Ultrasonic and endoscopic examinations are frequently used for medical observation of various organs located in or near various body cavities. For example, the uterus is easily accessible to ultrasound imaging. New trans-vaginal probes, originally designed to facilitate egg retrieval in in vitro fertilization (IVF), have further enhanced the quality and usefulness of uterine ultrasound imaging. This improvement has directly resulted from the high frequency-high resolution ultrasound probes made possible by the proximity between the probe, inserted vaginally, and the organ being analyzed—in this case, the uterus.
Clinical circumstances warranting ultrasound imaging of the uterus fall into two main categories. During pregnancy, ultrasounds are very often used to assess fetal growth and well-being. And in non-pregnant women, ultrasounds frequently serve to identify uterine pathologies, such as fibroids or polyps, particularly while investigating the resulting symptoms such as bleeding disorders (dysfunctional uterine bleeding, or “DUB”), cramping, and infertility.
One striking difference between ultrasound imaging of the pregnant and non-pregnant uterus is the presence of amniotic fluid in the pregnant uterus. During pregnancy, the intrauterine (amniotic) fluid serves as a remarkable contrast enhancer that markedly improves the resolution of ultrasound images. The structures that are most affected by the contrast enhancement provided by the amniotic fluid are those lying in the immediate vicinity of fluid inter-phases, such as the central nervous system structures.
Learning from the unique advantages of ultrasound imaging during pregnancy and the role played by amniotic fluid as a contrast enhancer, several investigators have tried to reproduce these advantages for assessing the non-pregnant uterus. Thus, in order to similarly improve the quality of ultrasound imaging of a non-pregnant uterus, researchers have infused sono-transparent or sono-opaque fluids into the uterine cavity for providing, respectively, negative (black) or positive (white) contrast enhancement for the resulting images.
Most commonly, about 10-40 milliliters of 0.9% sodium chloride (NaCl, or saline) solution—a sono-transparent solution providing negative contrast—is slowly, and continually or repeatedly, infused into the uterine cavity in order to maintain appropriate pressure to distend the uterus during the ultrasound examination. This is usually done with plastic catheters designed for embryo transfers, or various other catheter models. The fluid must be continually or repeatedly infused because—as would happen with any pressurized fluid in an open container—it continually leaks out, in this instance through the cervix and/or fallopian tubes. Sometimes, a catheter may be equipped with an inflatable balloon or other sealing mechanism, which is intended to reduce leakage at the cervical end, but not at the tubes.
Today, such a procedure involving infusion of fluid during a uterine ultrasound procedure is most commonly referred to as a “sonohysterography,” though it is also known by other names, including hysterosalpingo-contrast sonography (HyCoSY), saline hysterosonography, etc.
While simple in principle, the use of an intrauterine infusion of a NaCl or other solution as an ultrasound contrast enhancer is complex and cumbersome in practice. The intrauterine catheter connected to the NaCl syringe must be first introduced through the cervical canal into the uterus after a speculum is put in place. Then, the speculum needs to be removed while the catheter is held in the uterus, in order to accommodate the intra-vaginal ultrasound probe. Finally, the probe is inserted into the vagina with one hand, taking care not to displace the catheter, while the other hand holds the catheter and the syringe, pushing the plunger to initiate the intrauterine flow of fluid. Thus, a “3rd hand” is needed to make any necessary adjustments to the ultrasound machine, and to save iconographic documents.
The need to constantly flush contrast fluid through the uterine cavity while conducting the ultrasound examination, as it continually leaks out, also results in inconvenient and messy fluid puddles in the examination area, including on the examination table—which can be a further source of discomfort for the patient. Needless to say, sonohysterography is considered a time-consuming procedure by most gynecologists, who tend to use it reluctantly and only in certain cases that are deemed to warrant the extra inconvenience and discomfort. Despite these practical difficulties, the quality enhancement of ultrasound images achieved through sonohysterography is significant and allows more precise diagnoses of uterine pathologies, such as uterine fibroids and polyps, otherwise impossible or difficult to examine with plain ultrasounds.
Enhanced contrast ultrasounds provide better images of intrauterine pathologies. See, for example, FIGS. 1 through 4. FIGS. 1A, 2A, 3A, and 4A show the results of a plain uterine ultrasound in each of four patients. FIGS. 1B, 2B, 3B, and 4B show the results, respectively in the same four patients, of an enhanced contrast ultrasound using the medium of the instant invention. The substantially increased contrast and visibility attained with the instant invention is similar to that achieved even with typical sonohysterography (which would not provide the convenience and benefits of the instant invention, discussed below).
