

related

with

severity

of

fatigue

-LRB-

only

cardiorespiratory

fitness

-RRB-

and

quality

of

life

-LRB-

particularly

cardiorespiratory

fitness

-RRB-

in

this

group

These

findings

have

implications

for

the

development

of

rehabilitation

programs

for

liver

transplant

recipients

Introduction

Liver

transplantation

-LRB-

LTx

-RRB-

is

the

only

definitive

treatment

for

end-stage

liver

disease

Since

patient

survival

and

liver

function

after

LTx

have

improved

markedly

due

to

improved

technical

expertise

better

selection

of

patients

improved

post-LTx

management

of

complications

and

improved

immunosuppressive

therapy

-LRB-

Adam

et

al.

-RRB-

In

Europe

LTx

has

achieved

a

survival

rate

of

-LRB-

Burroughs

et

al.

-RRB-

Although

studies

have

reported

that

quality

of

life

improves

after

LTx

-LRB-

Gross

et

al.

van

der

Plas

et

al.

-RRB-

limitations

in

daily

function

still

remain

-LRB-

Gross

et

al.

van

der

Plas

et

al.

-RRB-

Amongst

these

limitations

liver

transplant

recipients

often

experience

fatigue

-LRB-

Aadahl

et

al.

Belle

et

al.

Leyendecker

et

al.

van

den

Berg-Emons

et

al.

-RRB-

Gross

et

al.

-LRB-

-RRB-

and

Belle

et

al.

-LRB-

-RRB-

reported

that

although

the

intensity

of

fatigue

was

reduced

after

LTx

fatigue

remained

the

most

distressing

symptom

year

after

surgery

Leyendecker

et

al.

-LRB-

-RRB-

found

that

months

after

LTx

complaints

of

fatigue

were

more

severe

in

the

LTx

group

than

in

the

general

population

In

a

previous

study

we

found

severe

fatigue

in

of

patients

up

to

years

after

LTx

and

these

complaints

did

not

decrease

over

time

-LRB-

van

den

Berg-Emons

et

al.

-RRB-

Rehabilitation

programs

might

be

effective

in

reducing

severity

of

fatigue

after

LTx

but

to

develop

appropriate

programs

knowledge

on

the

factors

associated

with

fatigue

after

LTx

is

necessary

However

data

on

these

factors

are

scarce

Aadahl

et

al.

-LRB-

-RRB-

and

van

den

Berg-Emons

et

al.

-LRB-

-RRB-

suggested

that

the

fatigue

experienced

by

liver

transplant

recipients

is

primarily

physical

rather

than

psychological

Furthermore

van

den

Berg-Emons

et

al.

-LRB-

-RRB-

found

that

severe

complaints

of

fatigue

in

liver

transplant

recipients

are

associated

with

low

levels

of

everyday

physical

activity

A

hypoactive

lifestyle

may

lead

to

a

negative

spiral

hypoactivity

leading

to

a

reduction

in

physical

fitness

and

deterioration

of

complaints

of

fatigue

leading

to

further

hypoactivity

Few

studies

have

investigated

the

physical

fitness

of

liver

transplant

recipients

but

the

limited

data

available

suggest

a

reduced

physical

fitness

after

LTx

-LRB-

Beyer

et

al.

Stephenson

et

al.

Unnithan

et

al.

-RRB-

Stephenson

et

al.

-LRB-

-RRB-

found

a

lower

maximal

oxygen

uptake

than

predicted

in

liver

transplant

recipients

Beyer

et

al.

-LRB-

-RRB-

reported

that

although

the

cardiovascular

and

neuromuscular

fitness

in

liver

transplant

recipients

improved

after

a

supervised

exercise

program

during

the

post-operative

year

maximal

oxygen

uptake

and

muscle

strength

remained

lower

compared

to

healthy

gender

and

age-matched

individuals

Also

in

pediatric

liver

transplant

recipients

deficits

in

cardiovascular

fitness

and

abdominal

muscle

strength

have

been

reported

-LRB-

Unnithan

et

al.

-RRB-

It

may

be

hypothesized

that

deficits

in

physical

fitness

in

liver

transplant

recipients

are

associated

with

complaints

of

fatigue

Furthermore

deficits

in

physical

fitness

may

lead

to

impaired

health-related

quality

of

life

-LRB-

HRQoL

-RRB-

However

to

our

knowledge

no

studies

are

available

on

the

relationships

between

these

parameters

in

liver

transplant

recipients

Because

of

the

scarcity

of

studies

on

physical

fitness

and

related

parameters

in

liver

transplant

recipients

the

present

study

assessed

physical

fitness

-LRB-

cardiorespiratory

fitness

neuromuscular

fitness

and

body

composition

-RRB-

in

liver

transplant

recipients

and

explored

whether

physical

fitness

is

related

to

severity

of

fatigue

in

this

group

The

relationship

between

physical

fitness

and

HRQoL

was

also

explored

Patients

and

methods

Patients

To

obtain

a

representative

sample

of

liver

transplant

recipients

with

respect

to

fatigue

we

recruited

liver

transplant

recipients

with

varying

severity

of

fatigue

according

to

the

distribution

of

severity

of

fatigue

as

found

in

our

previous

study

in

liver

transplant

recipients

-LRB-

van

den

Berg-Emons

et

al.

