The Correlation Between Intracavernosal Pressure and Cavernosal Blood Oxygenation

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The Correlation Between Intracavernosal Pressure and Cavernosal Blood Oxygenation jsm_1429

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Raanan Tal, MD, Alexander Mueller, MD, and John P. Mulhall, MD Male Sexual & Reproductive Medicine Program, Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA DOI: 10.1111/j.1743-6109.2009.01429.x

ABSTRACT

Introduction. Given that regular nocturnal erections are physiological, it has been suggested that erections are pivotal to the maintenance of erectile tissue health. It has been postulated that a critical element to erectile tissue protection is cavernosal oxygenation. It is accepted that the corpora cavernosa are oxygenated fully during a rigid erection. However, it remains unknown what degree of penile rigidity is required to achieve cavernosal oxygenation at the arterial level. Aim. This analysis was undertaken to define the correlation between intracavernosal pressure (ICP) and cavernosal oxygen partial pressure (pO2). Main Outcome Measures. Cavernosal pO2 at various ICPs. Methods. The study population was comprised of patients undergoing dynamic infusion cavernosometry (DIC) in the evaluation of erectile dysfunction or prior to penile reconstructive surgery. DIC was conducted with a standard vasoactive agent redosing schedule. One milliliter of corporal blood was aspirated at various ICPs into a heparinized syringe for later pO2 analysis. Blood was placed on ice immediately and transported to the laboratory upon completion of the DIC. Results. Twenty-one blood samples were analyzed from 13 patients. Mean patient age was 43 ⫾ 18 years. Blood specimens were collected at an ICP range of 6–90 mm Hg. Mean ⫾ SD pO2 was 39 ⫾ 11 mm Hg at ICP < 10 mm Hg, 87 ⫾ 3 at ICP 11–20 mm Hg, 89 ⫾ 6 at ICP 21–45 mm Hg and 96 ⫾ 13 at ICP > 45 mm Hg. Conclusions. Significant increases in cavernosal oxygenation occur in the earliest stages of erection at relatively low ICP. These findings suggest that partial erections may be sufficient to oxygenate erectile tissue and protect it from prolonged hypoxia-induced damage. Tal R, Mueller A, and Mulhall JP. The correlation between intracavernosal pressure and cavernosal blood oxygenation. J Sex Med 2009;6:2722–2727. Key Words. Cavernosal Oxygenation; Corpora Cavernosa; Intracavernosal Pressure

Introduction

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he changes in penile blood oxygenation during erection compared with the flaccid state were first described more than two decades ago [1]. Lue et al. were the first to measure penile blood oxygen partial pressure (pO2) in a monkey model and showed that cavernosal pO2 during erection increases compared with that of the flaccid state. In 1993, Kim et al. published their Supported by: The Sidney Kimmel Center for Prostate and Urologic Cancers.

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work on the physiological role of oxygen tension in the regulation of penile smooth muscle tone [2]. They showed in human subjects that in the flaccid state intracavernosal blood pO2 is venous, whereas during erection induced by an intracavernosal injection, intracavernosal pO2 rose rapidly to that of arterial blood. These authors showed that these changes in cavernosal blood oxygenation were shown to have a profound effect on cavernosal tissue physiology and the erectile process. Penile changes associated with the transition from flaccidity to a fully rigid erection are complex and include changes in penile dimensions, © 2009 International Society for Sexual Medicine

Intracavernosal Pressure and Cavernosal Blood Oxygenation mechanical properties, intracavernosal pressure (ICP), and cavernosal blood flow [3–5]. Our current understanding of erectile physiology supports the concept that increased cavernosal blood flow during erection results in improved cavernosal oxygenation, which is believed to be important for the maintenance of erectile tissue integrity. Absence of such oxygenation is purported to be associated with the potential for smooth muscle to undergo structural changes [6–8]. This is also true for other organ systems: in the pulmonary system, hypoxia induces smooth muscle cells proliferation, leading to blood vessel medial thickening, lumen obliteration, and pulmonary hypertension [9]. Although it has been demonstrated by Kim et al. that increased cavernosal blood oxygenation occurs in the early stages of erection, at relatively low ICP, these data were derived from a small study group and has never been corroborated. The current study was conducted to define the correlation between ICP and cavernosal blood oxygenation, potentially permitting the determination of a threshold rigidity level generating optimal erectile tissue oxygenation. Methods

