Epidemiology \200 Incidence has risen steadily since the mid-1970s. Reasons: ageing population, improved cancer registries, improved diagnostic accuracy, incidental cancer his tology of prostate \200\230chips \200\231 at TURP. But, most importantly, the widespread use of PSA testing (and TRUS biopsies) has led to the diagnosis of cancers that would not p reviously have come to clinical attention during a man \200\231 s lifetime. Very rare age <40, uncommon age <50. Common age >80 (found at post-mortem in 80%). 7 1 in 6 \231\202 will develop the disease, and 7 1 in 25 will die from it. \200 Average age at diagnosis 70 \200\223 74, average age at death 80 \200\223 84. \200 A variation in the prevalence of prostate cancer around the world (Europe, USA, and Australia > Asia and North Africa) suggests genetic factors. Black men > white men > Asian men (possibly s to hormonal differences). Familial predisposition also occurs ( 7 5 \200\223 10% cases). Such patients tend to present 7 5 \200\223 10 years earlier. X Other risk factors may have a limited role: obesity, diet (high in animal fat, low in veg etables), and hormones (there appear to be no differences in serum androgen concentrations, but the use of 5 A -reductase inhibitors for BPH reduces prostate cancer incidence overall , albeit with an increase in higher-grade tumors). Genetics \200 There is evidence for a genetic component, but the identi \201 cation of speci \201 c genes has proved dif \201 cult. Risk is increased x 2 in \231\202 with \211 1 affected \201 rst-degree relatives. Risk increases with the number of affected family members, especially if relatives are diagnose d at a young age (<60). There is a high rate of disease concordance in identical twins. \200 Several single nucle otide polymorphisms (e.g. in the 8q24 and 17q regions) are associated with an increased risk (the more SNPs present, the higher the risk) . The presence of BRCA1 and (particularly) BRCA2 mutations appears to increase risk (and worsen prognosis). PROSTATE CANCER: GENERAL 767 Recently, a novel G84E mutation in the transcription factor HOXB13 in the 17q region has be en associated with a signi \201 cantly increased risk of hereditary prostate cancer. Pathology \200 High-grade prostatic intraepithelial neoplasia (PIN) is a precursor of malignancy. It is intermediate between normal prostate epithelium and cancer. 95% adenocarcinomas. 4% have transitional cell morphology (arising from prostatic urethral urothelium). Squamous cell and neuroendocrine tumors are v ery rare. 70% arise in the peripheral, 15 \200\223 20% in the central, and 10 \200\223 15% in the transitional zone. Many cancers are multifocal, involving multiple zones. Local invasion causes spread into the bladder neck (transition zone tumors) and ejaculatory ducts and seminal vesicles (peripheral zone tumors). Capsular penetration, with spread along the perineural or vascular spaces, occurs relatively late. Metastasizes to bone more commonly than any other site, causing sclerotic lesions. The natural history of the disease is extremely variable. Some low-grade tumors follow an indolent course, whilst others rapidly invade and metastasize. Clinical features Prostate cancers are often identi \201 ed in asymptomatic patients, foll owing an abnormal screening PSA level or DRE (or as an incidental pathologic \201 nding a t TURP). Local disease \200 LUTS (often late and more likely to be s to BPE), erectile dysfunction , haematospermia. Urinary retention, back or leg pain, and frank haematuria were more common in the pre-PSA era. Advanced disease \200 Weight loss and anorexia. \200 Anemia. \200 Bone marrow suppres sion. \200 Skeletal pain. \200 Spinal cord compression. \200 Leg swelling and pain s to venous and lymphatic obstruction. \200 Uraemic symptoms from obstructive uropathy. Physical examination \200 DRE: nodules, changes in texture, asymmetry. Obliteration of the lateral sulcus or seminal vesical involvement indicates locally advanced disease. (cid: 2) Many cancers are found in glands that feel normal. Furthermore, an abnormal prostate on DRE should always be investigated, even if the PSA is normal ( 7 20% patients). Distended bladder. \200 Abnormal lower limbs or neurological \201 ndings. CHAPTER 9 Essential urology 768 Prostate cancer: investigation Investigations \200 Urine for M,C+S. \200 PSA ( b p. 772 ). \200 U&E, eGFR, Ca 2+ , alkaline phosphatase (skeletal involvement). \200 Transrecta l ultrasound (TRUS): Used to evaluate abnormalities on DRE and to guide biopsy. \200 Tumors are often, but not universally, hypoechoic. \200 Also permits gland volume measurement. \200 Useful prior to focal therapy (e.g. cryotherapy) and for the detection of seminal vesicle invasion or extracapsular extension. \200 Biopsy is usually necessary, regardless of TRUS appearances, as TRUS alone is not suf \201 