A Novel System for Patient Ventilation and Dosing of Hyperpolarized 3He for Magnetic Resonance Imaging of Human Lungs

: A versatile ventilator for controlling a patient's breath cycle and dosing 3He gas has been designed and constructed. It is compatible with a medical magnetic resonance imaging scanner and can be incorporated into routine human lungs imaging procedure that employs hyperpolarized noble gas as a contrast agent. The system adapts to the patient's lung volume and their breath cycle rhythm, providing maximum achievable com fort during the medical examination. Good quality magnetic resonance lung images of healthy volunteers were obtained. The system has the capability of recycling the exhaled gas to recover the expensive 3He isotope, and can be also adapted to human lung imaging with hyperpolarized 129Xe.


Introduction
In recent y ears, n ovel m agnetic resonance im aging (M RI) techniques u sin g h yp erpolarized (HP) gases as im aging agents for in-vivo im aging of hum an lungs have been developed [1]. They successfully co m p lem en t the stand ard p ro ton im ag in g an d co m p u ted to m o g ra p h y (C T ) in p ro v id in g h ig h resolu tio n stru ctu ral in fo rm atio n , on w h ich v ery sen sitiv e d iag n o stic m eth o d s fo r lu n g d iseases su ch as asth m a, C O P D (ch ro n ic o b stru ctiv e p u lm o n a ry d isease), and cy stic fibrosis are b ased [2 ]. M oreover, dynam ic ventilation studies that are im practical using other techniques can be perform ed [3 ].  [4 ] and 129X e [5 ]. There are several specific requirem ents for their ap p licatio n in the M R im ag in g th at take in to a cco u n t th e relaxatio n o f u n reco v erab le p o larizatio n d u rin g storage an d d eliv ery [6]. A carefu l ch o ice o f co n stru ctio n m aterials for th e gas co n tain er w ith all co n n ectin g tu bes is n ecessary to m in im ize relaxatio n losses. M oreover, th e m a g n etic field strength and h om ogeneity along the tran sferrin g route from the gas container to the patient has to be optim ized. A dditionally, due to recent dram atic rise of 3H e cost, it is im portant to collect the exhaled gas for recycling [7].

applied sciences
For the m ethod to be reliable and reprod ucible, it is n ecessary to em p loy a d ed icated system for m o n ito rin g and co n tro llin g the p atie n t's b reath cy cle an d d o sin g h y p erp o larized 3H e. It sh ou ld be com patible w ith the M RI scanner, w hich utilizes a high field m agnet that is located in the Faraday cage to elim inate any R F interference. Therefore, the com p on en ts o f the v en tilato r th at m u st b e in sid e the Faraday cage have to be m ade of non-m agnetic m aterial and should not be controlled by the electrical AC power. A dditionally, the system should provide a triggering circuitry to synchronize its operation w ith the im age acquisition sequence.
The first M RI com patible ventilators w ere developed for anim al studies applications [8,9 ]. Since the cooperation of an anim al is im possible, the ventilators w ere equipped w ith the gaseous anesthesia unit, as w ell as the b reath and h ea rt rate m easu rin g d ev ices for trig g erin g th e M R im ag in g seq u en ce [10].
In the case of hum an lung studies, full cooperation of the patient w ith the m edical scanner operator is usually feasible, so that a fast M RI sequence can be applied during the breath hold [11]. H ow ever, in the case of children, critical care patients, or those requiring perm anent m echanical ventilation, the breath control and the seq u en ce trig g erin g m ay b e still n ecessary to o b tain good im age quality. F o r su ch applications, the standard ven tilators w ere m odified b y sim ply exten d in g the gas d elivery tubes that connect the m ain unit located outside the Faraday cage to the patient [12]. M ore advanced devices w ere also bu ilt, in w h ich o n ly n o n -m ag n etic co m p on en ts w ere u sed [13,14]. H ow ever, all above system s could not hand le the hyp erpolarized gases.
The first in-vivo M R im ages of the rat lungs w ere obtained in 1994 [15], using hyperpolarized 129Xe as a gaseous im aging agent inhaled by the anim al. Subsequently, in-vivo M R im ages of hum an lungs w ere acquired in 1996, w ith the application of h yp erpolarized 3H e [16,17]. These results opened new possibilities for the application of the technique in m edical diagnostics, and stim ulated the developm ent of dedicated ventilators w ith the noble gas adm inistration capability. A detailed description of a device m odified for sm all anim al studies w as given in [18][19][20]. It w as follow ed by a fully scalable system that cou ld be u sed for h u m ans [21], and a so p h isticated v en tila tio n system d ed icated to M R I o f h u m an lungs w ith the u se hyp erpolarized noble gases [22].
T his w o rk d escribes a n ovel, reliable sy stem for p recise h u m an b rea th m o n ito rin g an d con trol, including the noble gas adm inistration and initial lung flushing by nitrogen capabilities. The exhaled gas is collected for recycling. The perform ance of the ventilator has been assessed by integrating it w ith the 1.5T Siem ens Avanto M RI m edical scann er and the high field 3H e M EO P (m etastability exchange optical pum ping) polarizer th at operates inside the M RI m agn et bore [2 3].