Study Population The study was approved by our institutional review board and all subjects gave their informed consent to participate in the study. The study population was comprised of men undergoing dynamic infusion cavernosometry (DIC) for ED evaluation or as a part of preoperative evaluation for penile reconstructive surgery for either Peyronie’s disease or congenital penile deviation. Cavernosometry DIC was performed using a standard vasoactive redosing schedule using Trimix 100 units (1 mL) (papaverine 30 mg/mL, phentolamine 1 mg/mL, prostaglandin E [PGE] 10 mcg/mL). ICP was measured using a 19-gauge butterfly needle placed intracavernosally and connected to a pressure transducer (Life-Tech, Stafford, TX, USA). During the gradual increase in ICP in response to the vasoactive agent, 1 mL of cavernosal blood was aspirated through the 19-gauge butterfly needle into a heparinized syringe. The aspiration was performed at different ICP levels. Blood samples were transferred for analysis on ice. Following corporal blood aspiration, DIC proceeded in the usual

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fashion. Recorded data included: subject’s age; indication for the DIC study; equilibrium pressure; flow-to-maintain value at 90 mm Hg (FTM90); pressure decay (over 30 seconds, from a pressure of 150 mm Hg); arterial inflow gradient (AIG; defined as the difference between systolic blood pressure, measured by a standard arm sphygmomanometer, and cavernosal arterial occlusion pressure, defined as the cavernosal pressure at which a Doppler signal from the cavernosal artery is lost). To determine the vascular diagnosis, an FTM of >3 mL/min and/or a pressure decay of >45 mm Hg defined venous leak and an AIG > 30 mm Hg defined arterial insufficiency.

Blood Gas Analysis Blood gas analysis was performed using a standard automated clinical blood gas analyzer (Synthesis 25, Instrumentation Laboratory, Lexington, MA, USA). This analyzer directly measures the oxygen partial pressure using a polarographic (Clark) oxygen electrode (platinum cathode and silver– silver chloride anode) with 700 mV polarizing voltage. Measurement range is 0–800 mm Hg with a resolution of 1 mm Hg. Oxygen partial pressure results were corrected to a body temperature of 37°C Statistical Analysis We hypothesized that cavernosal blood oxygen partial pressure increases as ICP rises. Statistical analysis was performed using a commercially available software package (SPSS 15.0, SPSS Inc., Chicago, IL, USA). Descriptive statistics included patients’ age (mean ⫾ standard deviation [SD]), DIC indication (proportions), equilibrium pressure, FTM90, pressure decay, and AIG (mean ⫾ SD), and vascular diagnoses (proportions). A plot of cavernous blood oxygen partial pressure against ICP with logistic regression bestfit curve and 95% confidence intervals was plotted and R square was calculated using curve-fitting software (GraphPad Prism 5, GraphPad Software Inc., La Jolla, CA, USA). Mean ICP was calculated for grouped measurements at various ICP ranges: ⱕ10; 11–20; 21–45; and >45 mm Hg. Results

Study Population The study group included 13 patients and 21 blood samples were collected (1–3 samples per each patient, mean ⫾ SD 1.6 ⫾ 0.8, median 1). J Sex Med 2009;6:2722–2727

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Mean ⫾ SD patient age was 43 ⫾ 18 years (range: 20–64). Full clinical data were available for 11 patients. Indications for DIC included evaluation of erectile function etiology (N = 6) and prior to penile reconstructive surgery in cases of Peyronie’s disease (N = 4) or congenital penile deviation (N = 1).

Cavernosometry Data Mean equilibrium pressure for the study group was 40 ⫾ 15 mm Hg, mean flow-to-maintain value at ICP of 90 mm Hg was 14 ⫾ 20 mL/min, mean pressure decay from a pressure of 150 mm Hg during 30 seconds was 61 ⫾ 32 mm Hg and mean arterial inflow gradient between the brachial artery and the cavernosal arteries was 29 ⫾ 16 mm Hg. Vascular diagnoses were arterial insufficiency in two patients (18%), cavernous veno-occlusive disease in three (27%), mixed vascular ED in 2 (18%), and normal erectile hemodynamics in four patients (37%). Oxygenation Data Cavernosal blood specimens were collected at an ICP range of 6–90 mm Hg. A scatter plot of cavernosal blood oxygen partial pressure against ICP with a logistic regression best-fit curve and 95% confidence interval curves is depicted in Figure 1. The R square value for the best-fit curve was 0.675. Rapid increase in cavernosal oxygen partial pressure was evident at low ICPs, ranging from 6 to

Figure 2 Mean cavernosal blood oxygen partial pressure (pO2) and 95% confidence interval (CI) at various intracavernosal pressure categories: cavernosal blood partial pressure is in the venous range during penile flaccidity (intracavernosal pressure <10 mm Hg), increases rapidly in the initial stages of tumescence and reaches arterial oxygen partial pressure at intracavernosal pressure >45 mm Hg, before fully rigid erection is achieved. N = number of determinations per each category.