ciently sensitive. TRUS-guided biopsy: Indicated for tissue diagnosis in those with i PSA or abnormal DRE. \200 Performed as an ambulatory technique under LA. \200 Extended biopsy protocols, with more extensive sampli ng, is now the norm. These usually involve the removal of at least 10 \200\223 12 cores. Repeat biopsy may be necessary. \200 A transperineal (TP) approach is also commonly used and has the advantage of allowing additional samples to be taken (particularly when a TRUS biopsy has proved inconclusive). Complications: haematospermia (common), haematuria, pain, 1 infection, voiding dif \201 culties, PR bleeding. Imaging: USS pre- and post-micturition (with \202 ow rate) + upper tracts if signi \201 cant BOO or residual bladder volume. \200 Further imaging contributes to pre- treatment staging: Both CT and MRI can detect local tumor invasion and lymphadenopathy. MRI generally provides more accurate T staging. Endorectal MRI, via an endorectal probe, improves spatial resolution of MRI for zonal anatomy, extracapsular extension, and seminal vesicle involveme nt. Pre-biopsy 3-Tesla multiparametric MRI is increasingly used to identify suspicious areas th at can subsequently be targeted for TRUS or TP-biopsy. These scans can also generate a canc er risk score. MR spectroscopy imaging (MRSI), a technique that utilizes metabolite ratios within prostate tissue to distinguish normal from malignant tissue, has a n evolving role. Bone scan: if T3 or T4 disease, PSA >20ng/mL, skeletal symptoms, i Ca 2+ or alkaline phosphatase. Correlate with plain X-rays. Prostascint scan: a radiolabelled mAb to prostate-speci \201 c membrane antigen can locali ze soft tissue metastases. FDG-PET has only limited utility: tracer uptake is variable, and accumulation in the bladde r obscures the area of interest. PROSTATE CANCER: INVESTIGATION 769 Staging \200 Staging guides initial therapy and is undertaken using the TNM system. \200 In addition, histological grade is determined from biopsy specimens, using the Gleason score. Gleason grade is based on the extent to which the epithelium has a normal glandular structu re (1 \200\223 5). Experience and skill on the part of the pathologist is essential. Based on growth pattern and degree of differentiation, tumors are graded from 1 to 5 where grade 1 is the most and grade 5 the least differentiated. Adding together the values for th e two most prevalent patterns of differentiation derives a composite Gleason score, e.g. fo r a biopsy consisting of predominant grade 4 and secondary grade 3 disease, the composite s core is 4 + 3, or 7. 2 \200\223 4 = low-grade or well-differentiated; 5 \200\223 7 = moderate grade or moderately differentiated; 8 \200\223 10 = high-grade or poorly differentiated. \200 In the TNM classi \201 cation, anatomic staging is undertaken both clinically (cT) and pathologically (pT) (see Table 9.12). \200 cT (based on DRE, imaging, and TRUS b iopsy) informs initial treatment decisions but may underestimate disease extent. pT (restaging at prostatectomy) provides a more exact assessment. Table 9.12 The 2010 TNM stage classi \201 cation for prostate cancer T Primary tumor Subdivided a \200\223 c, based upon the extent of gland involvement cT1 Not palpable or visible on imaging (e.g. identi \201 ed at TURP, or on TRUS biopsy perform ed to investigate elevated PSA) cT2 Palpable, con \201 ned to prostate cT3 Extends through capsule. cT4 Fixed to, or invades, adjacent structures pT2 Con \201 ned to prostate Subdivided a \200\223 c, based upon the extent of gland involvement pT3 Extraprostatic extension pT4 Invasion (rectum, pelvic wall, or levator muscles) N Regional nodes Nx Not assessed N0 Negative N1 Distant metastases Positive M M0 No metastases M1 Distant metastases \200\224 subclassi \201 ed, according to location(s) CHAPTER 9 Essential urology 770 Disease-free survival for localized prostate cancer varies widely, as treatment outcomes depend on tumor aggressiveness. With this in mind, the 2010 TNM classi \201 cation uses clinical stage, Gleason score, and PSA to inform \201 ve prognostic groups. Other models have previously been developed to predict higher risk disease. Examples: Memorial Loan-Kettering Cancer Center risk groups (M http://www.msk cc.org/mskcc/html/10088.cfm ) and Partin tables (M http://urology.jhu.edu/prostate/partinta bles.php ). There is also growing interest in molecular prognostic markers, such as p53, E-cadherin, ca thepsin-D, and angiogenesis (microvessel density). Overall, 5-year survival for low-volume, localized disease (often detected through screenin g) is 100% but 7 30% in those with metastases. PROSTATE CANCER: INVESTIGATION 771 CHAPTER 9 Essential urology 772 Prostate cancer: screening Introduction Cancer screening Successful screening requires accurate, acceptable, and cost-effective tes ts that identify clinically