Patent Application: US-201213367225-A

Abstract:
a breathing circuit for use in conjunction with a ventilator serving a mechanically - ventilated patient includes an expiratory gas airflow pathway ; an inspiratory gas airflow pathway ; and a gas mixing mechanism operable to mix inspiratory gas and expiratory gas in an amount sufficient to equilibrate the patient &# 39 ; s p et co 2 and arterial pco 2 such that the patient &# 39 ; s p et co 2 is a clinically reliable approximation of the patient &# 39 ; s paco 2 .

Description:
the present invention based on the discovery that end - inspiratory delivery of a gas comprising carbon dioxide ( for example a gas that has a partial pressure of carbon dioxide that simulates carbon dioxide intake associated with rebreathing exhaled gas ), in ventilated patients with pulmonary dysfunction , reduces the partial pressure gradient between the patient &# 39 ; s p et co 2 and paco 2 to the extent that the patient &# 39 ; s p et co 2 becomes a better approximation of the patient &# 39 ; s paco 2 . this reduction in partial pressure gradient may serve diagnostic purposes in patients that are ventilated due to abnormal regional or global gas flow distribution due to inflammation , bronchospasm and increased secretions in the airways such as due to asthma , allergy , bronchitis , pneumonia , autoimmune bronchitis and alveolitis , inhalation of toxic or caustic vapors or liquids , aspiration of stomach contents , systemic effects of sepsis , liver failure , renal failure ; changes in regional lung compliance due to lung edema ( of various etiology such as infection , heart failure , trauma , exposure to caustic and irritant gases and liquids , fibrosis , in combination these are known as adult respiratory distress syndrome ( ards ); increases in the lung diffusion barriers at the alveoli due to pulmonary edema , pneumonia , fibrosis , infiltration with cancer cells ; changes in lung perfusion due to changes in pulmonary artery pressure , shunting of blood in the heart or ductus arteriosus , obliteration of alveolar capillaries , or blood clots such as pulmonary embolism , increased pulmonary artery pressure , pulmonary hypertension , pulmonary artery hypotension , regional increases in blood flow due to inflammation , decreases in blood flow due to regional increases in resistance such as due to hypoxic pulmonary vasoconstriction . values of p et - aco 2 and acceptable margins of error for purposes of the invention are attainable according to the invention by delivering co 2 to effect a convergence in paco 2 and p et co 2 values . gancel ( gancel p e , roupie e , guittet l , laplume s , terzi n . accuracy of a transcutaneous carbon dioxide pressure monitoring device in emergency room patients with acute respiratory failure . intensive care med 2010 november 11 .) had indicated that with a low bias ( 0 . 1 mmhg ), the limits of agreement ranging from − 6 . 0 to 6 . 2 mmhg “ was clinically acceptable ”. the aforementioned study by gancel et al . investigated a transcutaneous pco 2 measurement as a surrogate for paco 2 . they deemed the ± 6 . 0 mmhg difference between the trans - cutaneous pco 2 and paco 2 “ clinically acceptable ”. such low ranges are seldom obtainable in p et - aco 2 and certainly cannot be expected to be predictably obtainable as a rule without the present invention . in studies performed by the inventors in sick adult pigs with severe lung atelectasis and pneumonia the p et co 2 and the paco 2 were statistically indistinguishable over a wide range of p et co 2 and oxygen levels , with the average p et - aco 2 ( mean ± se ) of − 0 . 13 ± 0 . 12 , 95 % cl : − 0 . 36 , 0 . 10 ( p = 0 . 3 ). the inventors found that p et - aco 2 ( fig1 a ) did not differ from the difference in paco 2 between duplicate arterial blood samples ( fig1 b ) (− 0 . 19 ± 0 . 06 mmhg , 95 % cl : − 0 . 32 , − 0 . 06 ) ( p = 0 . 66 ) indicating that the p et - aco 2 was the same as the difference between two consecutive invasive blood gas analysis . thus not only was p et co 2 a precise surrogate for paco 2 , but was no worse than an invasive blood gas measurement at measuring paco 2 . a surrogate value of paco 2 obtained according to the invention herein is considered a “ clinically reliable approximation ” or one involving an “ acceptable margin of error ”. for purposes herein , this means reliable for diagnostic purposes including purposes for which an invasive procedure to measure of arterial pco 2 is warranted . note that this term is used to describe the accuracy of predicting a paco 2 value from a p et co 2 value post - administration of co 2 to effect a convergence in those values . in a quantitative sense the phrase “ clinically reliable approximation ” will invariably encompass a degree of deviation from actual that constitutes an acceptable standard error for the condition of the patient under evaluation . as a bench mark for a grave condition we note that the above - mentioned criteria of gancel et al . ( gancel p e , roupie e , guittet l , laplume s , terzi n . accuracy of a transcutaneous carbon dioxide pressure monitoring device in emergency room patients with acute respiratory failure . intensive care med 2010 november 11 ) were established with respect to emergency room patients with acute respiratory failure . according to the invention as herein defined “ clinically acceptable ” for the purpose of defining an acceptable margin of error means reliably no less accurate than +/− 6 . 