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InternalMed_Harrison. FIGURE 7e-2 The effects of testosterone therapy on body composition, muscle strength, bone mineral density, and sexual function in intervention trials. The point estimates and the associated 95% confidence intervals are shown. A. The effects of testos terone therapy on lean body mass, grip strength, and fat mass in a meta-analysis of randomized trials. (Data derived from S Bhasin et al: Nat Clin Pract Endocrinol Metab 2:146, 2006.) B. The effects of testoster analysis of randomized trials. (Data derived from a meta-analysis by MJ Tracz et al: J Clin Endocrinol Metab 91:2011, 2006.) C. The effects of testosterone therapy on measures of sexual function in men with baseline testosterone less than 10 nmol/L (290 ng/dL). (Data derived from a meta-analysis by AM Isidori et al: Clin Endocrinol (Oxf) 63:381, 2005.) (Reproduced with permission from M Spitzer et al: Nat Rev Endocrinol 9:414, 2013.)


InternalMed_Harrison

InternalMed_Harrison. The most commonly used AAS include testosterone esters, nandrolone, stanozolol, methandienone, and methenolone. AAS users generally use increasing doses of multiple steroids in a practice known as stacking.


InternalMed_Harrison

InternalMed_Harrison. The adverse effects of long-term AAS abuse remain poorly understood. Most of the information about the adverse effects of AAS has emerged from case reports, uncontrolled studies, or clinical trials that used replacement doses of testosterone (Table 7e-2). Of note, AAS users may administer 10–100 times the replacement doses of testosterone over many years, making it unjustifiable to extrapolate from trials using replacement doses. A substantial fraction of AAS users also use other drugs that are perceived to be muscle-building or performance-enhancing, such as growth hormone; erythropoiesisstimulating agents; insulin; and stimulants such as amphetamine, clenbuterol, cocaine, ephedrine, and thyroxine; and drugs perceived to reduce adverse effects such as human chorionic gonadotropin, aromatase inhibitors, or estrogen antagonists. The men who abuse AAS are Abbreviation: HPT axis, hypothalamic-pituitary-testicular axis.


InternalMed_Harrison

InternalMed_Harrison. Abbreviation: HPT axis, hypothalamic-pituitary-testicular axis. Source: Modified with permission from HG Pope Jr et al: Adverse health consequences of performance-enhancing drugs: an endocrine society scientific statement. Endocr Rev 35:341, 2014. more likely to engage in other high-risk behaviors than nonusers. The adverse events associated with AAS use may be due to AAS themselves, concomitant use of other drugs, high-risk behaviors, and host characteristics that may render these individuals more susceptible to AAS use or to other high-risk behaviors. The high rates of mortality and morbidities observed in AAS users are alarming. The risk of death among elite powerlifters has been reported to be fivefold greater than in age-matched men from the general population. The causes of death among powerlifters included suicides, myocardial infarction, hepatic coma, and non-Hodgkin’s lymphoma.


InternalMed_Harrison

InternalMed_Harrison. Numerous reports of cardiac death among young AAS users raise concerns about the adverse cardiovascular effects of AAS. High doses of AAS may induce proatherogenic dyslipidemia, increase thrombosis risk via effects on clotting factors and platelets, induce vasospasm through their effects on vascular nitric oxide, and induce myocardial hypertrophy and fibrosis. Replacement doses of testosterone, when administered parenterally, are associated with only a small decrease in high-density lipoprotein (HDL) cholesterol and little or no effect on total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels. In contrast, supraphysiologic doses of testosterone and orally administered, 17-α-alkylated, nonaromatizable AAS are associated with marked reductions in HDL cholesterol and increases in LDL cholesterol.


InternalMed_Harrison

InternalMed_Harrison. Long-term AAS use may be associated with myocardial hypertrophy and fibrosis as well as shortening of QT intervals. AAS use suppresses LH and FSH secretion and inhibits endogenous testosterone production and spermatogenesis. Consequently, stopping AAS may be associated with sexual dysfunction, fatigue, infertility, and depressive symptoms.


InternalMed_Harrison

InternalMed_Harrison. In some AAS users, hypothalamic-pituitary-testicular axis suppres-7e-3 sion may last more than a year, and in a few individuals, complete recovery may not occur. The symptoms of androgen deficiency during AAS withdrawal may cause some men to revert back to using AAS, leading to continued use and AAS dependence. As many as 30% of AAS users develop a syndrome of AAS dependence, characterized by long-term AAS use, despite adverse medical and psychiatric effects. Supraphysiologic doses of testosterone may also impair insulin sensitivity, predisposing to diabetes. Elevated liver enzymes, cholestatic jaundice, hepatic neoplasms, and peliosis hepatis have been reported with oral 17-α-alkylated AAS. AAS use may cause muscle hypertrophy without compensatory adaptations in tendons, ligaments, and joints, thus increasing the risk of tendon and joint injuries. AAS use is associated with acne, baldness, and increased body hair.