10 mm Hg, and reached a plateau at higher ICPs. Mean cavernosal pO2 was 39 mm Hg at ICPs of 10 mm Hg or less, 87 mm Hg at ICP range of 11–20 mm Hg, 89 mm Hg at ICP of 21–45 mm Hg and 96 mm Hg at ICP > 45 mm Hg (Figure 2). Discussion

Figure 1 The association of cavernosal blood oxygen partial pressure (pO2) and intracavernosal pressure (ICP): Each point represents one blood sample. The independent variable (horizontal axis) is intracavernosal pressure, measured at cavernosometry and the dependent variable (vertical axis) is oxygen partial pressure, measured by blood gases analysis. A best-fit curve (solid line) and the corresponding 95% confidence interval curves (dashed lines) are shown, R2 = 0.675.

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The role of cavernosal oxygenation in penile physiology is well established. In the flaccid state, cavernosal oxygen partial pressure is close to venous pO2. Low pO2 levels impair neuronal and endothelial synthesis of nitric oxide (NO) and thus smooth muscle relaxation may be impaired. Wayman et al. have shown in a canine model (anesthetized and ventilated) that reduction in inspired oxygen level results in impaired cavernosal smooth muscle response to cavernous nerve stimulation [10]. During erection, increased oxygenation favors the synthesis of NO and consequent smooth muscle relaxation. Kim et al. showed that during acute hypoxia not only is NO production reduced, but so also is erectile tissue responsiveness to NO and NO-mediated smooth muscle relaxation [2]. Moreland et al. described the role of hypoxia in the pathophysiology of erectile tissue structural alterations, including the increased synthesis of

Intracavernosal Pressure and Cavernosal Blood Oxygenation fibrogenic cytokines, transforming growth factor b1 and platelet-derived growth factor (PDGF) and reduced synthesis of PGE, a connective tissue synthesis inhibitor [11–13]. In 1983, Lue et al. published their pioneering study describing penile hemodynamics and oxygenation during erection in a monkey model (three monkeys) [1]. They induced erections by cavernous nerve electro-stimulation and measured arterial blood flow, corporal pressure, and pO2, in the proximal and distal corpora, before and 1, 5, 20, and 30 minutes after the monkeys achieved a sustained erection. They showed that during erection, corporal blood had a higher pO2 than in the flaccid state and it remained oxygenated for the whole erection duration, even after 30 minutes of full erection. These findings were later corroborated in human subjects, during a fully rigid erection, cavernosal oxygen partial pressure is close to arterial oxygen partial pressure. Knispel et al. reported that after penile injection of an erectogenic agent (papaverine/phentolamine), cavernosal oxygen partial pressure rose continuously and gradually, starting at 35–60 seconds and continued up to 8.5 minutes after injecting [14]. This is in contradistinction to the steep increase in cavernosal oxygen partial pressure, immediately after injections, followed by a plateau, reported by Kim et al. [2]. Although Knispel et al. did not measure ICP simultaneously with cavernosal pO2, Kim et al. showed that an increase in oxygenation occurs before ICP elevation and development of rigidity. Improved oxygenation occurs probably secondary to arterial dilatation and increased cavernosal blood flow. Knispel et al. assessed duplex Doppler ultrasound peak arterial flow with maximal cavernosal oxygen partial pressure and found good correlation in 71% of the cases. They hypothesized that in the remaining cases, lack of correlation was caused by isolated cavernous perfusion defects, a hypothesis that has neither been confirmed nor refuted [14]. Although in men with good erectile function a change in penile rigidity from complete flaccidity to full erection is associated with maximal penile oxygenation, it remains of interest if partial erections are sufficient for adequate oxygenation. In clinical practice, the association of erection rigidity and cavernosal oxygenation state is important in men who wish to protect their erectile tissue from hypoxic damage but struggle to achieve spontaneous or medication-induced fully rigid erections, for example, men in the early stages after radical pelvic surgery. Iacono et al. biopsied men before