0 mm hg and what the inventors found that the delivering co 2 to effect a convergence of paco 2 and petco 2 values reliably surpasses this standard . according to one embodiment of the invention , a gas delivery system according to the invention functions in the manner schematically illustrated in fig1 . the term “ equalizer ” is coined to refer to a device that delivers a gas comprising carbon dioxide to the patient for a portion of each of a plurality of consecutive inspiratory cycles to minimize the partial pressure gradient between the patient &# 39 ; s p et co 2 ( end tidal partial pressure of co 2 ) and paco 2 whereby the patient &# 39 ; s p et co 2 is a clinically reliable approximation of the patient &# 39 ; s paco 2 . according to one embodiment of the invention the device is operatively associated with or part of a breathing circuit in a manner that channels airflow from the ventilator to one of the limbs for a first portion of an inspiratory cycle and diverts airflow generated by the ventilator to the other limb of the circuit ( a limb housing expired gas ) during any second portion of an inspiratory cycle , in order to deliver the patient &# 39 ; s expired gas to the patient . optionally , the gas delivery system employs a means , for example a valve , that is controlled ( e . g . mechanically based on a set opening pressure or via a controller ) to combine the flow of two gases or alternate flow repeatedly between a first gas , for example a gas that closely matches the patient &# 39 ; s respiratory requirements ( a principal inspiratory gas ), and a gas comprising co 2 , for example , as a result of being set to cycle based on time , or based on a pre - determined volume of inspired gas , or based on being synchronized to a ventilator . the term “ subject ” and “ patient ” are used interchangeably . arrows indicate the direction and path of air flow to and from the ventilator through the equalizer . fig1 comprises panel a showing airflow during the expiratory portion of a breathing cycle , panel b showing airflow during the first part of the inspiratory portion of a breathing cycle , and panel c showing airflow during a second part of inspiration . as shown in fig1 , at the end of expiration , expired gas ( dark shaded area ) remains in the expiratory tubing of the expiratory limb 22 after each expiration ( a ). in one embodiment of the invention , a length of expiratory tubing 28 that holds expired gas constitutes an expiratory gas reservoir portion 40 of the expiratory limb 22 . during initial inspiration ( b ) the ventilator 20 blocks the movement of expired gas from the expiratory gas reservoir portion 40 of the expiratory limb / tubing 28 and inspiratory gas flows into the patient via the inspiratory tubing 32 of the inspiratory limb 24 ( labeled in b ). airway pressure increases during the course of inspiration . in one embodiment of the invention , the equalizer 10 is represented by a breathing circuit or portion thereof that includes an airflow control system . the airflow control system 30 operates such that an airflow blocking member , optionally part of a valve , switches at a set ( adjustable ) time or pressure to route the inspiratory flow of gas from the ventilator to the subject / patient via the expiratory tubing 28 ( c ), pushing the previously expired gas in the tubing ahead of it into the subject / patient &# 39 ; s lungs ( rebreathing ). this is shown in ( c ) by an arrow and the shaded area moved towards the patient . a suitable capnographic instrument 80 for determining the partial pressure of carbon dioxide in the patient &# 39 ; s end tidal exhaled gas can then be used as a surrogate measure of the arterial partial pressure of co2 . fig2 , 3 and 4 show the design of an equalizer 10 comprising an airflow control system 30 optionally including components of a breathing circuit comprising an airflow control system according to one embodiment of the invention wherein the equalizer operates as or is in the form of a valve , for example a valve that can be used with conventional breathing circuits used in ventilating patients , for example a valve that can be interposed in the breathing circuit even while in use in a ventilated patient , for example such valve switching the direction of gas flow from the inspiratory to the expiratory limb when a circuit pressure threshold is reached , and re - establishing its previous configuration during the expiratory phase of the ventilator . the nature of the valve can vary . optionally , the valve switches flow as a result of cycling based on time , or based on a pre - determined volume of inspired gas , or based on being synchronized to a ventilator . according to one embodiment , as shown in fig2 , the valve