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InternalMed_Harrison. Unsafe injection practices, high-risk behaviors, and increased rates of incarceration render AAS users at increased risk of HIV and hepatitis B and C. In one survey, nearly 1 in 10 gay men had injected AAS or other substances, and AAS users were more likely to report high-risk unprotected anal sex than other men. Some AAS users develop hypomanic and manic symptoms during AAS exposure (irritability, aggressiveness, reckless behavior, and occasional psychotic symptoms, sometimes associated with violence) and major depression (sometimes associated with suicidality) during AAS withdrawal. Users may also develop other forms of illicit drug use, which may be potentiated or exacerbated by AAS. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: AAS users generally mistrust physicians and seek medical help infrequently; when they do seek medical help, it is often for the treatment of AAS withdrawal syndrome, infertility, gynecomastia, or other medical or psychiatric complications of AAS use. The suspicion of AAS use should be raised by increased hemoglobin and hematocrit levels; suppressed luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels; low HDL cholesterol; and low testicular volume and sperm density in a person who looks highly muscular (Table 7e-3). A combination of these findings and a self-report of AAS use by the patient, which usually can be elicited by a tactful interview, are often sufficient to establish a diagnosis in clinical practice.


InternalMed_Harrison

InternalMed_Harrison. Accredited laboratories use gas chromatography and mass spectrometry or liquid chromatography and mass spectrometry to detect AAS abuse. In recent years, the availability of high-resolution mass spectrometry and tandem mass spectrometry has further improved the sensitivity of detecting AAS abuse. Illicit testosterone use is most often detected by the urinary testosterone-toepitestosterone ratio and further confirmed by the use of the 13C:12C deteCtion of the use of anaboliC-androgeniC steroids Clinical indicators that should raise suspicion of anabolic-androgenic Detection of anabolic-androgenic steroids LC-MS/MS analysis of urine Detection of exogenous testosterone use Isotope ratio mass spectrometry analysis to detect differences in 13C:12C ratio in exogenous and endogenous testosterone Abbreviations: FSH, follicle-stimulating hormone; LC-MS/MS, liquid chromatography and tandem mass spectrometry; LH, luteinizing hormone.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: FSH, follicle-stimulating hormone; LC-MS/MS, liquid chromatography and tandem mass spectrometry; LH, luteinizing hormone. ratio in testosterone by the use of isotope ratio combustion mass spectrometry. Exogenous testosterone administration increases urinary testosterone glucuronide excretion and, consequently, the testosterone-to-epitestosterone ratio. Ratios above 4 suggest exogenous testosterone use but can also reflect genetic variation. Genetic variations in the uridine diphosphoglucuronyl transferase 2B17 (UGT2B17), the major enzyme for testosterone glucuronidation, affect the testosterone-to-epitestosterone ratio. Synthetic testosterone has a lower 13C:12C ratio than endogenously produced testosterone, and these differences can be detected by isotope ratio combustion mass spectrometry.


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InternalMed_Harrison. The nonathlete weightlifters who abuse AAS rarely seek medical treatment and do not typically view these drugs and the associated lifestyle as deleterious to their health. In turn, many internists erroneously view AAS abuse as largely a problem of cheating in competitive sports, whereas, in fact, most AAS users are not athletes. Also, physicians often have a poor understanding of the factors motivating the use of these performance-enhancing drugs, the long-term health effects of AAS, and the associated psychopathologies that may affect treatment choices.


InternalMed_Harrison

InternalMed_Harrison. In addition to treating the underlying body dysmorphia disorder that motivates the use of these drugs, the treatment should be directed at the symptoms or the condition for which the patient seeks therapy, such as infertility, sexual dysfunction, gynecomastia, or depressive symptoms. Accordingly, therapy may include some combination of cognitive and behavioral therapy for the muscle dysmorphia syndrome, antidepressant therapy for depression, selective phosphodiesterase-5 inhibitors for erectile dysfunction, selective estrogen receptor modulators or aromatase inhibitors to reactivate the hypothalamic-pituitary-testicular axis, or hCG to restore testosterone levels. Clomiphene citrate, a partial estrogen receptor agonist, administered in a dose of 25–50 mg on alternate days, can increase LH and FSH levels and restore testosterone levels in a vast majority of men with AAS withdrawal syndrome. However, the recovery of sexual function during clomiphene administration is variable despite


InternalMed_Harrison

InternalMed_Harrison. LH and FSH levels and restore testosterone levels in a vast majority of men with AAS withdrawal syndrome. However, the recovery of sexual function during clomiphene administration is variable despite improvements in testosterone levels. Anecdotally, other aromatase inhibitors, such as anastrozole, have also been used. hCG, administered by intramuscular injections of 750–1500 IU three times each week, can raise testosterone levels into the normal range. Some patients may not respond to either clomiphene or hCG therapy, raising the possibility of irreversible long-term toxic effects of AAS on Leydig cell function.