-RRB-

Severity

of

fatigue

in

this

previous

study

ranged

from

no

signs

of

fatigue

to

most

disabling

fatigue

and

was

assessed

with

the

Fatigue

Severity

Scale

of

Krupp

et

al.

-LRB-

-RRB-

-LRB-

see

below

-RRB-

Inclusion

criteria

for

the

present

study

were

LTx

between

and

years

ago

sufficient

knowledge

of

the

Dutch

language

and

age

between

and

years

Exclusion

criteria

were

multiorgan

transplant

recipients

severe

comorbidity

and

contra-indication

for

a

progressive

maximal

cycle

ergometer

test

Of

the

original

sample

of

patients

in

the

previous

study

-LRB-

van

den

Berg-Emons

et

al.

-RRB-

patients

had

died

patient

had

emigrated

patients

were

transplanted

more

than

years

previously

and

patients

were

not

eligible

because

of

contra-indications

for

a

maximal

cycle

ergometer

test

Of

the

eligible

patients

patients

-LRB-

-RRB-

agreed

to

participate

There

were

no

significant

differences

in

relevant

characteristics

between

the

patients

who

decided

to

participate

and

the

non-participants

The

study

was

approved

by

the

Medical

Ethics

Committee

of

the

Erasmus

University

Medical

Center

Written

informed

consent

was

obtained

from

all

subjects

Table

shows

the

characteristics

of

the

study

group

Table

of

the

study

group

-LRB-

n

-RRB-

Age

-LRB-

years

-RRB-

Gender

disease

-LRB-

n

-RRB-

a

since

transplantation

-LRB-

years

-RRB-

Immunosuppressive

agentsb

are

presented

as

mean

SD

or

numbersaChronic

primary

disease

cholestatic

-LRB-

n

-RRB-

viral

-LRB-

n

-RRB-

miscellaneous

-LRB-

n

-RRB-

acute

primary

disease

intoxication

-LRB-

n

-RRB-

bImmunosuppressive

agents

agent

cyclosporine

or

tacrolimus

agents

prednisone

with

tacrolimus

agents

prednisone

with

tacrolimus

and

azathioprine

Measurements

Physical

fitness

cardiorespiratory

Cardiorespiratory

fitness

was

measured

with

a

progressive

maximal

aerobic

test

on

a

cycle

ergometer

-LRB-

Jaeger

Toennies

Breda

The

Netherlands

-RRB-

The

test

was

preceded

by

a

warm-up

period

-LRB-

W

-RRB-

The

test

started

at

W

and

resistance

was

increased

every

minute

by

or

W

depending

on

the

ability

of

the

patients

Individual

protocols

were

constructed

such

that

the

total

exercise

time

ranged

from

to

min

The

pedal

rate

was

rpm

and

strong

verbal

encouragement

was

given

during

the

test

The

test

was

terminated

when

the

subject

voluntarily

stopped

due

to

exhaustion

or

when

the

patient

was

unable

to

maintain

the

initial

pedal

rate

Gas

exchange

and

heart

rate

-LRB-

HR

-RRB-

were

measured

continuously

using

a

breath-by-breath

gas

analysis

system

-LRB-

COSMED

Rome

Italy

-RRB-

Subjective

strain

was

measured

immediately

after

the

final

stage

by

the

Borg

Category

Scale

for

Rating

of

Perceived

Exertion

-LRB-

Borg

-RRB-

Patients

were

asked

to

indicate

how

strenuous

they

had

experienced

the

test

by

giving

a

number

from

-LRB-

no

effort

at

all

-RRB-

to

-LRB-

maximal

effort

-RRB-

Cardiorespiratory

fitness

was

defined

as

the

mean

oxygen

uptake

during

the

last

s

of

exercise

-LSB-

in

ml

kg

min

and

in

ml

kg

fat-free

mass

min

-LRB-

ml

kgFFM

min

-RRB-

-RSB-

In

addition

the

ventilatory

anaerobic

threshold

-LRB-

VAT

expressed

as

percentage

of

predicted

-RRB-

was

estimated

by

the

ventilatory

equivalent

method

when

and

increased

while

and

remained

stable

-LRB-

Reinhard

et

al.