comprises an inspiratory ventilator portion 26 a and inspiratory limb portion 26 b constituting a first airway 26 fluidically connectable between the ventilator and the inspiratory limb and an expiratory ventilator portion 28 a and expiratory limb portion 28 b constituting a second airway 28 fluidically connectable between the ventilator 20 and the expiratory limb 22 and at least one air flow blocking member 50 movable between a first airway occluding position and a second airway occluding position . optionally , the valve comprises at least one biasing element in the form of magnet 42 for biasing the airflow blocking member 50 towards the second airway occluding position during the first portion of each inspiratory cycle . the position of the magnet 42 relative to a metal plate 44 mounted on rod 46 ( supported , in part , by a channel in fixed plate 74 ) may be controlled by a screw 48 . the locations of the magnet 42 and plate 44 may be interchanged . the airflow blocking member 50 is driven towards the first airway occluding position in response to an increase in airway pressure in the inspiratory limb . according to the embodiment illustrated in fig2 , magnet 42 is used as a biasing element to form a latch switch so that the valve changes position from valve seat 56 to valve seat 58 only after a set pressure acting on a pressure responsive member , for example a diaphragm 54 is exceeded . alternatively , the position can be set to change based on time or a ventilator setting . attraction of the magnet returns the airflow closure member 50 to its resting ( expiratory ) position . alternatively , a spring or gravity may be used to return a closure member to an expiratory limb occluding position . fig2 illustrates one embodiment of an equalizer in the form of a valve during expiration . wide arrows show direction of air flow . the biasing element in the form of magnet 42 operatively associated with a metal plate 44 hold an airflow blocking member 50 against valve seat 56 . thus expired flow travels along the expiratory limb 22 to the ventilator 20 . circuit pressure is expiratory pressure as set by the ventilator 20 . as shown in fig3 , the valve comprises an air pressure responsive member 64 which is operatively connected , for example via a shaft 46 or rod , to the airflow blocking member 50 and also movable between a first airway occluding position and a second airway occluding position . for example , the air pressure responsive member 64 may be positioned to oppose the action of the biasing element 42 in response to an airway pressure rise in inspiratory limb 24 during initial inspiration . for example , the air pressure responsive member may take the form of a diaphragm 64 which is in fluid communication with the first airway , optionally through pressure vents 70 leading to a chamber 72 under the diaphragm 64 . as long as airway pressure in the inspiratory limb 24 and in the chamber 72 covered by the diaphragm 64 is insufficient to overcome the magnetic force holding the metal plate 44 against the magnet 42 , the ventilator output enters patient inspiratory limb 24 . as seen in fig4 , as airway pressure rises during inspiration , the pressure under the diaphragm 64 increases to a threshold after which it causes the diaphragm to bow out from convex to concave shape , and displace the shaft 46 , separating the metal plate 44 from the magnet 42 and shifting the valve plate 50 from valve seat 56 to valve seat 58 . inspiratory gas is then directed down the expiratory limb 22 to the patient pushing previously exhaled gas ahead of it . note that the airway pressure in the inspiratory limb 24 also continues to climb as the inspiratory and expiratory limbs are connected by a y - piece 90 at the patient airway interface ( e . g . an endotracheal tube — not shown ). at the end of inspiratory phase of the ventilator , the airway pressure is reduced for exhalation . this reduces the pressure on the circuit side of the diaphragm 64 . the attraction of the magnet 42 for the metal plate 44 resets the valve plate 50 against valve seat 56 and the expiratory configuration is re - established . fig5 illustrates a device according to one embodiment of the invention in which an equalizer in the form of an air flow control system is interposed into a standard ventilator circuit to passively implement rebreathing at end - inspiration . as seen in fig5 a airway pressure rises during inspiration ( fig5 a ). during inspiration , the airway pressure ( paw ) rises in the inspiratory limb 24 , simultaneously pressurizing the piston 100 . before the paw reaches a threshold valve if it is biased into position a in which it occludes the expiratory limb . when the paw reaches a threshold value , the piston collapses the spring ( s ) 102 and pulls airflow closure member in the form of a shuttle member 106 into position b to occlude the inspiratory limb 24 and direct the inspiratory gas down the expiratory limb 22 ( fig5 b ). the gas in the expiratory limb 22 contains exhaled gas 108 ( hatched ) which is displaced into the patient &# 39 ; s lung ( hence rebreathing ). during exhalation , an airflow blocking member , optionally in form of a mushroom valve 104 is collapsed and spring ( s ) 102 recoils to re - establish the position shown in fig5 a . the spring 102 can be bi - stable or magnets can be incorporated to achieve the same effect . fig6 shows the results of a study with eight newborn yorkshire pigs with various combinations of acquired viral pneumonia , persistent patent ductus arteriosus , and patent foramen ovale were mechanically ventilated via a partial rebreathing circuit to implement end - inspiratory rebreathing . arterial blood was sampled from an indwelling arterial catheter and tested for paco 2 . a variety of alveolar ventilations resulting in different combinations of end - tidal pco 2 ( 30 to 50 mmhg ) and po 2 ( 35 to 500 mmhg ) were tested for differences between p et co 2 and paco 2 ( p et - aco 2 ). the p et - aco 2 of all samples was ( mean ± 1 . 95sd ) 0 . 4 ± 2 . 7 mmhg . the agreement between p et co 2 and paco 2 is shown in the fig1 below . fig7 a to 7 f show the results of agreement between p et co 2 and paco 2 from 6 studies taken from the literature . each shows that the gradients are at least an order of magnitude greater than we were able to achieve in our animal model that had comparable lung pathology . methods of targeting end tidal concentrations of gases , for example to alter a surrogate measure of paco2 ( e . g . post co2 gas delivery and convergence of end tidal and paco 2 values ) are described in wo / 2007 / 012197 and in slessarev m , et al . prospective targeting and control of end - tidal co 2 and o 2 concentrations j . physiol . 2007 jun . 15 ; 581 the disclosures of which are hereby incorporated by reference . fig9 illustrates an alternative circuit for testing the invention . to enable sequential gas delivery during mechanical ventilation the inventors placed a sequential gas delivery ( sgd ) circuit similar to that used for spontaneous ventilation ( see fig7 of published us patent application 2002 / 0185129 ) in a rigid container to form a functional “ bag in box ” secondary circuit ( fig9 ). the assembly was then interposed between the ventilator and the animal &# 39 ; s endotracheal tube . this circuit functioned as that described by slessarev et al . ( 7 ) with the ventilator displacing gas from the reservoir bags and the valves acting passively to provide the gas from the gas blender first , followed by the rebreathed gas . study subjects : 8 yorkshire newborn pigs , 3 - 4 weeks of age with a mean weight of 3 . 6 kg ( table 1 ) in an animal operating room setting . eight newborn yorkshire pigs with various combinations of acquired viral pneumonia , persistent patent ductus arteriosus , and patent foramen ovale were mechanically ventilated via a partial rebreathing circuit to implement end - inspiratory rebreathing . arterial blood was sampled from an indwelling arterial catheter and tested for paco 2 . a variety of alveolar ventilations resulting in different combinations of end - tidal pco 2 ( 30 to 50 mmhg ) and po 2 ( 35 to 500 mmhg ) were tested for differences between p et co 2 and paco 2 ( p et - aco 2 ). results : the p et - aco 2 of all samples was ( mean ± 1 . 95sd ) 0 . 4 ± 2 . 7 mmhg . the probability of obtaining this level of agreement between p et co 2 and paco 2 by chance is & lt ; 0 . 0001 . observations : rebreathing at end - inspiration reduces p et - aco 2 to a clinically useful range in a ventilated animal model with lung pathology and cardiac shunting . animal preparation : anesthesia was induced with a 0 . 2 ml / kg mixture of ketamine 58 . 8 mg / ml , acepromazine 1 . 18 mg / ml , and atropine 90 μg / ml administered by intramuscular injection , followed by 3 % isoflurane in o 2 to deepen anesthesia for surgical preparation . a catheter was inserted into the ear vein for continuous intravenous infusion anesthesia ( 22 mg / kg / h ketamine and 1 mg / kg / h midazolam ). a 4 mm i . d . uncuffed pediatric endotracheal tube and a catheter for gas and pressure sampling were placed in the trachea via a tracheotomy . a catheter for arterial blood sampling was inserted into the carotid artery via surgical cut - down . study : piglets were initially mechanically ventilated with an o 2 and air mixture in pressure control mode with peak inspiratory pressures between 15 - 20 cmh 2 o , peep 0 cmh 2 o , frequency of 25 - 30 / min , and inspiration : expiration ratio of 1 : 3 . a secondary circuit providing gas from a gas blender , followed by previous exhaled gas (“ sequential rebreathing ”) ( fig5 ) was interposed between the ventilator and the endotracheal tube . peak inspiratory pressures were adjusted to induce rebreathing as evidenced by a rise in the capnograph tracing during the latter part of inspiration . tidal volumes required to achieve rebreathing , ranged between 80 - 150 ml . the intra - tracheal catheter was used to monitor airway pressures and sample tidal gas for partial pressure analysis . after the piglets were stabilized on the ventilator , pancuronium bromide 0 . 