S1
S2
S3
S4
Gallop
Splitting
2012年3月20日 星期二
Benign prostate hyperplasia
According McNeal’s model of the prostate [7], four different anatomical zones may be distinguished that have anatomo-clinical correlation (Figure 2):
1) The peripheral zone : is the area forming the postero-inferior aspect of the gland and represents 70% of the prostatic volume. It is the zone where the majority (60-70%) of prostate cancers form.
2) The central zone : represents 25% of the prostate volume and contains the ejaculatory ducts. It is the zone which usually gives rise to inflammatory processes (eg prostatitis).
3) The transitional zone : this represents only 5% of the total prostatic volume. This is the zone where benign prostatic hypertrophy occurs and consists of two lateral lobes together with periurethral glands. Approximately 25% of prostatic adenocarcinomas also occur it this zone.
4) The anterior zone : predominantly fibromuscular with no glandular structures.
The prostate weighs approximately 20g by the age of 20 and has the shape of an inverted cone, with the base at the bladder neck and the apex at the urogenital diaphragm [8].The prostatic urethra does not follow a straight line as it runs through the centre of the prostate gland but it is actually bent anteriorly approximately 35 degrees at the verumontanum (where the ejaculatory ducts joins the prostate) [9].
Figure 2. 1= Peripheral Zone, 2= Central Zone, 3= Transitional Zone, 4= Anterior Fibromuscular Zone. B= Bladder, U= Urethra, SV= Seminal Vesicle (adapted from Algaba[10]).
![1= Peripheral Zone, 2= Central Zone, 3= Transitional Zone, 4= Anterior Fibromuscular Zone. B= Bladder, U= Urethra, SV= Seminal Vesicle (adapted from Algaba[10]).](https://lh3.googleusercontent.com/blogger_img_proxy/AEn0k_vPUSS4mTOGUiWlqngzo6kt6gzGXABXFZ3MWwsr_R9mPiAetDoa7k8ij3ITGAeGWrVnJV8ncWaNfEzrHphMDr_ReLlpqmhlU9zOr67Xp9CVdpHg1FXAihVQag=s0-d)
Testosterone
Prostatic epithelial cells express the androgen receptor[31]. From the beginning of embryonic differentiation to pubertal maturation and beyond, androgens are a prerequisite for the normal development and physiological control of the prostate[32]. Androgens also help maintain the normal metabolic and secretory functions of the prostate. They are also implicated in the development of benign prostatic hyperplasia (BPH) and prostate cancer. Androgens do not act in isolation and other hormones and growth factors are being investigated[33].
Androgens also interact with prostate stromal cells which release soluble paracrine factors that are important in the growth and development of the prostate epithelium [4]. These paracrine pathways may be critical in regulation of the balance between proliferation and apoptosis of prostate epithelial cells in the adult[33].
The appropriate balance between testosterone and its 5 α reduced metabolites are key to normal prostate physiology (note the metabolic pathways for androgen metabolism are described in the Chapter 2 on Androgens by D Handelsman). The metabolism of testosterone to dihydrotestosterone (DHT) and its aromatisation to estradiol are recognised as the key events in prostatic steroid response.
Testosterone, to be maximally active in the prostate, must be converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase (Figure 5)[34]. DHT has a much greater affinity for the androgen receptor than does testosterone [35, 36]. DHT is about twice as potent as testosterone in studies of rats at equivalent androgen cconcentrations[37].DHT due to its greater affinity for the androgen receptor may have effects intraprostatically independent of serum fluctuations in serum testosterone levels. [35, 36].
The impact of serum androgen manipulation on prostate tissue hormone levels in normal men is unknown. Studies of men with prostate cancer have suggested that prostatic androgens are preserved in the setting of castration. Tissue androgens might stimulate prostate growth, producing adverse clinical consequences.[38] In a small study of healthy subjects, despite a 94% decrease in serum T with medical castration, intraprostatic T and dihydrotestosterone levels remained 20-30% of control values, and prostate cell proliferation, apoptosis, and androgen-regulated protein expression were unaffected. [38] Future therapies may need to take such findings into account if they are reproduced.