Wasserman

et

al.

-RRB-

Finally

patients

performed

the

submaximal

walk

test

-LRB-

-RRB-

-LRB-

Guyatt

et

al.

-RRB-

Patients

were

instructed

to

walk

not

run

as

far

as

they

could

along

a

marked

tape

in

a

hall

during

a

period

Standardized

encouragement

was

provided

with

the

following

phrases

You

are

doing

well

and

Keep

up

the

good

work

Patients

were

allowed

to

stop

and

rest

during

the

test

but

were

instructed

to

resume

walking

as

soon

as

they

felt

able

to

do

so

The

walk

distance

-LRB-

-RRB-

was

registered

Physical

fitness

neuromuscular

Isokinetic

muscle

strength

of

the

knee

extensors

was

assessed

in

both

legs

by

a

Biodex

dynamometer

-LRB-

Shirley

New

York

USA

-RRB-

recording

strength

as

torque

in

Nm

The

patients

were

seated

against

a

back-rest

firmly

strapped

at

the

hip

and

thigh

The

rotational

axis

was

aligned

with

the

lateral

femoral

epicondyle

After

five

familiarization

repetitions

isokinetic

strength

was

measured

at

s

with

maximal

contractions

and

at

s

with

maximal

contractions

Strong

verbal

encouragement

was

given

during

the

test

Peak

torque

-LRB-

PT

-RRB-

was

defined

as

the

maximum

torque

generated

by

the

patients

throughout

one

series

of

repetitions

at

each

velocity

Physical

fitness

body

composition

Height

and

body

mass

were

measured

without

shoes

Body

mass

was

measured

using

a

Cormier

Paribel

weighing

chair

-LRB-

FH

Balances

Cormier

Romainville

France

-RRB-

Body

mass

index

-LRB-

BMI

kg

m

-RRB-

was

calculated

from

height

and

body

mass

Waist

circumference

-LRB-

cm

-RRB-

was

measured

mid-way

between

the

lowest

rib

and

the

iliac

crest

while

standing

Thickness

of

four

skinfolds

-LRB-

biceps

triceps

subscapular

suprailiaca

region

-RRB-

was

measured

twice

at

the

right

side

of

the

body

with

a

Harpenden

Skin-Fold

Caliper

-LRB-

Burgess

Hill

UK

-RRB-

The

mean

of

the

two

measurements

was

used

as

representative

for

each

site

Percentage

body

fat

-LRB-

BF

-RRB-

was

predicted

from

skinfold

thickness

according

to

the

method

of

Durnin

and

Womersley

-LRB-

-RRB-

Severity

of

fatigue

Severity

of

fatigue

was

assessed

by

the

Dutch

version

of

the

Fatigue

Severity

Scale

-LRB-

FSS

-RRB-

-LRB-

Krupp

et

al.

-RRB-

The

FSS

is

a

self-administered

questionnaire

with

answers

ranging

from

-LRB-

strongly

disagree

-RRB-

to

-LRB-

strongly

agree

-RRB-

The

mean

score

of

the

nine

inquiries

ranges

from

-LRB-

no

signs

of

fatigue

-RRB-

to

-LRB-

most

disabling

fatigue

-RRB-

Internal

consistency

reliability

validity

and

sensitivity

of

the

FSS

have

been

established

in

several

patient

groups

-LRB-

Krupp

et

al.

Merkies

et

al.

-RRB-

In

addition

to

the

FSS

severity

of

fatigue

was

assessed

with

a

horizontal

visual

analogue

scale

-LRB-

VAS

-RRB-

Patients

were

asked

to

mark

the

line

according

to

how

intense

they

had

experienced

fatigue

during

the

last

month

-LRB-

denotes

no

fatigue

experienced

and

denotes

the

most

severe

fatigue

-RRB-

-LRB-

ter

Borg

et

al.