Numerous studies have validated the improvement provided by the addition of an intrauterine contrast medium over plain uterine sonography. Specifically, a wealth of data has demonstrated the superior positive and negative prediction value of saline sonohysterography for identifying intrauterine pathologies, when compared to the results and abilities of plain uterine ultrasounds. The pathologies easily identified by sonohysterography include submucosal fibroids and endometrial polyps, two common causes of dysfunctional uterine bleeding. Yet despite ample clinical value documented by many academic studies, actual use of sonohysterography remains relatively limited because of the difficulties and time-consuming nature of the procedure. It is for these practical reasons that sonohysterography is not commonly used in everyday gynecology.
One variation of saline sonohysterography uses sono-opaque solutions such as Echovist®-200, Albunex®, or similar products instead of the sono-transparent solutions such as normal saline, in order to render the uterine cavity hyperechogenic (“white”) instead of hypoechogenic (“black”). The value of “white” hyperechogenic contrast over “black” hypoechogenic products such as saline has been debated.
For hysterosonography using hyperechogenic (“white”) medium, the products used (Echovist and similar products) were designed for intra-vascular injection and contrast enhancement of cardiac ultrasounds. Hence, their use in obstetrics and gynecology has been an afterthought. They are all fluid and require infusion throughout the procedure, just like NaCl or other “black” hypoechogenic products. One claimed advantage of a hyperechogenic, or positive contrast, procedure is the resulting enhanced contrast image of the Fallopian tubes, particularly in their proximal segment, as compared to the relative lack of contrast when using negative contrast (such as saline) sonohysterography for such imaging.
Today, however, while many physicians recognize that positive contrast sonohysterography can be used to verify tubal patency, classic hysterosalpingography (HSG), an examination using x-rays, remains the primary mode for studying tubal anatomy because of the superior quality of tubal imaging obtained. While we agree that HSG is generally superior to positive contrast hysterosonography for assessing tubal anatomy, we believe that positive contrast hysterosonography may have a role to play for studying tubal functionality (peristaltic contractions).
Irrespective of its indications, positive contrast sonohysterography is as cumbersome a “3 hand” procedure as negative sonohysterography. It, too, requires simultaneously instilling the contrast fluid, holding the ultrasound probe, and making necessary adjustments on the ultrasound machine. As positive contrast preparations such as Echovist-200 are injectable, fluid preparations, the products typically still need to be continuously or periodically instilled during the examination. Hence, these procedures, too, require keeping the catheter in the uterine cavity during the procedure to allow continued or frequent replenishment of the medium, and commonly result in unpleasant watery leakages on the examination table.
Hysteroscopy, in contrast to ultrasound procedures, is an endoscopic investigation of the uterus intended to provide a direct visualization, rather than a contrast image. Accordingly, such a procedure typically does not require use of a contrast enhancing agent, but it still uses an “image enhancing” medium to distend the uterus, which otherwise is a virtual cavity—that is, one that is ‘collapsed’ and thus difficult to visualize. This type of procedure, however helpful, has significant disadvantages that prevent its widespread use. These disadvantages include pain and discomfort caused to the patient during the procedure, and the need to re-sterilize the expensive instruments after each examination.
During a hysteroscopy, the hysteroscope is introduced into the uterine cavity through the cervical os. In operative hysteroscopies, the procedure is conducted under anesthesia, which usually is general anesthesia, but may be a spinal or local (cervical block) anesthesia. The procedure typically requires dilatation of the cervix to approximately 7 to 9 mm to permit insertion of the relatively large instrument—the surgical hysteroscope. Constant infusion of a solution, such as a NaCl solution, Ringers, or glycine (if monopolar coagulation is envisioned), or of a gas, such as CO2, is needed to constantly distend the cavity and to wash away bleeding.
In some circumstances, a thicker solution, such as Hyscon™ is infused during the hysteroscopy procedure. While sticky and slightly thicker than saline, Hyscon still does not distend the cavity by itself without being infused under pressure. And Hyscon, too, leaks out, so again the procedure requires constant or periodic infusion.
Hysteroscopes are typically configured in such a way that, if needed, mini-surgical instruments may be inserted through the hysteroscope to cut and remove abnormal structures such as polyps, sub-endometrial fibroids and scar tissue (synechiae), or to burn them away using electrocoagulation or laser beams. Accordingly, operative hysteroscopes tend to be anything but compact.