DHT concentrations may remain similar to those in young men in the prostate of elderly men, despite the fact that serum testosterone levels may decline with age[34]. In the prostate, the total level of testosterone is 0.4 ng/g and the total of DHT is 4.5 ng/g[39]. The total concentration of testosterone in the blood (18.2nnmol/L[27]) is approximately 10 times higher than that of DHT. Circulating DHT, by virtue of its low serum plasma concentration and tight binding to plasma proteins, is of diminished importance as a circulating androgen affecting prostate growth.
DISEASE MANIFESTATIONS OF BPH
Lower urinary tract symptoms (LUTS) suggestive of BPH are highly prevalent and the majority of LUTS in men is produced by BPH, but may be contributed to by a variety of conditions (Fig. 5). LUTS are traditionally divided into voiding or obstructive and storage or irritative symptoms (Table 2). Voiding symptoms are more common, however it is storage symptoms that are most bothersome and have a greater impact on a patient's life[72, 73]. The prevalence of clinical BPH rises with age and approximately 25% of men age 40 or over will suffer from LUTS.
| Voiding or Obstructive Symptoms | Storage or Irritative Symptoms |
|---|---|
|
|
Table 4. A Summary of Diagnosis and Treatment Options in BPH
| EVALUATION of LUTS |
ESSENTIAL
|
| TREATMENT OPTIONS |
MEDICAL THERAPY
|
International Prostate Symptom Score (IPSS)
The American Urologic Association (AUA) Symptom Index was developed as a standardised instrument to assess the degree of bladder outlet obstruction in men [98]. It is widely used and consists of seven questions that assess emptying, frequency, intermittency, urgency, weak stream and straining with each graded with a score of 0-5. Total score ranges 0-35. The index categorises patients as:
- Mild (Score 7)
- Moderate (Score 8-19)
- Severe (20-35).
The International Prostate Symptom Score (I-PSS) is a modification of the AUA Symptom Index adding a single question assessing the quality of life or bother score based on the patient’s perception of the problem (Figure 8)[114]. Both the AUA and I-PSS questionnaires, although not specific for BPH, prostate volume, urinary flow rate, post-void residual volume or bladder outlet obstruction, have been validated and are sensitive enough to be to be used in the evaluation of symptoms and selection of treatment[115-117]. Many would argue that the bother score is the primary determinant of whether or not a patient proceeds to further treatment.
Figure 8. International Prostate Symptom Score (I-PSS) Sheet[118, 119]
![International Prostate Symptom Score (I-PSS) Sheet[118, 119]](https://lh3.googleusercontent.com/blogger_img_proxy/AEn0k_sABYiU2pBLSeeVMKJ-HUm0Ft5WUgmAGE-NKmlLOciqWXofBeBIWSN_pbgtV0WO5lB8V3KgTnu2UjiO62W_KZ7w6SshKHEHa4ZG41OlO6a7vXpfpJDPt0i7=s0-d)
Urodynamics
With regard to the investigation and diagnosis of conditions underlying LUTS, when considering inexpensive, safe and completely reversible treatments, one may opt to avoid urodynamics studies initially. However, when considering irreversible, expensive or potentially morbid therapy, such studies are considered mandatory. Many patients will not have urodynamics studies based on the first premise above[126]. However, in reality, many surgeons and physicians will have simple pressure-flow studies easily available and will perform these as part of an initial consultation. More complex studies require time and are costly, and so should be reserved for particular situations as discussed below.
Uroflowmetry is considered by some as the single most useful urodynamic technique for the assessment of obstructive uropathy. The purpose of the uroflow examination is to record one or more micturitions that are representative of the patient’s usual voiding pattern. Therefore, more than one micturition is often required and it is necessary to confirm with the patient if the flow was better, worse or about the same as their normal pattern, otherwise intra-individual variability may lead to false assumptions[127]. The study may be performed in the office or as part of other urodynamic studies in the laboratory or operating suite.
Figure 9 indicates the most common urinary flow parameters measured. Of these, the peak flow rate is the most closely correlated with the extent of outflow obstruction (Table 10). Total voiding time is prolonged in obstruction and has a reduced Qmax. Poor detrusor contractility is impossible to distinguish from bladder outflow obstruction on uroflowmetry so other urodynamics investigations such as a cystometry are indicated.