relevant cancers at a preclinical stage. Treatments should be a vailable that can improve outcomes when administered early (and not cause harm). Prostate cancer screening rationale Early detection and management of asymptomatic prostate cancer through screening could reduce morbidity and mortality, compared to treatment insti tuted at the time of clinical presentation and diagnosis. Prostate-speci \201 c antigen (PSA) \200 PSA is an epithelial cell glycoprotein that liq ue \201 es semen. \200 Malignant prostate tissue generates more PSA in the blood than no rmal or hyperplastic tissue ( i cellularity + disruption of the prostate: blood barrier). Developed for cancer surveillance, but use as a screening tool grew rapidly: by 2001, 75% a ged >50 in the USA had undergone testing. \200 PSA has doubled the lifetime risk of a dia gnosis of prostate cancer. \200 7 90% of prostate cancers are now detected through PSA sc reening. \200 It is dif \201 cult to de \201 ne a normal range for PSA \200\224 it is a continuum that increases with age >40 ( (cid:2) a \200\230normal \200\231 PSA does not rule out cancer). \200 Nonetheless, 0 \200\223 4.0ng/mL is the generally accepted range (see Box 9.4). A PSA of >4.0ng/mL gives: \200 7 20% sensitivity and 7 90% speci \201 city for prostate cancer. \200 Positive predictive value 7 30% (>50% for PSA levels >10ng/mL), i.e. 7 2/3 of \231\202 with an elevated PSA do not have cancer. \200 If PSA >10ng/mL, <50% tu mors will be prostate-localized. \200 Other causes of an i PSA: BPE, prostatitis, cystiti s, ejaculation (in previous 48h), perineal trauma, vigorous exercise, urinary retention, DRE (minimal effect), prostate biopsy (in previous 6 weeks). Conversely, treatment with 5 A -reductase inhibitors d PSA by 7 50%. Box 9.4 Measures to improve diagnostic utility of PSA \200 Lower PSA cut-off (e.g. <3ng/m L). Involves a trade-off between sensitivity (which improves) and speci \201 city (which deteriorates), i.e. more false pos itives and more unnecessary biopsies. PSA velocity. PSA increases more rapidly in \231\202 with cancer. A rise of >0.75ng/mL/year suggests increased risk. PSA density. Prostate cancers produce more PSA per volume of tissue than benign conditions. Requires TRUS or endorectal MRI to determine prostate volume , so a specialist tool only. Free PSA. PSA exists in a free, as well as bound, form. The ratio of free to total PSA is reduced in men with cancer (<25%). Age- (or race-) speci \201 c reference ranges , for example: Age 50 \200\223 59: 0 \200\223 3.0ng/mL; age 60 \200\223 69: 0 \200\223 4.0ng/mL; age > 70: 0 \200\223 5.0ng/mL. PROSTATE CANCER: SCREENING 773 Potential bene \201 ts \200 May detect prostate cancer before symptoms manifest. \200 May detect early cancer, enabling cure or life-extending treatment. Why the ongoing controversy? Screening is certainly associated with detection of more cance rs, but: \200 PSA testing was introduced without evidence from clinical trials. Although patchy observational data lend support to screening, the two largest randomized co ntrolled studies have proved inconsistent. \200 The European Randomized Study of Screenin g for Prostate Cancer (ERSPC) demonstrated a 20% d in mortality in men aged 55 \200\223 69 after 9 years. It suggested saving one life would require diagnosis and treatment in 48 me n. The United States Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial has found no bene \201 t after 13 years. Neither study is \202 awless \200\224 both have been subjected to criticism. \200 A si gni \201 cant number of tumors detected are clinically indolent, i.e. unlikely to cause clinical illness during a man \200\231 s lifetime. The ideal screening investigation would identify asymptomatic men with aggressive localized tumors. PSA testing falls short of this aspiration, as it cannot differentiate slow-growin g from aggressive cancers. PSA screening has inadequate sensitivity and speci \201 city. \200 Optimal screening int ervals are unclear. \200 PSA testing is not cancer-speci \201 c (also elevated in benign conditions) or diagnostic (it triggers further diagnostic investigation, i.e. biopsy). \200 It is not clear if it should be combined with DRE for initial screening (variably recommended in international guidelines). The optimal treatment for early cancer is unknown \200\224 active surveillance might be as good as radical prostatectomy or radiotherapy. \200 However, the majority with an early- stage cancer (understandably) opt for aggressive treatment. Such (over-) treatment can cause harm. Complications include urinary, sexual, and bowel dys function (as well as anxiety). Guidelines \200 Routine screening is not currently recommended in the UK. Rather, a progr am of informed choice is suggested, i.e. men concerned about prostate cancer should receive clear and balanced information about the