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and at 2 and 12 months after radical prostatectomy and described erectile tissue structural changes, including decreased elastic fibers and smooth muscle content with an increase in collagen content [15]. Schwartz et al. treated men with sildenafil on a regular every-other-night basis and demonstrated that regular use of this drug preserved erectile tissue architecture, and even increased smooth muscle content [16]. This important work is an important landmark in the evolution of penile rehabilitation, a contemporary concept where induction of erection and/or regular phosphodiesterase type 5 (PDE5) inhibitor use (not essentially with erectogenic intent) is aimed at limiting erectile tissue smooth muscle degenerative changes. Interestingly, hypoxia may have different effects on blood vessels in other organ systems. In the pulmonary system, hypoxia induces smooth muscle cells proliferation, directly and secondarily related to pro-proliferative factors secreted from proliferating fibroblasts and endothelial cells, leading to blood vessel medial thickening, lumen obliteration, and pulmonary hypertension [9]. Further increase in smooth muscle content occurs as fibroblasts transform to smooth muscle cells. In the urogenital tract, the effect of hypoxia on smooth cell proliferation was studied in an obstructed urinary bladder model. In the initial stages, the compensatory response to bladder outflow obstruction is smooth muscle hyperplasia and hypertrophy. With increased bladder wall thickness and mural pressure, bladder wall perfusion decreases with resultant hypoxia and eventual decompensation. Galvin et al. showed in a cell culture study that hypoxia did not induce apoptosis, however, it significantly reduced smooth muscle cells proliferation [17]. The preservation of erectile tissue integrity, resolution of neuropraxia and erectile function recovery, is believed to be predicated, in part at least, on cavernosal oxygenation [6]. Unfortunately, for clinical use, frequent cavernosal blood analyses or Doppler ultrasound flow measurements are not practical in monitoring such patients and a more applicable tool is needed to assure adequate cavernosal oxygenation. In the present study, we have demonstrated that cavernosal blood oxygenation occurs at low ICPs, during the initial stages of erections. Additional increases in ICP and consequently, in rigidity, leads to only minimal further increases in cavernosal blood oxygen partial pressure. These results corroborate for the first time previous findings by Kim et al. [2]. J Sex Med 2009;6:2722–2727

2726 For sexual intercourse, good penile rigidity is essential to allow for confident penetration and couple satisfaction [18]. However, if sexual intercourse is not the main goal, in cases where preservation of erectile tissue health is the primary concern, our results support the concept that partial erections are sufficient to achieve optimal cavernosal oxygenation. The question can therefore be asked: in a penile rehabilitation program do we need to be driving patients to maximum rigidity as we do with PDE5 inhibitor failures by using intracavernosal injections? Perhaps, the minimal response to a PDE5 inhibitor that many men obtain in the early stages after radical prostatectomy is sufficient for erectile tissue preservation? Unfortunately, this analysis cannot answer this question. Indeed, perhaps one of the ways erection protects erectile tissue is through stretching of the cavernosal smooth muscle. Maybe the stretch-contraction cycle is important to erectile tissue health, in the same way that loading of a skeletal muscle is essential to maintaining its integrity [19]? Recently, the use of a vacuum erection device as a rehabilitative strategy after radical prostatectomy has been proposed with demonstration of both improved erectile function and preservation of penile length in limited population size studies [20,21]. These vacuum erection deviceassociated beneficial effects after RP may be mediated by stretch forces, however, this hypothesis is yet to be established. Conclusions

Significant increases in cavernosal oxygen partial pressure and adequate cavernosal oxygenation occurs already in the early stages of erection at relatively low ICP. This increase in oxygenation is probably the result of increased blood flow and oxygen delivery, before an increase in ICP is achieved and penile rigidity is evident. Our findings suggest that achieving a fully rigid erection may not be needed to provide optimal cavernosal oxygenation. Low level spontaneous or pharmacologically assisted partial erections may be sufficient to protect the erectile tissue from damage induced by prolonged hypoxia; however, whether such erections optimally preserve erectile function preservation are beyond the scope of this study. Corresponding Author: John P. Mulhall, MD, Director, Male Sexual & Reproductive Medicine Program, Urology Service, Department of Surgery, Sidney Kimmel Center for Prostate & Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 353 East J Sex Med 2009;6:2722–2727

Tal et al. 68th street, New York, NY 10065. Tel: 646-422-4359; Fax: 212-988-0768; E-mail: [email protected] Conflict of Interest: None declared. Statement of Authorship

Category 1 (a) Conception and Design John P. Mulhall; Alexander Mueller (b) Acquisition of Data Raanan Tal; John P. Mulhall (c) Analysis and Interpretation of Data Raanan Tal; John P. Mulhall

Category 2 (a) Drafting the Article Raanan Tal (b) Revising It for Intellectual Content John P. Mulhall

Category 3 (a) Final Approval of the Completed Article John P. Mulhall References

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