Figure 9 indicates the most common urinary flow parameters measured. Of these, the peak flow rate is the most closely correlated with the extent of outflow obstruction (Table 10). Total voiding time is prolonged in obstruction and has a reduced Qmax. Poor detrusor contractility is impossible to distinguish from bladder outflow obstruction on uroflowmetry so other urodynamics investigations such as a cystometry are indicated.
Figure 10. Abnormal patterns of uroflowmetry: A) This is likely to represent the flowmetry pattern of a patient with bladder outlet obstruction. The maximum flow reached is around 10ml/sec and the flow rate is prolonged. A diagnosis cannot be made from this reading alone but is certainly characteristic of someone with obstructed voiding and having normal detrusor muscle function. B) This pattern of intermittent flow usually represents abdominal straining in an attempt to overcome outflow obstruction. The peak flow rate may be normal or high, especially if outlet resistance is reduced.
Various measurements may be used to define detrusor pressures (e.g. Abram-Griffiths nomogram) and urethral sphincter pressures as an aid to diagnosis in specific circumstances. This is relevant in patients with LUTS who have had a stroke (or other neurologic disease) where bladder function may have sensory deficits or unstable detrusor contractions, that may need alternate management. Nevertheless, detrusor instability is not considered a negative factor with respect to the outcome of BPH surgery[111], provided it is adequately managed. Some have even suggested that the detection of detrusor instability in patients with LUTS is only of minor diagnostic importance[128].
There is no evidence that pressure-flow studies should be mandatory prior to surgical (or medical) intervention. However, prior to transurethral resection of the prostate (TURP) it has been recommended that the following patients undergo pressure-flow studies:
- Previous unsuccessful invasive treatment of LUTS
- Elderly men (>80 years old), because of the risk of alternate pathology other than bladder outlet obstruction and operative morbidity
- Younger men (less than 50 years old) because of the risk of retrograde ejaculation and alternate diagnosis
- Neurogenic bladder suspected
- Previous radical pelvic surgery
- Post void residual of greater than 300ml (not on one reading)
MEDICAL THERAPY FOR BPH
The first line of medical treatment is an α-blocker, as the majority of patients treated have a prostate volume of less than 40ml.
- Prazosin (titrated up to 5mg day)
- Alfuzosin (5 mg bid or10 mg daily)
- Terazosin (2-10mg)
- Tamsulosin (0.4 mg once daily dose)
- Doxazosin (4-12mg/day)
PS. In a meta-analysis, all α 1-adrenoceptor antagonists seem to have similar efficacy in improving symptoms and flow rates. The difference between α 1-adrenoceptor antagonists is related to their side effect profile. Overall, alfuzosin and tamsulosin appear to be better tolerated than doxazosin, terazosin and prazosin
PS2. Compared to finasteride (5 α-reductase inhibitor), the α-blockers have a more rapid onset of action, are effective independent of prostate size, and show greater improvements in symptom scores but similar improvements in flow rate improvements
In men with larger prostates (greater than 40cc), finasteride alone or in combination with an α-blocker would be appropriate. Patients who are likely to respond to finasteride will do so at the same relative magnitude as an α-blocker, but it will take a longer period of time (months as opposed to weeks). This is likely to be a reduction in 20-30% symptoms and a 1-2ml per second increase in urinary flow[195]. Side-effect profiles of medical treatments are also important, as discussed above. For example, with regard to sexual function, tamsulosin has an increased risk of retrograde ejaculation and finasteride increases sexual dysfunction [83]. These may be important factors in choosing therapies.
Finasteride and Dutasteride
Because 5-α reductase inhibitors work by reducing prostatic tissue volume, baseline prostate size has a significant impact on the efficacy of 5-α reductase inhibitors, with larger glands (>50cc) more likely to respond[189, 190]. After treatment for one year, there is a significant decrease (17-30%) in total gland size with the greatest size reduction in the periurethral component of the prostate (with finasteride), which has the greatest impact on obstructive symptoms [87], [191, 192]. Both transition and peripheral zone volumes are equally affected by dutasteride.[193] There is a 60-70% decrease in DHT concentration , 25% decrease in prostate volume , a 13-30% symptom score reduction vs placebo 4-20% , flow rate improvement of 7-20% vs placebo 3-15%. Furthermore, there were more pronounced changes with larger prostates > 40cc , decreased libido in 10% , ejaculatory dysfunction 7.7% and impotence (15.8%) , they reduced risk of AUR (50%) and the need for surgery (30%).