pros and cons of PSA testing. In the USA, both the American Cancer Society and American Urological Association advocate screening. However, the in \202 uential Preventative Servi ces Task Force has recently recommended against it. This has refueled an already long runni ng debate in a country where prostate cancer screening costs an estimated $3 billion annual ly. \200 In general, screening, or at least a discussion about screening, is recommended for men aged \211 50 on an annual basis, unless life expectancy is <10 years (through com orbidity or age >75). Discussions should begin age 40 \200\223 45 in black men or those with a family history. CHAPTER 9 Essential urology 774 Prostate cancer: management Overview The overall direction of treatment should be guided by : \200 Life expectancy (as determined by age and comorbidity). \200 Predictions of tumo r aggressiveness. \200 Informed patient choice (see Table 9.13 for risk strati \201 cati on). Localized (prostate-limited) disease Overall 10-year survival is >90%. Treatments include r adical prostatec- tomy, radiation (either brachytherapy or external beam radiotherapy), and active surveillance. If any offers an advantage is controversial. Ongoing clinical trials (e.g. PIVOT, ProtecT) hope to resolve this. Table 9.13 Risk strati \201 cation for localized prostate cancer PSA (ng/mL) Gleason score Clinical stage \211 6 and and Low risk <10 T1 \200\223 T2a or or Intermediate 10 \200\223 20 7 T2b \200\223 T2c or or High risk >20 8 \200\223 10 T3 \200\223 T4 Table 9.14 Management options for localized prostate cancer Low risk Intermediate High risk Watchful waiting Option Option Option Active surveillance Preferred Option Not advocated Prostatectomy Option Preferred Preferred Brachytherapy Option Option Not advocated Radiotherapy Option Preferred Preferred Regular follow-up, including PSA, is mandatory. PSA post-prostatectomy should be <0.2ng/mL and post-radiation <0.5ng/mL. PSA doubling time may also be used as an indicator of the nee d for \200\230salvage \200\231 treatment. Locally advanced (non-prostate-limited) disease Androgen ablation with radiotherapy is gene rally advocated. Prostatectomy may be appropriate in selected cases. Metastatic disease The goals are to control symptoms and slow further progression. Treatment modalities See Table 9.14 for management options. PROSTATE CANCER: MANAGEMENT 775 Watchful waiting Monitoring with hormonal manipulation and palliation when disease pro- gre ssion occurs. Usually reserved for elderly, comorbid patients. Active surveillance De \201 nitive treatment (surgery/radiation) is deferred until evidenc e of progression, with the aim of avoiding unnecessary complications in those whose cancers may not progress. PSA is performed 3 \200\223 6-monthly and DRE annually. Most protocols include repeat biopsy(s). Radical prostatectomy \200 The prostate and seminal vesicles are completely removed. Lymp h node sampling and dissection is often undertaken. Retropubic approach: open or laparoscopic technique, the latter often with robotic assistan ce. Perineal approach: less pain, hidden scar, and shorter hospital stay, but less access t o lymph nodes. Complications: impotence, stricture, urinary and fecal incontinence. \200 X Surgical marg ins and lymph node positivity will determine need for adjuvant radiotherapy or hormone manipulation. Trials ongoing. External beam radiotherapy SE: radiation proctitis, cystitis, and urethritis. Erectile dysf unction. Brachytherapy Transperineal implantation of radioactive seeds. Hormone-based therapy (androgen deprivation) \200 Aims to decrease androgenic tumor stimu lation and 6 delay progression. Bilateral surgical orchidectomy (castration): effective but unpopular. \200 \200\230 Med ical \200\231 castration: Gonadotropin-releasing hormone (GnRH) analogs l d luteinizing hormone (LH) production l d testicular androgen synthesis. Initially, i androgen production , potentially causing disease \200\230 \202 are \200\231 . Examples: leuprolide, goserel in (depot formulations often used). \200 GnRH antagonists l block GnRH receptors without initial \202 are. Example: degarelix. Oestrogens l d hypothalamic GnRH release l d pituitary LH release l d testicular androgens. Example: diethylstilbestrol. \200 Anti-androgens l competitive blockade of androgen rece ptors. Since androgen levels remain normal, side effects (esp. impotence) are fewer (although gyna ecomastia can be problematic). Examples: bicalutamide, \202 utamide. Often used in togeth er with a GnRH analog, either initially (to d androgen \202 are) or continuously (to bloc k 10% contribution of adrenally synthesized androgens). SE: 2 common and require detailed discussion. Sexual dysfunction (majority), hot \202 ush es (majority), fatigue, anemia, muscle wasting, osteoporosis (and fractures), gynaecomastia , d genitalia