-RRB-

Visual

analogue

scales

have

been

found

to

yield

reliable

and

valid

data

-LRB-

Huskisson

Scott

and

Huskisson

-RRB-

Health-related

quality

of

life

HRQoL

was

assessed

by

the

validated

Dutch

version

-LRB-

-RRB-

-LRB-

van

der

Zee

and

Sanderman

-RRB-

of

the

Medical

Outcomes

Study

Short

-LRB-

-RRB-

-LRB-

Ware

and

Sherbourne

-RRB-

The

is

a

validated

self-administered

questionnaire

used

internationally

to

measure

health

status

with

respect

to

different

dimensions

physical

functioning

social

functioning

role

limitations

due

to

physical

problems

role

limitations

due

to

emotional

problems

pain

mental

health

vitality

general

health

perception

and

change

in

perceived

health

during

the

last

months

All

raw

scores

were

converted

to

a

scale

with

higher

scores

indicating

higher

levels

of

functioning

or

well-being

Procedure

On

the

day

of

the

measurements

patients

refrained

from

caffeine

nicotine

and

heavy

exercise

The

order

of

the

tests

was

standardized

patients

started

with

the

followed

by

the

questionnaires

-LRB-

completed

under

supervision

of

the

researcher

-RRB-

body

composition

measurements

strength

test

and

finally

the

progressive

maximal

aerobic

test

Exercise

tests

were

performed

under

supervision

of

a

physician

There

were

sufficient

rest

periods

between

the

tests

Statistics

Statistical

analysis

was

performed

using

SPSS

for

Windows

-LRB-

SPSS

Inc.

Chicago

IL

USA

-RRB-

Results

are

presented

as

mean

standard

deviation

-LRB-

SD

-RRB-

range

or

numbers

Results

on

cardiorespiratory

fitness

were

compared

to

normative

values

for

sedentary

persons

and

to

normative

values

for

people

who

exercise

no

more

than

h

a

week

-LRB-

recreational

-RRB-

-LRB-

Vos

et

al.

-RRB-

Results

on

neuromuscular

fitness

were

compared

with

the

normative

values

of

Akima

et

al.

-LRB-

-RRB-

and

was

compared

with

the

normative

values

of

Enright

and

Sherill

in

healthy

adults

aged

years

-LRB-

-RRB-

When

patients

were

younger

than

years

the

normative

values

of

Gibbons

et

al.

-LRB-

-RRB-

were

used

Obesity

was

defined

as

a

BMI

-LRB-

World

Health

Organization

-RRB-

a

waist

circumference

cm

in

men

and

cm

in

women

-LRB-

Lean

et

al.

-RRB-

or

percentage

BF

in

men

and

in

women

-LRB-

Lohman

-RRB-

Differences

in

physical

fitness

between

patients

and

normative

values

were

tested

with

the

non-parametric

Mann-Whitney

U

Test

Relationships

between

physical

fitness

and

severity

of

fatigue

and

between

physical

fitness

and

quality

of

life

were

explored

using

the

non-parametric

Spearman

correlation

coefficient

-LRB-

rs

-RRB-

A

probability

value

determined

statistical

significance

However

because

of

the

relatively

small

study

sample

also

results

on

the

α

level

are

presented

-LRB-

indicating

a

trend

-RRB-

Results

Physical

fitness

Mean

score

on

the

Borg

Scale

was

indicating

that

the

patients

experienced

the

maximal

ergometer

test

on

average

as

heavy

to

very

heavy

The

mean

HRmax

was

of

what

was

predicted

-LRB-

predicted

HRmax

-RRB-

-LRB-

Fox

et

al.

-RRB-

The

individual

results

of

the

patients

are

presented

in

Table

Table

shows

the

cardiorespiratory

fitness

and

neuromuscular

fitness

of

the

patients

compared

with

normative

values

in

ml

kg

min

was

-LRB-

P

-RRB-

and

-LRB-

P

-RRB-

lower

than

normative

values

for

respectively

sedentary

persons

and

those

who

exercise

recreationally

in

ml

kgFFM

min

was

-LRB-

P

-RRB-

and

-LRB-

P

-RRB-

lower

than

normative

values

for

respectively

sedentary

persons

and

those

who

exercise

recreationally

was

-LRB-

P

-RRB-

lower

than

normative

values

There

was

no

significant

deficit

in

neuromuscular

fitness

Table

shows

the

body

composition

of

the

LTx

group

According

to

the

cut-off

points

for

obesity

based

on

BMI

waist

circumference

and

percentage

BF

respectively

and

of

the

patients

were

classified

as

obese

Table

results

on

physical

fitness

in

the

liver

transplant

recipientsAge

-LRB-

year/Gender

-RRB-

BMI

-LRB-

kg

m

-RRB-

Waist

-LRB-

cm

-RRB-

aBody

fat

-LRB-

-RRB-

-LRB-

ml

kg

min

-RRB-

-LRB-

ml

kgFFM

min

-RRB-

bVAT

-LRB-

predicted

sed

-RRB-

VAT

-LRB-

predicted

recr

-RRB-

-LRB-

m

-RRB-

PT

extension

s

-LRB-

Nm

-RRB-

PT

extension

s

-LRB-

Nm

-RRB-

.3111.029.036.551.454.142.7652156.388.252

.4118.542.013.122.543.632.5495101.978.664

.7103.530.621.731.377.455.443099.962.624

.072.025.929.940.438.831.1660159.9111.546

.5100.025.828.238.048.638.7606151.688.563

.977.530.123.133.0108.664.846540.035.753

.999.623.620.727.156.742.6510149.396.839

.787.017.431.237.851.543.5547169.0111.833

.088.019.835.143.767.959.9510155.9116.963

.0103.034.815.824.257.943.230367.239.445

.775.022.730.238.156.246.8600115.967.932

.991.020.425.031.443.438.3576180.4124.658

Abbreviations

BMI

-LRB-

kg

m

-RRB-

body

mass

index

Waist

-LRB-

cm

-RRB-

waist

circumference

-LRB-

ml

kg

min

-RRB-

peak

oxygen

uptake

per

kg

-LRB-

ml

kgFFM

min

-RRB-

peak

oxygen

uptake

per

kg

fat-free

mass

VAT

-LRB-

predicted

-RRB-

ventilatory

anaerobic

threshold

as

percentage

of

predicted

sed

sedentary

normative

values

recr

recreational

normative

values

walk

distance

PT

peak

torqueaWaist

circumference

n

because

of

thickness

of

the

skin

at

the

place

of

the

cicatrice

in

four

patientsbBody

fat

and

n

because

the

thickness

of

the

subscapular

skinfold

could

not

be

measured

reliably

in

one

patientTable

fitness

and

neuromuscular

fitness

in

the

liver

transplant

groupLTx

groupNorm

valuesaPCardiorespiratory

fitness

-LRB-

ml

kg

min

-RRB-

-LRB-

sed

-RRB-

-LRB-

recr

-RRB-

-LRB-

ml

kgFFM

min

-RRB-

-LRB-

sed

-RRB-

-LRB-

recr

-RRB-

-LRB-

m

-RRB-

Neuromuscular

fitness

PT

extension

at

s

-LRB-

Nm

-RRB-

PT

extension

at

s

-LRB-

Nm

-RRB-

Results

are

presented

as

mean

SDAbbreviations

-LRB-

ml

kg

min

-RRB-

peak

oxygen

uptake

per

kg

-LRB-

ml

kgFFM

min

-RRB-

peak

oxygen

uptake

per

kg

fat-free

mass

VAT

-LRB-

predicted

-RRB-

ventilatory

anaerobic

threshold

as

percentage

of

predicted

sed

sedentary

normative

values

recr

recreational

normative

values

-LRB-

people

who

exercise

no

more

than

h

a

week

-RRB-

walk

distance

PT

peak

torqueaVos

et

al.

-LRB-

-RRB-

Enright

and

Sherill

-LRB-

-RRB-

Gibbons

et

al.

-LRB-

-RRB-

Akima

et

al.