There is some evidence that patients on finasteride experience fewer serious complications associated with the progression of BPH compared with those prescribed an α blocker, such as acute urinary retention or undergoing BPH-related surgery, but more prospective data is needed[194]. Adverse events associated with finasteride include decreased libido, ejaculation disorders and erectile dysfunction but overall are uncommon, with approximately 4% of patients discontinuing treatment for such events[169, 195]. Finasteride has also developed a role in the treatment of BPH-related haematuria although its role in reduction of perioperative bleeding is not well defined [93, 169].
Table 16. A Brief Summary from Larger Series Comparing Treatment Outcomes.
| Treatment | Evidence |
|---|---|
| MEDICAL | |
| 5 α-reductase inhibitors | |
| Finasteride | 2 point reduction in IPSS vs placebo 0.7 points [93, 178] Qmax improved 1.4ml/sec compared to placebo 0.3 [178] |
| Dutasteride | 5.5 point improvement in AUA-SS [179] |
| α-blockers | |
| Tamsulosin | IPSS reduced by 3 points compared to placebo at 6/12 Qmax improved 1.4ml/sec compared to placebo at 6/12 [180] |
| Terazosin | IPSS reduced 2.2 points over placebo IPSS [128] Qmax improved 1.4 mL/s compared with placebo |
| SURGERY | |
| TURP | Reduction 4.5 points symptom score versus watchful waiting Qmax improved 6 ml/sec versus 0.4 watchful waiting [154] |
| Laser | Noncontact: IPSS improved by 2.5 pointsQmax improved 3.18 ml/sec Contact: IPSS improved 2.9 pointsNd-YAG Qmax improved 1.91 ml/sec164HoLRP Comparable to TURP [164] |
知情同意與無效醫療
知情同意(Informed consent)=告知後同意
- 是臨床上處理醫患關係的基本倫理準則之一，也稱知情承諾原則
- 臨床醫師在為病人作出診斷和治療方案後，必須向病人提供包括診斷結論、治療決策、病情預後及診治費用等方面真實、充分的資訊，尤其是診療方案的性質、作用、依據、損傷、風險、不可預測的意外及其他可供選擇的診療方案及其利弊等資訊，使病人或家屬經深思熟慮自主作出選擇，並以相應方式表達其接受或拒絕此種診療方案的意願和承諾；在得到患方明確承諾後，才可最終確定和實施由其確認的診治方案。
- 需要符合幾個條件
- 前提: 病人及其家屬具有一定的文化基礎和自主決定的能力
- 根本條件: 有賴於醫務人員豐富的專業知識、經驗及高尚的醫德信念和修養。提供資訊的真實性、準確性和充分性，真實、詳細地說明病情資訊，告知預後情況，提供各種實際上可能給予的醫療方案，解釋清楚各種治療方案的可知後果
- 必要條件: 病人與家屬或代理人和經治醫師達成在病人利益和相互價值觀念上的一致性