size, d body hair, psychological changes. CHAPTER 9 Essential urology 776 Intermittent treatment regimens (according to PSA) are often used, with increasing evidence to support this approach. Eventual PSA \200\230escape \200\231 , despite castrate levels of testosterone heralding a deteriorating prognosis. Second-line hormonal treatments, including abiraterone and enzalutamide, signi \201 cantly improve survival and show that the androgen receptor remai ns a relevant therapeutic target despite castrate levels of testosterone. Corticosteroids, e.g. dexamethasone ( l ACTH suppression l d adrenal androgens) have a limited role. Other \200 Chemotherapy (docetaxel, cabazitaxel) reserved for \200\230castration-resistant \200\231 tumors. Several new agents have shown signi \201 cant promise and are either in, or about to enter , clinical practice. These include radioisotopes (alpharadin) and bone-targeting agents, su ch as bisphosphonates (zoledronic acid, mAb directed against RANKL (denosumab), and immunot herapy. 777 Chapter 10 Fluids and electrolytes Sodium: salt and water balance 778 Hyponatraemia \200\224 approach 780 Hyponatraemia \200 \224 assessment 782 Management of hyponatraemia 784 Hyponatraemia with encephalopathy 786 H ypernatraemia 788 Treatment of hypernatraemia 790 Oedema and its treatment 791 Diuretics 79 2 Potassium 794 Hyperkalaemia 796 Hypokalaemia 798 Bartter \200\231s, Gitelman \200\231s an d Liddle \200\231s syndromes 800 Calcium, magnesium, and phosphorus 802 Hypocalcaemia 804 H ypercalcaemia 806 Hypomagnesaemia 808 Hypermagnesaemia 810 Hyperphosphataemia 811 Hypophosp hataemia 812 Acid \200\223 base 814 Excretion: the kidney in acid \200\223 base 818 Metab olic acidosis 820 Renal tubular acidosis 824 Lactic acidosis 828 Alkalosis 830 Mixed distur bances 834 Tubular rarities 836 CHAPTER 10 Fluids and electrolytes 778 Sodium: salt and water balance The human body is made up of 50 \200\223 60% water by weigh t. More accurately, total body water (TBW) in litres can be estimated as weight (kg) x a co r- rection factor, as in Table 10.1. Table 10.1 Estimation of TBW \231\202 \231\200 <65 years old 0.6 0.5 >65 years old 0.5 0.45 So, in a 70kg \231\202 <65 years old, TBW = 0.6 x 70 = 42L. Water is contained in speci \201 c compartments: \200 Intracellular space ( 7 2/3 TBW, or 28L in a 70kg \231\202 ). \200 Extracellular \202 uid is then 7 1/3 TBW, or 14L in a 70kg \231\202 . This includ es: Interstitial \202 uid ( 7 2/3 ECF water, or 9.4L in a 70kg \231\202 ). \200 Plasma ( 7 1/3 ECF water, or 4.6L in a 70kg \231\202 ). The hydrophobic cell membrane acts as a barrier between intra- and extracellular \202 uid , and the capillary wall separates plasma from the interstitium. Every compartment maintain s osmotic pressure through an actively retained speci \201 c solute: \200 Intracellular: K + (pumped inwards by Na + /K + ATPase). \200 ECF: Na + (see next paragraph). \200 Pl asma: proteins (esp. albumin, impermeable through the normal endothelial barrier). Extracellular volume is controlled by Na + retention and excretion (water will passively fo llow salt). The body ignores the ECF as a whole and \200\230 sam- ples \200\231 a portion of it: the effective arterial blood volume (EABV). 1 \200 Amounts to 7 700mL (blood in t he arterial tree at any one time). \200 Is a function of cardiac output (CO) and systemic vascular resistance (SVR). Changes in EABV (due to hypovolaemia, d CO, or d SVR) are sensed by: \200 Systemic barore ceptors (carotid sinus, aortic arch). \200 Intrarenal volume sensors (juxtaglomerular app aratus). With d EABV, these volume sensors activate the sympathetic nervous system, with Na + then r etained by the kidney (often to u-Na + <10mmol/L). Conversely, with i EABV, salt wasting (> 100mmol/L) takes place with appropriate changes in TBW. This requires intact renal salt han dling (and kidney function) for such homeostasis. Low-pressure volume receptors, sited in the atria and the great veins ( NOT contributing to EABV sensing), are also important: i ECF leads to increased atrial natriuretic peptide (AN P) release and renal salt wasting, as well as suppressing sympathetic tone. These receptors may control non-osmotic ADH release if the ECF is under \201 lled. SODIUM: SALT AND WATER BALANCE 779 Falling EABV increases sympathetic tone \200 i circulating catecholamines, leading to i C O and i SVR. \200 Activated renin \200\223 angiotensin system, improving renal haemodyna mics and salt retention through s hyperaldosteronism. i non-osmotic ADH (vasopressin) release. Rising EABV (including low-pressure whole ECF sensing) \200 i ANP (atrial natriuretic pep tide, a potent natriuretic). \200 Suppressed renin production and thus angiotensin and al dosterone. Water handling TBW is mainly regulated by cerebral (circumventricular) and peripheral osmor eceptors ( not volume