D esign o f the Breath Cycle Control and H yperpolarized 3H e D osing System
The schem atic diagram of the ventilator is presented in Figure 1 and Figure 3a show s its photograph.
T he co m p on en ts lo cated b o th in sid e and ou tsid e the F a ra d a y cag e are in d icated . Initially, th e h ig h field M E O P 3H e polarizer is placed in the m ag n et bore to prod uce the h yp erp o larized gas. A fter the p o larizatio n is com p lete, the gas is tran sferred to the p lastic Tedlar b ag (B), w h ich is in sid e the rigid, herm etic pressure cham ber located in the high and hom ogeneous field of the m agnet. The access to the Tedlar bag is controlled by a nonm etallic pneum atic valve. A fter the bag is filled w ith hyperpolarized gas, the polarizer is rem oved from the m agnet to let the patient in. The procedure is described in detail in [20]. We found it more convenient than the direct application of the Tedlar bag filled w ith the noble gas. It is required to rep lace th e setu p for a new p a tie n t to en su re sterility. In h alin g , ex h alin g an d the n oble  ond start the im aginp procedure. en tire preaence of pure nitragen, w hich acts as the buffer gas, the T 1 relaxation tim e of 3H e is about 3 h. Therefore, the polarization losses are of the ordeu of 8%.

O peration o f the 3H e D osing an d Control System
The application of the dedi cated ventilator m akes it po ssible to perform su ccessful and re producible M R im aging o f h u m an lungs, p rovid ing a t the sam e tim e m axim u m possible co m fo rt for the patient.
A controlled am ount of noble gas of know n polarization supplem entsd w ith she buffer gas is delivered to fill th e lu n gs eneirely, so th a t tho exam in atio n tak es p lace in the fu ll in sp ieation m od e. A sh o rt train in g ie perfo rm ed befo re the actu al exp erim en t, to accu sto m th e p a tie n t w ith th e ap p aratu s and sh ow him ho w to q u it at a n f tim e in case; oS em ergency.  The M R lung im aging experim ent is carried out in tw o stages. First the patient is asked to breathe norm ally w ith the am bient air, so that his individual breathing param eters are recorded by the program.
Then the consecutive gas deliveries that are synchronized w ith the inhaling phases of the breath cycles are applied. T he valu es of the follow ing autom atic procedure param eters are chosen b y the operator: The n u m b er o f initial flu shin gs w ith n itro g en (from 0 to 1); the n u m b er o f h yp erp o larized gas doses, w ith or w ithou t an additional buffer gas filling; and the num ber of exhaling cycles before the valve to the m etalized b a g is closed . T he n itro g en flu sh in g can b e n ecessary to d ecrease the resid u al oxyg en co n ten t in the lu ngs, w h ich effects the relaxation o f h yp erp o larized gas [24]. T he 3H e gas d eliv ery is in itiated b y the beep signal accom p an ied b y a v erb al in stru ctio n from the o p erato r for the p atien t to take a deep breath and hold it for the tim e needed to acquire the data. It varies from about 5 to 30 s and is determ ined by the required num ber of orientations and slices. D epending on the lungs volum e and the am ount of 3H e that is available, an additional portion of nitrogen can b e supplied at this m om ent to fill u p th e lu n gs. A fter the im ag in g seq u en ce is co m p lete, a n o th er beep sign al tells the p a tie n t to breathe norm ally, and the exhaled gas is collected for recycling.

E xhaled Gas Storage System fo r 3H e R ecycling
It
The black vertical lines in Figure 4 indicate the m om ents w hen the ventilator valves are sw itched.
A fter initial breath stabilization, the nitrogen gas is applied (the first line from the left). N ext sw itching corresponds to the application of H P gas. A fter em ptying the H P storage bag, the system sw itches the valves again to d eliver nitrogen, so that the volu n teer m ay con tinu e the inhalation until his lungs are full. A t this m om ent the system opens the valve to the collector bag, to let the volunteer exhale the gas  The d escribed v en tilato r can be also u sed , a fter sm all m o d ification s, for th e H P 129X e lu n g im agin g, and this direction is bein g cu rrently explored in our group [26].
O u r v en tilato r com p ares fav o rab ly w ith sim ilar sy stem s th a t w ere rep o rted in the literatu re.
De Alejo et al. describe the ventilator for anim al applications, w hich im pose different requirem ents [21].
In contrast to hum ans, the anim als to be im aged do n ot cooperate and have to be anesthetized. In the case o f sm all an im als, lik e m ice or rats, th e in tu b atio n is n o t u sed , an d th e b reath in g an d h ea rt rate need to b e m o n ito red con tin u ou sly. Stab le b reath in g is ach iev ed b y su p p ly in g a con trolled m ixture o f air, oxyg en , and an esth etic. M oreover, the an im al is k ep t in co n sta n t tem p eratu re, b ecau se the tem perature self-control is not active in the sleep phase. The above procedure has to be carried out by a trained personnel, w hich is not necessary in im aging hum ans, w ho can control breathing by them selves. qu antitative inform ation about the oxygen-related relaxation of the HP helium gas is given in [24]. C om p u ted to m o g rap h y is the m o st w id e ly u sed tech n iq u e for lu n g im agin g. H ow ever, it is sensitive to soft tissue only and cannot im age the air spaces, w hich are dom inant in the lungs. The only co m p arable m eth o d is M R I u sin g h y p erp o larized xen o n , w h ich is m u ch less exp en sive. Its m ain disadvantage w hen com pared to HP 3H e M RI is the long tim e necessary to produce a sufficient am ount o f h y p erp o larized gas. N ev erth eless, this d irectio n is activ ely p u rsu ed in o u r lab [ 25] . A p a rt from stand ard im agin g, the h ig h so lu bility o f xen o n in b loo d m ak es it p o ssib le to ap p ly th e lo calized spectroscopy of 129X e to stu d y p erfu sion in the lungs and m etabolic processes in the brain.
B earin g in m ind the cost and tim e of exam ination, the application of our device w ill be probably lim ited to special cases, such as lung transplantology. It can also successfully replace C T w hen frequent exam inations are necessary, in order to avoid ionizing radiation dam ages. The device is still a prototype and needs further im provem ents to be ready for w id er distribution.