- 完全知情: 向病人提供他作出承諾必需的所有醫學資訊，即通過完整充分的說明和介紹，對病人有關詢問的必要回答和解釋，使病人全面瞭解診治決策的利與弊，為合理選擇奠定真實可靠的基礎。
- 有效同意: 病人在完全知情後，自主、自願、理性地作出的負責任的承諾。這種承諾需要滿足的條件是：病人具備自由選擇的權利、表達承諾的合法權利、作出正確判斷的充分的理解能力、作出理性選擇的必要的知識水平。應強調病人有權隨時收回、終止和要求改變其承諾
- 緊急情況: 清楚、立即的對生命、身體健康的嚴重威脅存在，若要得到病人的告知後同意將會嚴重損及病人康復之希望；病人有明顯的徵狀，無法有效行使同意權，如中風、休克。
- 病人放棄: 放棄是出於自願。醫師應清楚提醒病人，他有權接受完整的醫療資訊。
- 治療上的特權: 准許醫師在告知病人資訊將直接有害於病人健康的情況下，可以隱瞞該資訊，不必得到病人的告知後同意。如癌症病人之家屬一開始，往往會要求醫師隱瞞病情。
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無效醫療(medical futility)
- 嚴格定義
- 治療缺乏病理生理學依據
- 全面治療下仍然停止心跳
- 使用過該治療但已經失敗
- 寬鬆定義
- 無法達成有價值的治療目標
- 治療成功的機率極低
- 病人生活品質太低
- 預期效益比不上資源耗損
隨著醫藥科技不斷的進步，急重症加護技術的發展，使得重症病患的生命得以延長，愈來愈多的重症病人在生命末期階段進入加護病房接受照護。當疾病邁向不可治癒，死亡已是不可避免時，接下來的醫療處置是在延長病人的「生命」，還是在延長其「死亡的過程」？這些問題幾乎天天在加護病房上演。
西方醫學治療病人的方式基本上就是以治療過程的傷害痛苦換取疾病治癒的更大利益，治療一個業已被疾病徹底擊垮的病患，並不能給他帶來更多好處，但是治療對他造成的痛苦與風險卻只是有增無減，這似乎牴觸從古至今近乎黃金準則的「勿傷害」(Do no harm)原則。
依我國安寧緩和醫療條例第三條中明白定義末期病人為罹患嚴重傷病，經醫師(兩個以上位醫師，其中一位為專科醫師)診斷認為不可治癒，且有醫學上之證據，近期內病程進展進行至死亡已不可避免者
西方醫學之父希波克拉提斯早就說過：「醫師應拒絕治療那些被疾病徹底擊垮的病患。」(refus to treat those who are overmastered by their diseases.)
「醫師應拒絕治療那些被疾病徹底擊垮的病患。」絕不是叫我們放棄病患任其痛苦，至死方休。別忘了，西方醫哲卓度(Trudeau)曾經揭示的重要原則：「我們偶爾能治癒疾病，經常能緩解症狀，永遠都要記的寬慰病患」(to cure sometimes, to relieve often, to comfort always)。
美國醫療協會對無效醫療定義為：治療嚴重病人時，可能只是延長其末期的死亡過程，爾後的處置也是無效的
無效醫療所要探討的絕不是放棄，而是治療方向的調整。對於一個已被疾病徹底擊垮的病患，我們治療的手段是不是應該從侵入性、傷害性的轉換成緩解性的、寬慰性的；我們治療的目的是不是應該從「治癒」、「單純延長生物性生命」轉換成「舒緩」和「維繫生命與軀體的尊嚴」！
整理節錄自
2012年3月19日 星期一
Urinary bladder的nerve innervation
Bladder nerves
Somatic
- Pudental nerves (S2,S3,S4)
- motor & sensory fibres
- External urethral sphincter
Sympathetic
- Hypogastric nerves (L1,L2,L3)
- motor & sensory fibres
- Bladder wall relaxation
- Internal sphincter contraction
Parasympathetic
- Pelvic nerves (S2,S3,S4)
- motor & sensory fibres
- Bladder wall contraction
- Internal sphincter relaxation
Actions of bladder nerves
- Sympathetic postganglionic neurons release noradrenaline (NA)
- activates b3 adrenergic receptors
- relax bladder smooth muscle
- activates a1 adrenergic receptors
- contract urethral smooth muscle (internal sphincter?)