sensors) capable of sensing changes in ECF osmolality: i osmolality t riggers thirst and pituitary ADH (vasopres- sin) release. Relatively dilute urine arrives a t the collecting duct, as Na + reabsorption in the ascending limb of the loop of Henle occu rs without water (this is the basis for the countercurrent mechanism, leading to a hyperton ic medullary interstitium). Without ADH, this \202 uid is passed, little modi \201 ed, as urine (and polyu- ria of D I ( b p. 789)). ADH binds V 2 (vasopressin) receptors on the basolateral aspect of the prin cipal cells in the collecting duct, leading to translocation of aquaporins to the apical me mbrane where these water channels allow free water absorption along an osmolar gradient int o the hypertonic interstitium. With water loading , osmoreceptors sense a falling osmolality. Thirst and ADH release are s uppressed l dilute urine is formed, rapidly (within 6h) restoring normal osmolality ( 7 285 mOsmol/kg). With water depletion , osmoreceptors sense i osmolality, trigger ADH release, retain water, with (highly) concentrated urine. Increased thirst eventually corrects the absolute water de \201 cit. So, for normal water homeostasis, an individual needs: An intact thirst center. \200 Access to water. \200 The ability to secrete ADH (vasopre ssin). \200 A responsive collecting duct. Abnormalities in one or more of these components l abnormal water homeostasis. Reference 1. Schrier RW (1988). Pathogenesis of sodium and water retention in high-output a nd low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy (1). New Englan d Journal of Medicine , 319 , 1065 \200\22372. CHAPTER 10 Fluids and electrolytes 780 Hyponatraemia \200\224approach The NR for Na + is 135 \200\223 145mmol/L. As with many ele ctrolyte disorders, d Na + is relatively common in hospitalized patients \200\224 this is particularly true for elderly inpatients where up to 6% will have Na + <125. However, even in an apparently healthy elderly (>65) population, 7% of people have Na + <137. The effects of ageing on the kidney may impair free water excretion or, at least, slow the capacity to excrete a water load. This may be further exacerbated by prescribed drugs, such as diureti cs or NSAIDs. Most hyponatraemic patients are thought to be asymptomatic \200\224 but perception and gai t disturbances increase as Na + falls (and improve with correction). Investigators have cor related d Na + with fracture risk and compared the effects of chronic (apparently) asymptom atic hyponatraemia with similar features of alcohol use. 2 In hospital, symptomatic hyponat rae- mia is associated with a mortality of 10 \200\223 50%. As hyponatraemia usually occur s as a result of altered water balance, making the correct clinical assessment of body wate r is then the key to management. Assessment starts with volume status Is the patient clinically: \200 Hypovolaemic? \200 Euvolaemic? \200 Hypervolaemic? Pseudohyponatraemia Pseudohyponatraemia results when Na + is corrected for a falsely large volume, rather than the actual aqueous phase: occurs with i lipids, i plasma proteins ( 2 m yeloma), or hyperglycaemia ( 2 for every 5mmol/L above the normal range for glucose, correc t d by 1.7mmol/L). Glycine- or sorbitol-containing bladder irrigants may also be absorbed, esp. after prostatectomy, falsely d Na + . Causes Hypovolaemic hyponatraemia (depleted ECF where Na + loss > water loss) \200 Renal losses: Diuretics (thiazides, in particular). \200 Osmotic diuresis (glucose, urea in recovering ATN). \200 Salt-wasting nephropathy (due to chronic tubular dysfunction). \200 Addison \200\231s disease. Non-renal losses: Diarrhea or vomiting. \200 Sweating. \200 \200\230 Third space \200\231 losses (burns , bowel obstruction, pancreatitis). 2 Severe volume depletion causes a state of appropriate ADH secre- tion: although initially suppressed as Na + d , hypovolaemia overrides osmoreceptor-induced inhibition and is a pot ent stimulus for ADH release despite the Na + concentration. HYPONATRAEMIA \200\224APPROACH 781 Hypervolaemic hyponatraemia (excess ECF where water retention > Na + retention) \200 CCF. \200 Nephrotic syndrome or CRF. \200 Cirrhosis. Euvolaemic hyponatraemia (with a normal ECF) \200 Syndrome of inappropriate antidiuretic hormone secretion (SIADH): \200 Pneumonia, COPD, TB, other lung diseases (usually with d p O 2 ). \200 Malignancy (usually small cell lung cancer, occasionally head and neck tumors). Drugs (antipsychotics, NSAIDs, antidepressants). \200 Neurological disease (e.g. CVA, tra uma, acute psychosis, tumors). \200 Pain, opiates, stress ( (cid:2) surgery). Hypothyroidism. Reference 2. Renneboog B, Musch W, Vandemergel X, et al . (2006). Mild chronic hyponatremia is associated with falls, unsteadiness, and attention de \201 cits. American Journal of Medicine , 119 , 71e1 \200\223 8. CHAPTER 10 