-LRB-

-RRB-

bn

because

the

thickness

of

the

subscapular

skinfold

could

not

be

measured

reliably

in

one

patient

Significant

-LRB-

P

-RRB-

difference

between

patients

and

normative

values

Difference

between

patients

and

normative

values

at

the

α

level

-LRB-

trend

-RRB-

Table

composition

in

the

liver

transplant

groupBody

compositionMean

SDBody

weight

-LRB-

kg

-RRB-

Height

-LRB-

m

-RRB-

Body

mass

index

-LRB-

kg

m

-RRB-

Waist

circumference

-LRB-

cm

-RRB-

Body

fat

-LRB-

-RRB-

Results

are

presented

as

mean

SDaWaist

circumference

n

because

of

thickness

of

the

skin

at

the

place

of

the

cicatrice

in

four

patientsbBody

fat

n

because

the

thickness

of

the

subscapular

skinfold

could

not

be

measured

reliably

in

one

patient

Relationships

Table

shows

the

correlation

coefficients

between

the

physical

fitness

parameters

and

severity

of

fatigue

as

assessed

with

the

FSS

and

VAS

of

the

parameters

of

neuromuscular

fitness

or

body

composition

were

significantly

related

with

severity

of

fatigue

assessed

with

either

the

FSS

or

the

VAS

Table

correlation

coefficients

for

the

relationships

between

fitness

parameters

and

severity

of

fatigue

as

measured

with

the

Fatigue

Severity

Scale

-LRB-

FSS

-RRB-

and

the

Visual

Analogue

Scale

-LRB-

VAS

-RRB-

in

liver

transplant

recipientsPhysical

fitnessFatigueFSSVASRsPRsPCardiorespiratory

fitness

-LRB-

ml

kg

min

-RRB-

of

sedentary

norm

of

recreational

norm

-LRB-

ml

kgFFM

min

-RRB-

a

of

sedentary

norma

of

recreational

norma

VAT

-LRB-

predicted

sed

-RRB-

VAT

-LRB-

predicted

recr

-RRB-

-LRB-

m

-RRB-

of

norm

Neuromuscular

fitness

PT

extension

at

s

-LRB-

Nm

-RRB-

of

norm

PT

extension

at

s

-LRB-

Nm

-RRB-

of

Body

composition

Body

mass

index

-LRB-

kg

m

-RRB-

Waist

circumference

-LRB-

cm

-RRB-

b

Body

fat

-LRB-

-RRB-

Abbreviations

-LRB-

ml

kg

min

-RRB-

peak

oxygen

uptake

per

kg

-LRB-

ml

kgFFM

min

-RRB-

peak

oxygen

uptake

per

kg

fat-free

mass

VAT

-LRB-

predicted

-RRB-

ventilatory

anaerobic

threshold

as

percentage

of

predicted

sed

sedentary

normative

values

recr

recreational

normative

values

-LRB-

people

who

exercise

no

more

than

h

a

week

-RRB-

walk

distance

PT

peak

torquean

because

the

thickness

of

the

subscapular

skinfold

could

not

be

measured

reliably

in

one

patientbn

because

of

thickness

of

the

skin

at

the

place

of

the

cicatrice

in

four

patients

Significant

-LRB-

P

-RRB-

correlation

Correlation

at

the

α

level

-LRB-

trend

-RRB-

in

ml

kgFFM

min

-LRB-

absolute

and

expressed

as

percentage

of

recreational

normative

values

-RRB-

and

-LRB-

absolute

-RRB-

were

related

with

severity

of

fatigue

as

assessed

with

the

FSS

at

the

α

level

-LRB-

trend

-RRB-

With

respect

to

the

VAS

in

ml

kg

min

-LRB-

absolute

and

expressed

as

percentage

of

recreational

normative

values

-RRB-

in

ml

kgFFM

min

-LRB-

absolute

and

expressed

as

percentage

of

both

sedentary

and

recreational

normative

values

-RRB-

and

-LRB-

absolute

and

expressed

as

percentage

of

normative

values

-RRB-

were

significantly

-LRB-

P

-RRB-

correlated

with

severity

of

fatigue

in

ml

kg

min

as

percentage

of

sedentary

normative

values

was

related

with

severity

of

fatigue

as

assessed

with

the

VAS

at

the

α

level

-LRB-

trend

-RRB-

The

VAT

was

not

correlated

with

severity

of

fatigue

assessed

with

the

FSS

or

the

VAS

Table

shows

the

correlation

coefficients

between

physical

fitness

parameters

and

HRQoL

There

were

several

significant

correlations

between

physical

fitness

and

HRQoL

and

particularly

between

cardiorespiratory

fitness

on

the

one

hand

and

Physical

functioning

Social

functioning

and

Vitality

on

the

other

hand

Table

correlations

coefficients

for

the

relationships

between

physical

fitness

and

health-related

quality

of

life

as

assessed

with

the

RAND

in

liver

transplant

recipientsPhysical

domainPFSFRlpRleMHVTBPGHCHCardiorespiratory

fitness

-LRB-

ml

kg

min

-RRB-

of

sedentary

norm

of

recreational

-LRB-

ml

kgFFM

min

-RRB-

of

sedentary

norma

of

recreational

VAT

-LRB-

predicted

sed

-RRB-

VAT

-LRB-

predicted

recr

-RRB-

-LRB-

m

-RRB-

of

norm

Neuromuscular

fitness

PT

extension

at

s

-LRB-

Nm

-RRB-

of

norm

PT

extension

at

s

-LRB-

Nm

-RRB-

of

norm

Body

composition

Body

mass

index

-LRB-

kg

m

-RRB-

Waist

circumference

-LRB-

cm

-RRB-

b

Body

fat

-LRB-

-RRB-

a

To

enhance

the

clarity

of

the

table

only

significant

correlation

coefficients

-LRB-

P

bold

-RRB-

or

trends

-LRB-

P

not

bold

-RRB-

are

presentedAbbreviations

-LRB-

ml

kg

min

-RRB-

peak

oxygen

uptake

per

kg

-LRB-

ml

kgFFM

min

-RRB-

peak

oxygen

uptake

per

kg

fat-free

mass

VAT

-LRB-

predicted

-RRB-

ventilatory

anaerobic

threshold

as

percentage

of

predicted

sed

sedentary

normative

values

recr

recreational

normative

values

-LRB-

people

who

exercise

no

more

than

h

a

week

-RRB-

walk

distance

PT

peak

torque

PF

physical

functioning

SF

social

functioning

Rlp

Role

limitations

physical

Rle

Role

limitations

emotional

MH

mental

health

VT

vitality

BP

bodily

pain

GH

general

health

perception

CH

changes

in

healthan

because

the

thickness

of

the

subscapular

skinfold

could

not

be

measured

reliably

in

one

patientbn

because

of

thickness

of

the

skin

at

the

place

of

the

cicatrice

in

four

patients

Discussion

This

is

the

first

study

in

which

relationships

between

several

aspects

of

physical

fitness

and

severity

of

fatigue

are

explored

after

LTx

The

study

is

an

initial

step

in

identifying

factors

that

are

associated

with

fatigue

in

liver

transplant

recipients

A

limitation

of

this

study

may

be

that

the

sample

was

relatively

small

However

we

believe

that

this

sample

is

representative

for

patients

after

LTx

and

that

the

study

provides

important

information

for

the

development

of

rehabilitation

programs

for

liver

transplant

recipients

Physical

fitness

We

found

average

deficits

in

of

when

we

compared

the

results

in

the

liver

transplant

recipients

with

normative

values

for

respectively

sedentary

persons

and

those

who

exercise

no

more

than

h

a

week

We

believe

that

a

value

in

between

the

sedentary

and

recreational

normative

values

is

representative

for

healthy

Dutch

persons

of

the

same

age

as

the

liver

transplant

recipients

that

participated

in

our

study

was

lower

than

normative

values

This

subnormal

level

of

cardiorespiratory

fitness

-LRB-

both

and

-RRB-

is

in

agreement

with

findings

of

previous

studies

-LRB-

Beyer

et

al.

Stephenson

et

al.

Unnithan

et

al.

-RRB-

Furthermore

the

prevalence

of

obesity

was

higher

in

this

study

than

in

the

general

Dutch

population

of

the

patients

had

a

BMI

of

more

than

compared

to

in

the

general

Dutch

population

-LRB-

Gezondheidsraad

-RRB-

Impaired

cardiorespiratory

fitness

in

liver

transplant

recipients

may

be

due

to

the

use

of

immunosuppressive

medication

e.g.

glucocorticoids

and

calcineurin

inhibitors

which

may

influence

both

the

cardiovascular

system

and

skeletal

muscles

-LRB-

Hokanson

et

al.

Mercier

et

al.

-RRB-

Immunosuppressive

medication

can

also

induce

appetite

stimulation

and

diabetes

mellitus

this

in

association

with

emotional

conditions

can

cause

a

change

in

eating

habits

-LRB-

Correia

et

al.

Hussaini

et

al.

-RRB-

Furthermore

patients

with

primary

biliary

cirrhosis

and

some

patients

with

other

chronic

liver

disease

are

hypermetabolic

LTx

in

these

patients

may

lead

to

a

reduction

in

resting

metabolic

rate

and

can

also

cause

an

increase

in

BF

-LRB-

Hussaini

et

al.

Richardson

et

al.

-RRB-

Besides

immunosuppressive

medication

and

changes

in

appetite

and

metabolism

also

deconditioning

-LRB-

both

before

and

after

transplantation

-RRB-

may

contribute

to

the

impaired

cardiorespiratory

fitness

and

body

composition

-LRB-

Epstein

et

al.

Grose

et

al.

-RRB-

In

a

previous

study

we

found

that

severe

complaints

of

fatigue

were

associated

with

low

levels

of

everyday

physical

activity

in

liver

transplant

recipients

-LRB-

van

den

Berg-Emons

et

al.

-RRB-

Because

of

the

immunosuppressive

medication

and

deconditioning

we

also

expected

a

deficit

in

neuromuscular

fitness

However

this

was

not

demonstrated

in

the

present

study

in

contrast

to

Beyer

et

al.

-LRB-

-RRB-

who

found

a

lower

muscle

strength

in

liver

transplant

recipients

compared

to

age

and

sex-matched

sedentary

individuals

They

contributed

this

deficit

to

muscle

weakness

as

a

side-effect

of

glucocorticoids

The

discrepancy

between

the

findings

of

our

study

and

those

of

Beyer

et

al.

-LRB-

-RRB-

may

be

explained

by

the

use

of

Tacrolimus

instead

of

cyclosporine

in

the

majority

of

our

subjects

Tacrolimus

is

known

to

have

less

side

effects

than

cyclosporine

-LRB-

Maes

and

Vanrenterghem

-RRB-

Stephenson

et

al.

-LRB-

-RRB-

reported

an

early

VAT

in

liver

transplant

recipients

-LRB-

of

the

predicted

-RRB-

compared

to

of

the

in

healthy

persons

found

by

Davis

et

al.