2 mg / kg was administered intravenously as a bolus followed by an infusion at 1 mg / kg / h for the duration of the experiment . in fig5 we present an example of a simple improvised mechanism that can be applied to most ventilatory circuits ( including anesthesia circuits ) and adjusted to induce rebreathing at the end of the breath , for controlled ventilation without patient triggering . however , our aim was to study p et - aco 2 at a wide range of p et co 2 and p et o 2 rather than at the one level . the method of slessarev et al . 7 used to target end - tidal values already incorporates rebreathing before termination of each inspiration as part of its targeting strategy . va was varied systematically in the following three experiments to test the effect of delivering rebreathed gas at the end of inspiration on p et - aco 2 ( fig2 ): 1 . isoxic δpco 2 : from a va producing a baseline condition ( p et co 2 = 40 mmhg , p et o 2 100 mmhg ), va was systematically altered to target isoxic step increases and decreases of 10 mmhg p et co 2 in random order , returning to baseline after each step change . 2 . isocapnic δpo 2 . from baseline , va was changed systematically to target isocapnic step increases in p et o 2 to 500 mmhg ( protocol 2 a ) and step decreases in p et o 2 to 35 mmhg ( protocol 2 b ). 3 . δpco 2 + δpo 2 . from baseline , va was changed to target p et co 2 50 mmhg + p et o 2 300 mmhg , and p et co 2 30 mmhg + p et o 2 60 mmhg in a block fashion , returning to baseline between steps . changes in target p et co 2 required adjustments of tidal volume and frequency settings of the ventilator to assure an element of rebreathing ( as evidenced by an increase of the inspired pco 2 on the capnograph ) with every breath . every step change was maintained for 3 min , and p et co 2 was taken as the average p et co 2 of all breaths during the last minute of every step . an arterial blood sample was drawn during the last minute of each step and analyzed within 30 min of collection ( abl 700 , radiometer copenhagen , denmark ). statistical analysis of the data was performed using the sas system v . 9 . 1 . 3 ( sas institute inc , cary n . c ., usa ). a series of mixed - effect repeated measures models ( mmrms ) was performed to determine whether differences in p et co 2 and paco 2 values were significantly greater than zero , and whether the magnitude of these differences varied across sequences , and across target pco 2 and po 2 levels . a subject identifier was included as a random effect in each of these models to account for the relatedness of observations taken on the same subject . two separate model analyses were conducted , the first to examine p et - aco 2 as a function of sequence , and the second to examine p et - aco 2 as a function of target p et co 2 . bonferroni - adjusted pairwise comparisons were used to examine whether p et - aco 2 was significantly smaller in the sequence in which both pco 2 and po 2 were varied than in the sequence when p et o 2 was maintained constant . a bland - altman analysis 8 was used to calculate the limits of agreement between p et co 2 and paco 2 . data are presented as means ± sd . table 1 lists the differences between measured p et co 2 and paco 2 for all three protocols : in every instance , p et co 2 moved in the same direction as paco 2 . the current example elaborating on an animal model is analogous to a clinical study in which each animal represents a single patient studied over time and at various levels of ventilation . the animals had various combinations and severity of underlying pulmonary disease and cardiac shunts . the animals may also have had undetermined changes in cardio - pulmonary pathophysiology as a result of the severe hypoxia , hypercarbia and hypocarbia induced in protocol 3 . nevertheless , bland - altman analysis of our data indicated that the agreement between p et co 2 and paco 2 was 0 . 4 ± 2 . 7 mmhg ( fig5 ). the probability of obtaining our level of agreement between p et co 2 and paco 2 by chance is & lt ; 0 . 0001 . 9 the consistently small pet - aco 2 in our study contrasts with those of most other studies in which p et - aco 2 varies widely between subjects and in the same subjects over time . mcdonald et al . 2 studied 1708 sample pairs of p et co 2 and paco 2 in 129 children in an intensive care unit ; p et - aco 2 ranged between 0 to & gt ;− 30 mmhg and only 74 % of samples changed in the same direction . tobias et al . 3 reported a range of p et - aco 2 of 5 to − 22 mmhg in 100 sample sets in 25 infants and toddlers . for perspective , the studies by mcdonald et al . 2 and tobias et al . 3 suggested that even the broad pet - aco 2 in their studies of − 4 . 7 ± 8 . 2 mmhg and − 6 . 8 ± 5 . 1 mmhg respectively were still within a “ clinically acceptable ” range . yamanaka et al . 10 , in a study of 17 ventilated adults in a critical care unit , found that the correlation between p et co 2 and paco 2 was too poor for p et co 2 to be used even as an indicator of direction of changes of paco 2 . others too have found poor , or no , correlations between p et co 2 and paco 2 in adults with multi - 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