Fluids and electrolytes 782 Hyponatraemia \200\224assessment Symptoms and signs Rare if chronic or Na + >125mmol/L. Com mon if acute or Na + <110mmol/L. Headache, apathy, confusion (esp. in elderly) l seizures a nd coma. Symptoms due to cerebral swelling as osmolality falls: the encephalopathy is exace rbated by d p O 2 of any cause. If i ECF (overloaded) or d ECF (dry), the diagnosis is usually apparent. Investigations 2 Everything depends on good clinical volume assessment. Recheck an abnormal result ( (cid:2) \200\231 drip arm \200\231 Na + in patients on 5% de x- trose infusions). \200 U&E, plasma osmolality (normal/ i if pseudohyponatraemia). \200 d K + and d Mg 2+ potentiate ADH release ( (cid:2) diuretics). \200 Urine osmolality (u-O sm should be <100mOsmol/kg and will be if ADH suppressed (e.g. psychogenic polydipsia)). Urine Na + (if <20mmol/L = non-renal salt losses; if >40mmol/L = SIADH (unless salt intake low)) \200\224 (cid:2) diuretics may confound interpretation of urinary electrolytes. Urine dipstick for SG and protein. \200 TSH and 9 a.m. cortisol if indicated. \200 Ca 2 + , albumin, glucose, LFT. d s-urate is common with SIADH. 2 Consider Addison \200\231s if d Na + , i K + , and volume depletion \200\224 check ran- dom cortisol and ACTH, and, if u nwell, treat with vigorous 0.9% saline replacement and IMI hydrocortisone. Diagnosing SIADH \200 d Na + in patients not on diuretics. \200 Euvolaemic (i.e. no oed ema). \200 Normal renal, adrenal, and thyroid function. \200 Urine osmolality >100mOsmo l/kg, often >300mOsmol/kg. \200 Urine Na + >20mmol/L (unless salt-restricted). \200 Ser um urate may be d as well. 2 ADH may be released inappropriately from the pituitary or from cells of neuroendocrine origin in the lungs. HYPONATRAEMIA \200\224ASSESSMENT 783 Cerebral salt-wasting Brain injury of any cause (SAH, trauma, tumor) l brain natriuretic pe ptide (BNP, 8 ANP; see b p. 778) release, resulting in salt wasting and volume depletion. d ECF l appropriate ADH release and d Na + . Is probably overdiagnosed. Con \201 rm if: Volume-deplete. \200 With volume resuscitation, u-Osm rapidly rises (with ADH suppression). CHAPTER 10 Fluids and electrolytes 784 Management of hyponatraemia In all cases \200 Identify those at most risk for neurologica l complications, and manage those most at risk with repeated review: \200 Acute hyponatraemia (<48 hours). \200 Thi azide-induced d Na + . \200 Premenopausal \231\200 (? estrogen, i responsiveness to ADH) . \200 Malnourished or alcoholic patients. \200 Even if well, i surveillance, as for sy mptomatic patients, with repeated Na + checks (see below). Assess the volume status correctly ( b pp. 12 and 114): the key to correct diagnosis and management. Stop contributing drugs 9 \202 uids ( (cid:2) 5% dextrose). \200 Correct d K + ( b p. 7 98) and d Mg 2+ ( b p. 808), if present. Is the patient symptomatic (encephalopathic) or is Na + <120mmol/L? \200 No: respond acco rding to volume status ( b see below). As a general rule, err on the side of cautious correction (if correction is needed at all). Yes: see b p. 786. Requires action \200\224 urgent if symptomatic. Managing asymptomatic hyponatraemia Hypovolaemic hyponatraemia \200 Resuscitate with 0.9% NaCL (154mmol/L NaCl) at 1 \200\223 3mL/kg/hr. Always correct d K + in concert by adding 20 \200\223 40mmol KCl to each 1L 0.9% NaCl. Euvolaemic hyponatraemia \200 Usually SIADH in hospitals and in the elderly (see b p. 785 ). Hypervolaemic hyponatraemia \200 Manage conservatively \202 uid restriction <1L/day ( 8 5 cups/day), and consider 20 \200\223 40mg furosemide od. MANAGEMENT OF HYPONATRAEMIA 785 Managing asymptomatic SIADH \200 Fluid restrict <800mL/day \200\224 but do not expect th is alone to work. \200 Salt and loop diuretic: PO NaCl as 600mg 4 \200\223 8 tablets dai ly (contains 10mmol/tab Na + , e.g. Slow Sodium ), furosemide 20 \200\223 40mg/daily (f ree water excretion in excess of urinary salt loss). (cid:2) Monitor closely (reserve as an inpatient tool). Demeclocycline 150 \200\223 300mg 6-hourly induces nephrogenic diabetes insipidus, reversing ADH effect. Use with caution in chronic hyponatraemia, as diuresis may be brisk. Gut side effects often limit longer-term use. Urea 30 \200\223 90g/day (not readily available in the UK). An alternative strategy would involve using vaptans : \200 Tolvaptan (oral) and conivapta n (parenteral use for <4 days) are \200\230 aquaretics \200\231 . Serious liver injury has limited use, and evolving data suggests a limited role for these agents. Oral competitive vasopressin (V 2 ) receptor antagonists, blocking the action of ADH on V 2 (and V 1 ) receptors, so preventing tubular water uptake. Cause increased excretion of free water (without electrolyte disturbance) by reducing AQP2 activity in the collecting duct, leaving cells insensitive to ADH and less