- activates b3 adrenergic receptors
- Parasympathetic postganglionic axons in pelvic nerve release acetylcholine (ACh)
- stimulate M3 muscarinic receptors in the bladder smooth muscle
- bladder contraction
- stimulate M3 muscarinic receptors in the bladder smooth muscle
- Somatic axons in the pudendal nerve release ACh
- activates nicotinic cholinergic receptors (neuromuscular junction)
- contract external sphincter striated muscle
- activates nicotinic cholinergic receptors (neuromuscular junction)
Bladder nerve supply
- Sensory fibers in pelvic nerves sense the degree of stretch in the bladder wall
- Stretch signals from posterior urethra are more powerful in initiating the micturition reflex
- Motor nerves transmitted in the pelvic nerves terminate on ganglion cells located in the wall of the bladder
- postganglionic nerves innervate the detrusor muscle
- Pudendal nerves carry skeletal motor fibers to external sphincter
- Control the voluntary skeletal muscle sphincter
- Sympathetic innervation from the sympathetic chain through the hypogastric nerves
- Sympathetic innervation mainly to blood vessels
- Important in the sensation of fullness/pain
- lower abdomen
- In males – mediate the contraction of the bladder muscle (internal sphincter)
- that prevents semen from entering the bladder during ejaculation
- retrograde ejaculation
Bladder physiology and micturition
Bladder filling & emptying
Bladder filling
- Empty bladder
- 0 - intravesicular pressure
- 30-50 ml urine in bladder
- pressure: 5-10cm of water
- 200-300 ml urine in bladder
- pressure rise minimum
- more than 300ml urine
- rapid increase in pressure
First sensation of bladder filling is experienced at a volume of 100 – 150 ml in an adult. Then the 1st desire to void/urinate is when the bladder contains about 150-250 ml of urine. A person becomes uncomfortably aware of a full bladder when the volume is 350-400 ml. The volume of urine that normally initiates a reflex contraction is about 300-400 ml. An increase in volume to 700 ml creates pain and loss of control!
Cystometrogram
- A plot of intravesical pressure vs volume of fluid in the bladder
- Ia - initial slight rise in pressure
- Ib - long nearly flat segment
- Law of Laplace
- Pressure in a spherical viscus is equal to twice the wall tension divided by the radius
- P = 2T / r
- Due to its ability to stretch, T (Tension) increase will cause r (radius) increase as well, therefore P (pressure) will not increase much.
- This gives us the ability to fill the bladder beyond 300ml
- II - sudden sharp rise in pressure ( micturition reflex triggered)
Micturition Reflex
A single complete cycle of:
- Progressive & rapid increase of pressure
- A period of sustained pressure
- Return of the pressure to the basal tone of the bladder
Receptor
- Sensory stretch receptors in bladder wall
- receptors in the posterior urethra are highly sensitive to stretch when the area begins to fill with urine at the higher bladder pressures
Afferents
- through pelvic nerves
Center
- Spinal cord
- Pons
- Medulla
- Hypothalamus
- Cortex
Efferents
- through pelvic nerves
Effector organ
- Detrusor muscle
- Internal & external sphincters
Micturition Reflex - Process
- Sensory signals from the bladder stretch receptors sent to spinal cord
- Parasympathetic efferent fibers discharge
- produce ‘micturition contractions’
- initially die out immediately, but with increasing pressure in bladder these become stronger & last longer & more frequently
- Reflex will not empty the bladder always
- may become inhibited for a period of few minutes to one hour before another reflex occurs
- ‘self-regenerative’
- Urination occur when
- powerful micturition reflex
- cortical inhibition removed
- relax external sphincter
- relaxation of pelvic floor muscles
- Increase intra-abdominal pressure
- by contracting abdominal muscles
- Relaxation of internal & external sphincters
Higher Centers for Micturition
The higer centers keep the micturition reflex partially inhibited, except when desired/during urination. It can prevent micturition, even if the micturition reflex occurs, by tonic contractions of the external sphincter until it is convenient to urinate. When it is time to urinate, thecortical centers can facilitate the sacral micturition centers to help initiate the external urinary sphincter so that urination can occur.
Cerebral lesions (like tumors, Parkinsons, vascular accident) are known to affect the perception of bladder sensation and can result in voiding dysfunction (loss of control/dribbling)
- Facilitatory areas
- Pons
- Posterior hypothalamus
- Inhibitory areas
- Cerebral cortex
- Midbrain
Micturition in young children
- micturition is purely reflex
- occurs whenever the bladder is sufficiently distended
- myelination not complete
- occurs whenever the bladder is sufficiently distended
- About 2 1/2 years old, it begins to come under cortical control
- About 3 years old, complete control is achieved
- cortex takes over control
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