-LRB-

-RRB-

They

contributed

this

early

anaerobic

threshold

in

liver

transplant

recipients

to

the

cyclosporine-induced

decrease

in

mitochondrial

oxygen

consumption

-LRB-

-RRB-

However

the

European

Respiratory

Society

-LRB-

ERS

Task

Force

-RRB-

reported

that

there

is

a

wide

range

of

normal

predicted

values

-LRB-

-RRB-

Therefore

it

is

difficult

to

indicate

whether

the

VAT

in

our

patients

was

reduced

compared

to

normal

-LRB-

and

of

predicted

for

respectively

sedentary

persons

and

those

who

exercise

recreationally

-RRB-

Physical

fitness

and

severity

of

fatigue

Although

relationships

between

severity

of

fatigue

-LRB-

as

measured

with

the

FSS

and

VAS

-RRB-

and

physical

fitness

were

not

univocal

this

study

demonstrates

a

relationship

between

cardiorespiratory

fitness

and

severity

of

fatigue

after

LTx

Patients

with

more

severe

complaints

of

fatigue

had

larger

deficits

in

cardiorespiratory

fitness

than

patients

with

less

severe

complaints

of

fatigue

Although

this

cross-sectional

study

does

not

allow

us

to

conclude

that

a

reduced

cardiorespiratory

fitness

results

in

fatigue

-LRB-

or

vice

versa

-RRB-

there

may

be

an

interaction

between

parameters

complaints

of

fatigue

leading

to

decreased

physical

activity

-LRB-

van

den

Berg-Emons

et

al.

-RRB-

and

decreased

physical

fitness

leading

to

further

deterioration

of

complaints

of

fatigue

It

may

then

be

hypothesized

that

rehabilitation

programs

aimed

at

enhancing

cardiorespiratory

fitness

can

be

effective

in

breaking

through

this

negative

spiral

and

-LRB-

partly

-RRB-

reduce

complaints

of

fatigue

in

this

population

However

this

hypothesis

has

to

be

confirmed

in

future

randomized

trials

In

contrast

to

our

expectations

the

present

study

indicates

that

other

aspects

of

physical

fitness

neuromuscular

fitness

and

body

composition

do

not

seem

to

be

related

with

severity

of

fatigue

after

LTx

However

it

should

be

realized

that

our

study

sample

was

relatively

small

and

some

of

the

studied

relationships

may

have

failed

to

show

statistical

significance

Physical

fitness

and

HRQoL

Previous

studies

on

healthy

persons

indicate

that

physical

activity

fitness

and

body

fatness

are

associated

with

HRQoL

and

mood

-LRB-

Han

et

al.

Stewart

et

al.

-RRB-

There

are

also

indications

that

physical

activity

is

related

to

HRQoL

after

LTx

-LRB-

Painter

et

al.

van

den

Berg-Emons

et

al.

-RRB-

Therefore

we

expected

to

find

a

relationship

between

physical

fitness

and

HRQoL

in

our

study

group

In

agreement

with

the

study

of

Stewart

et

al.

-LRB-

-RRB-

in

healthy

elderly

subjects

we

found

several

significant

correlations

between

physical

fitness

-LRB-

particularly

cardiorespiratory

fitness

-RRB-

and

HRQoL

in

our

liver

transplant

recipients

Patients

with

large

deficits

in

physical

fitness

experienced

worse

HRQoL

than

patients

with

small

deficits

in

physical

fitness

However

in

contrast

with

studies

in

healthy

persons

-LRB-

Han

et

al.

Stewart

et

al.

-RRB-

we

found

only

few

relationships

between

body

composition

and

HRQoL

Our

results

on

the

relationships

between

physical

fitness

and

HRQoL

imply

that

rehabilitation

programs

aimed

at

improving

physical

fitness

-LRB-

particularly

cardiorespiratory

fitness

-RRB-

may

consequently

result

in

improved

HRQoL

particularly

in

improved

physical

and

social

functioning

vitality

and

bodily

pain

However

these

implications

have

to

be

confirmed

in

future

randomized

trials

on

the

effects

of

such

rehabilitation

programs

in

liver

transplant

recipients

Conclusion

Cardiorespiratory

fitness

in

the

liver

transplant

recipients

was

distinctly

impaired

and

the

prevalence

of

obesity

was

higher

than

in

the

general

population

there

were

no

indications

that

neuromuscular

fitness

is

impaired

after

LTx

Based

on

the

relationships

we

found

between

cardiorespiratory

fitness

and

severity

of

fatigue

a

rehabilitation

program

aimed

at

enhancing

cardiorespiratory

fitness

may

help

in

reducing

complaints

of

fatigue

after

LTx

Such

rehabilitation

programs

may

also

result

in

improved

HRQoL

O O O B O O O O O O B I B O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I I O O O O O O O O B I I O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B I O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O

liver transplantation
fatigue
peak oxygen uptake
isokinetic muscle strength
body composition