permeable to water. Demonstrated in phase II and III trials to effectively reverse hyponatraemia in euvolaemic and hypervolaemic states. Expect i Na + 6 \200\223 7mmol/L on tolvapatan 15mg od. \200 (cid:2) Do not \202 uid-r estrict \200\224 allow patients access to free water, and monitor serum Na + regularly. Predominantly studied in chronic hyponatraemia with Na + >120mmol/L. Uncertain: indications for treatment (level of Na? Symptoms?), long-term survival advantage (may d hospital stay), duration of treatment. CHAPTER 10 Fluids and electrolytes 786 Hyponatraemia with encephalopathy X The brain and d Na + The skull limits the brain \200\231s capacity to increase in size: w ith d Na + , a falling osmolality l i intracellular water and symptomatic brain swelling. T he tight junctions between endothelial cells and astrocyte foot processes that constitute t he blood \200\223 brain barrier permit aquaporin-mediated water movement along osmotic gra dients. In response, the cerebral ECF is rapidly reduced (to allow more room) and intracell ular organic sol- utes (including the amino acid taurine) exported (lessens the osmolar gra dient that causes water in \202 ux) over 1 \200\223 2 days. If too rapid correction of chronic d Na + occurs, osmotic or central pontine myelinosis (CP M) may occur. As the brain cannot restore the solute contri- bution to intracellular tonici ty quickly, when the ECF osmolality is rapidly normalized, water leaves cells, causing cere bral dehydration and demyelina- tion (affecting the whole brain, not just the pons, as in t he original descrip- tion). Symptoms become apparent after around 24 hours. Manage in high dependency setting. \200 Na + by as little as 3 \200\223 7mmol/L will usu ally treat symptoms. \200 Repeat Na + every 2 hours initially, and then 4-hourly. IF acute, <48 hours \200\231 duration (often post-operative): \200\223 Aim for i Na + by 2mmol/L/h or until asymptomatic. \200\223 Never correct by >10 mmol/L/24 hours. IF chronic, >48 hours \200\231 duration: \200\223 Always consider CPM . \200\223 Aim for i Na + by 0.5mmol/L/h to i by 6mmol/L or until asymptomatic. \200\223 Aim for +8mmol/L in 24 hours, and do not correct by >10mmol/L/24 hours . Other measures: \200\223 Add in furosemide to prevent volume overload (as 20mg IVI 8-hourly). The diuresis caused will be hypotonic (i.e. water in excess of salt), adding to sodium correction. \200\223 In volume-overloaded patients intolerant of salt loads, 20% mannitol may be useful to allow use of 3% saline. \200\223 Do not correct by >10mmol/L/24 hours. Calculate Na + de \201 cit, and select appropriate mode of administration. Na + de \201 cit = total body water x [desired Na + \200\223 actual Na + ]. \200\223 TBW = 60% body weight in \231\202 and 50% body weight in \231\200 . \200\223 I f age >65, use 50% BW in \231\202 and 45% BW in \231\200 . \200\223 For example, aiming for a safe Na + of 125mmol/L in 53-year-old 70kg \231\202 with Na + 115, de \201 cit = 0. 6 x 70 x 10 = 420mmol Na + . \200 Generally, use 2.7% or 3% (hypertonic) saline, containi ng 462mmol and 513mmol NaCl, respectively, per 1L. Deliver via a central line. \200 Estimate effect of infusion by calculating change in Na + : HYPONATRAEMIA WITH ENCEPHALOPATHY 787 +Na Infusion fluid Na Na TBW + + = Change in Na for 1,000mL infusio nn + 1 For example, in the above patient, using 3% hypertonicsalline 1L over 24hours: \210\222 513 115 + 42 1 + = = Change in Na 9. 25 mmol/ ol/ LL L If a rapid increase were required (e.g. if \201 tting) and a target of >120mmol/L were de sired over 3 hours (see next paragraph), aim to infuse [5/9.25 x 1L] = 540mL of 3% saline a t 180mL/h. X An alternate strategy in \201 tting patients is to give a bolus of 100mL 2.7 % or 3% NaCl, and repeat after 10 minutes. Sodium \200\230 guesstimates \200\231 : for every 1L infused, a crude estimate of the sod ium change in plasma might be: \200 3% NaCl (Na + 513mmol/L) i 13mmol/L. \200 0.9% NaCl (Na + 154mmol/L) i 1.4mmol/L. \200 5% glucose (Na + 0) d 3.5mmol/L. Do not guess if you have time. CHAPTER 10 Fluids and electrolytes 788 Hypernatraemia Serum Na + >146mmol/L is usually due to a water de \201 cit and is associ- ated with severe underlying disease and signi \201 cant mortality ( 9 50%). With i Na + , ECF osmolality i , increasing osmotic drag on the intracellular compartment. This leads to cellular dehydration, most importantly in the brain: loss of volume creates vascular shear stress, resulting in bleeding and thrombosis. As in hyponatraemia ( b p. 780), compensation begins with cellular retention of salts and organic solutes in the brain, increas- ing cel lular tonicity and lessening water losses to the hyperosmolar ECF (occurs over days). Overz ealous correction leads to too rapid intracranial expansion of the brain, with potential te ntorial herniation. Causes include: