Invited Comment 55

Myocardial Proteetion and Ischemia Tolerance ofthe Globally Ischemic Heart Gen eral pa thop hy siologicalfundam en tals with sp ecial referen ce to th e contributions of Beye rsdorfe t al., Guvendik et al., and Wilson et al., in Issu e 1, 1990 ofthis Journ al Martha-Maria Gebhard

Summary The pathophysiological fund am ent als of th e toler an ce of the heart to the ischemi c condition are discussed , with special reference to three contributions in Issu e 111990 of this journal. The relati onship 'duration of/da mage don e by' isch emia is of sigmoidal form. The time needed to recover from the dam age caus ed is dependent on th e extent ofthe dam age and not on th e duration ofischemia . This time is thus a measure of the damage caused. The two ma in means of redu cing this dam age are cardioplegia and hypothermi a . The funda menta l differ ences in the various cardioplegic methods, and the factors on whi ch th eir effectiveness depend s, ar e explained. The background to th e use of hypoth ermia and the limits in its appli cation are pr esented. The dep end en ce on hypothermia to extend the useful duration of isch emia demands , however , a care ful considera tion of th e ph ysiological the rmodyna mics involved , when estimating th e prob able extent of dam age reached at any time. Myokardprotektion und Ischämietoleranz des global ischämischen Herzens Unter Bezug auf die Arbeiten von Bey ersdorf et al., Guvendik et al. und Wilson et al. in Heft 1 (1990) dieser Zeitschrift werd en die pathophysiologischen Grundl agen der Ischämi etoleran z des Herzens dargest ellt. Die ischämische Schädigung nimmt mit zun ehm end er Ischämie zeit zunächst langs am und dann steil ansteigend zu (s. Abb . 1). Entspre che nd der sigmoiden Zunahme der Schädi gung mit der Ischämiezeit ist auch die postischämisch e Erh olung proportional der ischä mische n Schädigung und nicht der Ischämi ezeit. Verschied ene Her zen könn en na ch jeweils identische r Ischämiezeit u. U. erhe blich unt ers chiedliche postischämische Erholungszeiten benötigen. Die Beziehung zwisch en Ischämi ezeit und Ischämieschad en ist von eine r Reihe prä- und intrai schä mischer Fakt oren abhängig, die diese Beziehung im Sinne einer Rechts- oder au ch Linksvers chiebung der Kurve verändern könn en. Was die präischämischen Ausgangsbedingung en ang eht , so schr änken chronische oder auch akut e Erkrankungen des Herzens die myokardiale Ischämietoleranz ein, d.h. tr otz gleicher Ischämiezeit kommt es zu einem höher en Ischämi eschaden und damit auch einem höh eren postis chäm ischen

Erholungsbeda rf. In gleicher Weise wirken alle pr äis chämischen Bedingunge n, die den myokardi alen 0 2-Bedarf steigern , wie z. B. Fieber oder eine symp atho adrenerg e Stimulation . Im entgegengesetzten Sinne wirkt eine geeignete Narko se , u. U. in Verbindung mit einer mechanis chen Entlastung des Her zens . Die zuverläs sigste und quanti tativ effizienteste Meth ode, die Beziehung zwischen Ischämi ezeit und ischämis cher Schädigung im Sinne einer Verb esserung der Ischämi etoler an z des Herzens zu beeinfluss en, ist die Kardiopl egie. Es werd en die Wirkprinzipien der bekan ntesten kardioplegisch en Lösungen dar gestellt, wobei die sogena nnte Blutka rdioplegie kritis ch beleuchtet wird. Bei der technische n Anwendu ng der Kardio plegie ist besonders auf eine ausreichend e Äquilibri erung des Myokard s zu achte n, denn eine unvollständige Äquilibrieru ng bewirkt notwendig erw eise auch eine unvollständi ge Protektion. Neben der Kardiople gie ist die Hypothermi e die zweite wirksame Methode, die Ischäm ietoleran z des Herzens zu ver bess ern . Wichtig ist dab ei, daß die Hypoth ermi e da s gesamte Myokard homogen betrifft. Inhomo genitäten der Temperatur bedeuten , wie Inhom ogenit äten der Kardi oplegie, region al eine Reduzi erung des pro tektiven Effektes. Die Ischämi etoler an z des Gesa mtorgans wird unter solchen Umständen imm er durch die Ischämi etoler an z des jeweils am höchs ten ischämieb elasteten Anteils bestimmt. Desh alb ist die mittler e Myokardtemp er atur, d. h. die über die gesa mte Ischämiezeit gemitte lte Myokardtem per atur, sorgfältig abzuschätze n. Hier ist wichtig zu beobachten, daß während der Ischämi ezeit eine sponta ne Aufwärmung des primär abgekühlten Myokards stattfind et , die expone ntiell und nicht linear verläuft. Selbst unter der Voraus setzung eine r weitgehend homogenen Erwä rmung bedeut et dies, daß die mittlere Myokardtemperatur wegen der exponentiell verla ufenden Temp er aturkurve einen Wert erre icht, der mind est ens 70%, aber keinesfalls nur 50 % über der min imal en Myokardtempera tur liegt. Zum Schluß wird die Frage behand elt, in welcher Weise die tiere xperim ent ell gewonnenen Daten auf die klinisch e Situation der Chirurgie am offenen Herzen üb ertragen werde n könn en. Keywords Cardiac ischemic damage - Recovery time from ischemia Cardioplegia types - Effective hypothermi e temp erature Limits ofto lera ble dur ation of cardiac ischemia

In standardized dog experiments the duration of global ischemia tolerated by a normothermic heart could be extended from 5-10 minu tes to about 100 minutes by Intro duction of cardioplegia. At a simultaneous temp erature of 25 "C, global ischemia was now toler ated for about 250

minut es as compare d to a pr evious maximum of 30-40 minutes. Nevertheless , protection ofthe heart against global ischemia is still a centra l probl em. This is reflected by the fact that the pr evious issue of this journal contained three publications on this topic (2, 11, 15). This must prompt a

Thorac. cardiovasc. Surgn 38 (1990) 55-59 © Georg Thieme Verlag Stuttgart · NewYork

Received for Publication: February 6, 1990

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Physiologyand PathophysiologyCenter. UniversityofGöttingen,Göttingen, FRG

Marth a-Maria Cebhard

Thorac. cardiovasc. Surgn 38 (1990) ISCHEMIC DAMAGE [%]

Ischemic stress and r evivability

100

The developm ent ofisch emi c myocardial damage is primarily th e manifestation of a developing ene rgy deficit of th e tiss ue. A short -interval analysis of th e myocardial ade nosine tri ph osphat e (ATP) cont ent in th e course of global ischemia shows a sigmoid decr eas e with time (4). Th e developm en t of the ATP deficit over th e isch emi a tim e thus resembles the dep enden ce of th e isch emi c dam age on th e duration of isch emia. In a pr eisch emi cally health y myocardium , th e beginning of the st eep rise of isch em ic damage roughly corresponds to a n ATP reduction to tw o thirds, th e end of th e steep rise cor res ponds to a n ATP reduction to about one th ird of th e normal ph ysiologieal value. An ATP deficit of about 30 % compa re d to no rmal, the beginn ing of the stee p rise of isch emi c damage, and a time required for postis chemi c recovery of not mor e than 20 to 30 minutes mark th e practical limit of th e revivability of th e isch em ic heart - th e so-called ATP tim e (t-ATP) defin ed in th e 1960s (4). In principle, even lat er points in th e curve of development of ische mie da mage might be defined in terms of a specific myocardial ATP deficit a nd postisch em ic recove ry time requiremen t. However, Fig. 1 also shows th at qua ntificatio n ofthe ischemi c dam age as we il as ofthe tim e requir ed for postis chemi c recovery is subjec t to inc re asing un certainty beyond t-ATP. For this reason, t-ATP ofthe globally ischemic heart had been defin ed as the measure of a certain ischemic stress with a practically tolerabl e post isch emi c demand in recover y time. For the sa me reason it is used in the pr esent a rticle as the sta ndard of com pa rison for th e pr otective efficacy of differe nt methods of myoc a rdial protection.

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DURATION OF ISCHEMIA AND RECOVERY

Fig. 1 The relationsh ip between duration 01 ischemia,duration of recovery Iromischemia, and ischemic damage

path oph ysiologist to recall some of th e facts learnt in th e course of collaborating over many yea rs on establishing th e principles of myoc a rdial pr otection . Ischemic stress of the heart Interruption of the coronary circulation and thus ofmyocardial oxygen supply unavoidably results in altera tions in tissu e metabolism a nd ultrastructure. Th e isch emi c damage in th e h eart always takes a cha racte ristic course. It initially unfolds slowly the n incr eas es sharply in degr ee and cornplexity and finally approach es th e maximum, the isch emi c necrosis (Fig. 1). As ind ieated by th e sigm oid development of damage with th e duration of isch emia, th e requirem ent for postischemic recov ery of ultrastructure, function , an d ene rge tics is not prop orti onal to th e duration of isch emia, but pr oportional to th e isch em ic damage. Ischemi c dam age and n ot th e durati on of ische mia is thus th e actual cor relate of the so-called isch em ie stress. This is well-know n from gene ra l expe rience: afte r an identi cal durati on of global ischemia, differ ent hearts may requir e substantially different postisch emi c recovery tim es . The postisch emic recovery time (under st andardized conditions of rep erfusion) is th e actual cor rec t ya rdstick for th e pri or isch emi c stress. The sigmoid incr ease of isch em ic dam age with duration of isch em ia an d th e resul ting alm ost expone ntial increase of recover y tim e dep ending on th e duration of ischemia is an immanent pathoph ysiological principle. However , th er e is a seri es of pr eisch emi c and intraischem ic factors which may alter thi s corre lation in terms of a substantial shift of th e curve to th e right or to th e left (Fig. 1). Factor s which shift th e position of th e curve to th e right improve cardiac isch emia tolerance. Th at means , they eithe r reduce the ischemie damage and thus th e postischemic recovery tim e required with a given duration of isch emia, or th ey prol ong th e duration ofisch emia availabl e up to th e development of a certa in degree of ische mic dam age and postischemie recovery requirem ent. On th e othe r hand, all factor s whi ch displace th e curve to the left reduc e th e ischemi a tolerance of the heart. Th ey eithe r bring a bout mor e ische mie damage for a given duration of ische mia and thu s require a long er postis ch emi c recovery tim e, or th ey sh orten th e dura tion of ische mia need ed to ca use a certain degree of damage, with its un changed requirem ent for postisch emic recovery .

Ische mic stress and preischemic state ofthe heart Major factors whie h may shift th e corre lation bet ween ischemie dam age and duration of isch emi a to th e left or to the righ t as show n in Fig. 1 can already act in the pr eischemie ph ase. For example it is a matter of clinical expe rience that chronic or ind eed acute dis ea ses of th e heart restri et its tolerance of isch emia in terms of a displacement of the cur ve to th e left. Such conditions may be associated with a very gre at isch em ie dam age and thu s an es pecially long postischem ic tim e required for recovery despite a not extrao rdina ry durati on of ische mia . However , a large numb er of conditions whi ch act on th e heart only in that th ey increa se its oxygen requirem ents have a simil ar effect (1). These include for exa mple hyperthyr eosis , fever, or also an intense sympathoadren ergi c ton e. In contra st, measures concomita nt with a minimization of th e dir ect preisch emi c ene rgy requirem ent of th e heart ha ve a n opposite effect: they result in a displ acem ent of the curve to the right. So in the sta nda rdized experime nt in dogs a suitable an esthesia (possibly in conjunctio n with a mec ha nieal reduction in th e load on th e heart) incr eases t-ATP by th e factor 5, i. e. from fully 5 minutes to 25- 30 minutes of n ormothermic global ischemia (4). Cardioplegia weak ens this close correlation between pr eischemie ene rgy turnover and cardiac tolerance ofischemi a in tha t it preisch emi cally redu ces myocardial oxygen requirem en t (MV0 2) . MV0 2 under resting conditions am ounts to about 10 mVmin/100 g of h eart weight, dur ing vent ricula r fibrillat ion it comes to a n ave ra ge of 6 rnl/ min/lOOg heart weight (8). In cardioplegie coron ary perfu sion, how ever, it is reduc ed to 0. 8-0 .9 ml/rnin/I 00 g in nor-

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56

Myoca rdial Protection and lschemia Tolerance of the Globally Ischemi c Heart

NaCI (mmol/L) KCI (mmol/L) CaCI2 (mmol/ L) MgCI 2 (mmol/L) BufferSubstances (mmol/ L)

83 30 0.5

Substrates (mmol/L)

28 Glucose

Pharmaca (mmol/ L) Osmolality (mosmol/ L)

27 NaHC03

362

SI.Thomas' Hospital

92 15 1 15 1 KH 2P O. 1 MgSO. 25 NaHC0 3 1 Procaine·HCI 318

,HTK, Bretschneider

57

Table 1 Composition 01crystalloidcardioplegic solutions

15 9 4 180 Histidine 18 His·HCI 2 Tryptophan 1 K·Ketoglutarate 310

moth ermia or to 0.1-0.2 mVmin/100 g in hypothermia of 10 "C. Nevertheless , as th e investigations of Guve ndik et al. (2) on dog hearts show, that th e lowering of a high preischemic puls e rate by of only 10 % togeth er with areduction of a pr eisch emi c hypertension by no more than 15 %, achi eved by pr emedication with calcium antagonists, in th e case of subsequent cardioplegia with St. Thomas Hospital solution is alre ady abl e to give ris e to a slight improvement in myocardial isch emia tolerance 0 , 11 , 13). Isehemie stress and eardiopIegie solutions The quantitatively most effieient meth od of shifting the correlation betw een iseh emia tim e and ischemie damage to the right (Fig. 1) in terms of an improveme nt of th e ischemia toleran ce of th e heart is eardioplegia. The large number of solutions bein g used clinically at pr esent are essentially based on three electrolytic principles of induction of artificial eardiac arrest (Table 1): 1) the increas e of extracellular potassium eonce ntration {Kirklin}, 2) th e incre ase of th e extrace llular magnesium conee ntration (St. Thomas' Hospital), and 3) th e redu etion of extraeellular sodium and calcium coneentration to approximat ely cyto plasmic values {Brets chn eider} (6, 8). Although th ese eonce pts differ in their mechanism of action, the pr otective efficaey against global isehemia at th e same temp erature is eomparable . Only the substitution of the histidine buffer for the inert osmolyte mannitol (HTK Br etschn eider) (4) improves the low-sodium low-calcium conc ept as compared to Kirklin's or St. Thomas' Hospital solution by ab out the factor 2 (6). However , th e pr er equisite for th e correctn ess ofthis appraisal is that the soluti ons are us ed in th eir original composition. Thus for example th e addition of only 50 ILmoVL calcium to the nomin ally calciurn-free HTK solution (9) or th e substitution of the buffer system histidine/histidin e hydro chloride by THAM (tris-hydroxyme thyl-aminomethane) or bicarbonate in th e same dosage (unpublished investigation) results in a measurable redu etion in the pr oteetive action of the solution. Addition of lactat e to the cardioplegic solution of St. Thomas ' Hospital app ears likely to give ris e to similar pr oblems (1 ). Each ofthese measures brings about a shift of the isehemi c damage eurve to th e left in relati on to th e dur ati on of ische mia. In terms of its eleetrolytic conee pt, blood cardioplegia is a potassium cardioplegia (2). It differ s from the cardioplegic solutions sp ecified abov e in that erythroeytes are added. Their hematocrit (Hct) is sp ecified as being ab out 15 %. On the one hand , erythrocytes in a eardioplegic solution as in blood act as che mical buffers. In whol e blood with 45 % Het th eir buffer capacity amounts to about 16 mmoVUpH, in hemodilution with 15 % Het it eorre spondingly is redueed to

one third, and totals not more than 5 % of the histldine/hisHel buffer capacity in th e eardioplegic solution HTK. On th e other hand, erythrocytes in a cardioplegie solution raise th e oxygen cont ent at a given p02' In particular this latter argument requires some quantitative considerations with regard to a possible significanc e for myocardial toleranee of ischernia : the myocardial O2 supply take s place by diffusion of oxygen, mainly from th e capillary part of th e coronary system. When calculated very liber ally, th e volume of th e capillaries as weil as that of the also very thin-walled venules and sm all veins accoun t for about 10 mV100mg of myocardium. At p02 ;:: 100 mmHg a solution hematocrit of 15% corres ponds to an O2 content of the cardioplegic solution of 7 mV100mI or to an O2 conte nt of the myocardium of 0.7 ml per lOOg myocardium in th e form of Hb-0 2. To appraise the total myocardial O2 reserve available during global ische mia, about 0.5 ml O2 per 100mgmyocardiumin form of 0 2-myogIobin and 0.28-0.34ml O2 per lOOg myocardium in the physically diss olved form . Ther e results a maximum O2 content of 1.55 mV100g myocardium. This O2 reserve, however , is sufficient for at best 10 minutes of global ischemia, even pr esupposing th e minimum oxygen requir ement of ab out 0.15 ml/m in/I 00 g myocardium with a myocardial temp erature of 10 °C, such as is obtained in optimal induction of cardioplegia , with any of th e cardioplegic solutions specified abov e. However , if the MV02 is 0.3 mVmin/100g myocardium, as specified for blood cardioplegia (2), the maximum ae robic laten cy attainable is reduc ed to a total of five minutes. Of th ese Iatencies 4.5 minutes in the former case and 2 in the latt er re sult from HbO2, Ofcour se , to return to th e diagram introduced abov e in Fig. I , even 5 minutes corresp ond to a certain shift of the correlation betw een ischemic damage and duration of ischemia to th e right. But in relati on to even a normothermic ATP time of about 50 minutes after Kirklin's or St. Thomas ' cardioplegia or about 100 after HTK cardioplegia, th e gain att ain ed by raising myocardial O2 reserves is betw een 5 % and 10 %. Isehemie stress and eardiopIegic teehnique Like the action of an y drug, th e action of a cardioplegic solution is not solely a function of compos ition but in addition is also a function of th e observance of cert ain dosage and application regulations. The pr otective actions of th e cardioplegic solutions specified in Table 1 thus essentially depend on the standard of equilibration of th e myocardium du ring the commencement of cardioplegia. Optimal equilibration is attained when th e composition ofthe intravascular and interstitial fluid in th e myocardium is the same as that of th e respective cardioplegic solution. Incomplete

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Kirklin

Thora c. cardiovasc. Su rgn 38 (1990)

Thora c. cardiovasc . Surgn 38 (1990)

equilibra tion automatically entails incomplet e protection, i. e. (to return to Fig. 1) a mor e or less incomplet e displacement of th e curve of ische mic damage to th e possible optimum (5). Crite rion of a full equilibra tion is neither th e occurren ce of cardiac arres t nor th e att ainme nt of a temp er ature equilibrium between th e respective cardioplegic solution and th e myocardium . Both are rea ched relatively rapidly. On th e contrary, th e crite rion is th e reduct ion of MV0 2 to a new minimum steady st at e (12). In th e favorable case of a com plete equilibra tion, this minimum is rou ghly equa lly low for eac h of th e solutions Iist ed in Tabl e 1. It is at about 0. 1 mlJmin/l 00 g at 5 °C or 0.2 mlJmin/l 00 g myocardium at 15 °C (6, 8). Depending on th e com pos ition of a ca rdioplegic solution , however, this minimum pr eis ch em ic myocardial oxygen requirem ent is attain ed a t differ ent rat es even with th e same technique of perfusion . Thus for exa mple th e shift of the interstitial sodium or potassium conce ntration only takes about half as long as th e minimization of the int erstitial calcium or th e adjustment of th e histidine level in th e interstitium to that of th e ca rdioplegic solution . Naturally, the minimization of th e myocardial oxygen requirem ent tak es lon ger th e more myocardial tissue is to be equilibrated and th e mor e th e corona ry vascula r bed is alte re d in terms of a coro na ry heart dis ea se. Inadequat e equilibratio n in terms of a n ina de quate perfusion tim e, inad equate perfusion volume , or an inappropriat e perfusion pressure regim e during th e peri od of equilibration ca n thu s once mor e restriet th e protectiv e acti on of a primarily effective ca rdioplegia in terms of a displ ac em ent ofthe curve in Fig. 1 to th e left (15). Th e choice of th e application of a solution in terms of a singl e-d ose or multi-d öse regim e is partly a routin e aspec t of cardioplegic technique. Int er mittent ca rdioplegic rep erfusion in th e course of agIob aI ische mia oft he heart is necessary whe n the ca rdioplegic solution is diluted owing to a high non- cor onary collate ra l blood f1ow. Similar to a n incomplete primary equilibra tion , thi s redu ces th e pr otective acti on of the solution. Thi s reduction is naturally greate r the more pr onounced th e solution com position diverges from that ofplasma (14) . However, apart from this particular situation, an intermittent cardioplegic rep erfusion in th e course ofa global ischemia ac ts in terms ofa reduction ofthe ischemic stre ss of th e heart. On th e on e hand , it is accornpani ed by a n int ermittent ae ro biosis ofthe myocardium a nd thus by th e possibility of a ce rtain res ynthesis , espe cially of cre atinin e ph osphate, but also of ATP from ADP an d AMP (4). On th e othe r hand , it a lso rem oves end pr odu cts of anae robic metabolism, espec ially proton s and la ctate. An incre ase in conce ntrat ion of th ese m etabolites in th e myocardium might oth erwise impair a nae ro bic glycolytic energy gain, and thus possibly also act in terms of sp eeding up the progr ession ofthe ischemic damage (4, 7,10). This second criterion is of particular relevance for all cardioplegic soluti on s with relatively low buffer ca pac ity (Tabl e 1). Provided th at a rep eated int erim ca rdioplegic perfusion does not lead to th e "th erapeutic" dos e range of the soluti on being exce ede d , th e multi-dose procedure com pa re d to th e meth od of single-d öse ca rdioplegia always entails a displa cem ent of the curve ofisch emi c darnage to th e right, even wh en th e myocardial temperature is identical in both cases . Where thi s fact is not taken into conside ration in a com pa rative inv estigation of cardioplegic solutions (Bey ersdorj et al. [11]) the value of any conclusions reached is Iimited.

Ma rtha-Ma ria Cebha rd

Ischemic stress and temperature Besid es ca rd ioplegia , hypoth ermia is th e second effective meth od of improving the isch emi a toleran ce of th e heart or of shi fting the curve ofischemic dam age to the right dep ending on th e duration of isch emia (Fig. 1). Lowering th e ternperature of a heart by 10 °C for th e duration of agIobaI isch emi a brings about an increase in t-ATP by a factor of 2 com pa red to normoth ermia . However, the protecti ve action of a redu ced myocardial temperature is gre ates t near to norm oth ermia, and becom es less a t lower temper atures. For exam ple, at 20 °C, a lowering of the temperature by 10 °C no lon ger incr eas es t-ATP by the facto r 2, but only by ab out the facto r 1.6 . For myoca rdial pr otection in pr actice, this mea ns th at in th e ph ase of cooling oft he heart the re is a rapid shift to the right , but conve rsely in the warming-up phase th er e is also an incr easingl y rapid displacem ent of the ischemi c damage curve to th e left dep ending on th e durati on ofischemi a . If th e pr otective principles of hypothermia and ca rdioplegia a re combine d, th e effects a re multiplied . Thus for example, in the dog heart St. Th orna s ' cardioplegia at normothe rmia brings abo ut an incr eas e of t-ATP-time fro m about 5 to 50 minut es com pa red to globa l isch emia wit ho ut pr otective measures. Simultaneou s lowering of myocardial temperatur e by 10 "C for the isch emi c period pr olon gs the tATP to ab out 120 minutes (4, 6, 8). However, this qu antitative appra isa l always pr esupposes that n ot only th e ca rdio plegia but also the hyp oth ermia homogen eously enc om passes th e entire myocardium . Inhomogen eiti es oftemperature as weIl as inhomogen eities of cardioplegia entail a regional redu ction of the protective ac tion. Th e ische mia tolerance of th e entire organ is always determined by th e isch emi a tolerance ofthe reg ion with th e most severe ische mic stress. Fr om what ha s been sai d, it becom es evide nt th at th e quantitative appra isa l of th e utili zabl e ische mia tolerance time of th e heart where both th e pr otective principles hypoth ermia and ca rdioplegia are used pr esupposes an especially ca re ful a ppra isal in particular of the mean temper ature of the myocardium during th e ischem ia peri od . In doing so, it is important to take int o acco unt that during th e ischemic period spontan eous warming of th e ca rdioplegically cooled myocardium takes pla ce, whi ch follows a n exponential, not lin ear course . Therefore, as a first approximati on , th c temper ature-rise of th e myocardium will be a t

MYOCAROIAL TEMPERATURE

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Fig.2 Evaluation01 themeantemperature stress01aglobally ischemic heart which, aftercardi oplegic coronary perfusionand cooling,iswarmingup tothetemperature01 the surroundings

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