Office hysteroscopy is a simplified version, performed for diagnostic purposes only. The smaller instrument size used in office hysteroscopy (3-5 mm in diameter) allows the physician to avoid cervical dilatation and anesthesia. Nevertheless, pain and discomfort still accompany the procedure, and so resort to this form of the procedure, too, remains somewhat limited. As in operative hysteroscopy, a solution or a gas must be infused throughout the procedure, in order to distend the uterine cavity, thereby permitting visualization. Of course, the infusion itself (which takes place under pressure), and the typical accompanying mess of leaked fluid, are additional sources of discomfort for the patient.
Thus, a product that provides (1) the ultrasound contrast enhancing properties of negative or positive intrauterine contrast enhancers and slightly distends the uterine cavity for offering a contrast interphase but without the leakage requiring constant fluid perfusion during the ultrasound examination, or (2) the distension required for a hysteroscopy procedure while allowing optical clarity, but without the need for bulky apparatus to continually perfuse the medium, or both, would be a huge advance in both aspects of the field. Such a product would make the procedures less burdensome, uncomfortable, and messy, and more convenient and efficient.
Such a product should have gel-like viscosity, or otherwise be able to remain in the uterine cavity after intrauterine infusion for the duration of the examination. This would permit the physician to remove the speculum and intrauterine catheter after infusion, and to perform the ultrasound or hysteroscopy procedure freely without having to constantly infuse the product during the examination. One added advantage would be that images generated would be free of image artifacts generated by the intrauterine catheter. The ideal product should then liquefy after a reasonable period of time, or otherwise facilitate easy removal, so that it is not permanently retained, but rather expelled from the uterine cavity after completion of the ultrasound examination. Intrauterine retention of a substance remaining in viscous gel consistency would be improper because of the potential to interfere with fertility.
As used herein, an “image enhancing” medium means a medium that enhances or facilitates contrast and/or direct visualization during medical examination procedures, such as by distending a body or organ cavity during a procedure such as ultrasound or endoscopy, and/or by providing improved contrast during imaging procedures such as ultrasounds. Thus, contrast enhancement is used here more broadly than the pure sense of merely enhancing or improving a contrast image. Instead, we use the term herein, as appropriate in context, to refer to enhancing or facilitating imaging, radiographic, visualization and similar techniques generally, whether by literally increasing the contrast, or by facilitating distension of the surface being examined, or both.
As used herein, a “phase-changing” or “phase-shifting” medium is one that is more of a solid or semi-solid (such as a gel) initially in a body or organ cavity during a medical examination procedure, but then changes or shifts to more of a liquid to facilitate removal or expulsion from the cavity, preferably after the procedure is completed. In contrast, a “viscosity-changing” or “viscosity-shifting” medium is one that is more viscous when used in a body or organ cavity during a medical examination procedure, but then becomes less viscous to facilitate removal or expulsion from the cavity, preferably after the procedure is completed.
As used herein, a medium that is in a “solid,” “semi-solid,” or “gel” state or phase is in a form that is sufficiently stable physically (i.e., relatively solid or viscous rather than fluid or gaseous) to substantially remain in a body or organ cavity typically without requiring constant or frequent replenishment during a medical examination procedure.
As used herein, “sufficient time” to conduct a medical examination procedure is typically on the order of at least several minutes, generally about 3 to 10 minutes, and preferably about 5 to 7 minutes. By the time the inventive composition is in place for such a sufficient time, the procedure is generally completed. Whether or not it liquefies or decreases in viscosity, the composition then is allowed to leak from the body or organ cavity, or is removed quickly and easily. Generally the cavity is mostly free of the composition within about 7 to 20 minutes of its initial placement in the cavity, preferably within about 10 to 15 minutes.
As used herein, “medical imaging” refers to imaging, radiographic, visualization, or other similar procedures for examining body or organ cavities or contiguous tissue, for various purposes including evaluation, diagnosis, observation, treatment, etc., whether prompted by specific concerns or symptoms or simply as precautionary measures. Such procedures include, for example, ultrasound, endoscopic procedures, MRI, x-rays, hystero-salpingograms (HSG), and CT (Computed Tomography) scans (each a “medical imaging procedure”). Similarly, a medical imaging composition or medium is intended for use in such medical imaging procedures.