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InternalMed_Harrison. Lower urinary tract symptoms (LUTS) in men include storage symptoms (urgency, daytime and nighttime frequency, and urgency incontinence), voiding disturbances (slow or intermittent stream, difficulty in initiating micturition, straining to void, pain or discomfort during the passage of urine, and terminal dribbling), or postmicturition symptoms (a sense of incomplete voiding after passing urine and postmicturition dribble). The overactive bladder syndrome refers to urgency with or without urgency incontinence, usually with urinary frequency and nocturia, and is often due to detrusor muscle overactivity. LUTS have historically been attributed to benign prostatic hyperplasia, although it has become apparent that the pathophysiologic mechanisms of LUTS are complex and multifactorial and may include structural or functional abnormalities of the bladder, bladder neck, prostate, distal sphincter mechanism, and urethra, as well as abnormalities in the neural control to the lower urinary


InternalMed_Harrison

InternalMed_Harrison. may include structural or functional abnormalities of the bladder, bladder neck, prostate, distal sphincter mechanism, and urethra, as well as abnormalities in the neural control to the lower urinary tract. A presumptive diagnosis of benign prostatic hyperplasia should be made only in men with LUTS who have demonstrable evidence of prostate enlargement and obstruction based on the size of the prostate. Diuretics, antihistamines, antidepressants, and other medications that have anticholinergic properties can cause or exacerbate LUTS in older men. The intensity of LUTS symptoms tends to fluctuate over time.


InternalMed_Harrison

InternalMed_Harrison. LUTS is highly prevalent in older men, affecting nearly 50% of men over the age of 65 and 70% of men over the age of 80. LUTS adversely affects quality of life because of its impact on sleep, ability to perform activities of daily living, and depressive symptoms. LUTS is often associated with erectile dysfunction. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: Medical evaluation should include assessment of the symptom severity using the International Prostate Symptom Score and, in some patients, a frequency-volume chart. The impact of LUTS on sleep and activities of daily living and quality of life should be evaluated. Evaluation should also include verification of medications that may contribute to LUTS, digital prostate examination, neurologic examination focused on perineum and lower extremities, urinalysis, fasting blood glucose, electrolytes, creatinine, and prostate-specific antigen (PSA). Urodynamic studies are not required in most patients but are recommended when invasive surgical therapies are being considered.


InternalMed_Harrison

InternalMed_Harrison. Men who have mild symptoms can be reassured and followed. Men with mild to moderate LUTS can be treated effectively using α-adrenergic antagonists, phosphodiesterase-5 (PDE5) inhibitors, steroid 5α-reductase inhibitors, or anticholinergic agents alone or in combination. Selective α-adrenergic antagonists are typically the first line of therapy. In men with probable benign prostate obstruction with gland enlargement and LUTS, therapy using a steroid 5a-reductase inhibitor, such as finasteride or dutasteride, for 1 or more years improves urinary symptoms and flow rate and reduces prostatic volume. Long-term treatment with 5α-reductase inhibitors can reduce progression to acute urinary retention and need for prostate surgery. Combined administration of a steroid 5α-reductase inhibitor and α1-adrenergic blocker can rapidly improve urinary symptoms and reduce the relative risk of acute urinary retention and surgery. PDE5 inhibitors, when administered chronically alone or in combination


InternalMed_Harrison

InternalMed_Harrison. α1-adrenergic blocker can rapidly improve urinary symptoms and reduce the relative risk of acute urinary retention and surgery. PDE5 inhibitors, when administered chronically alone or in combination with α-adrenergic blockers, are effective in improving LUTS and erectile dysfunction through their effects on nitric oxide– cyclic guanosine monophosphate (cGMP) in the bladder, urethra, and prostate. PDE5 inhibitors do not improve urinary flow parameters. Anticholinergic drugs are used for the treatment of overactive bladder in men with prominent urgency symptoms and no evidence of elevated postvoid residual urine. Surgery is indicated when medical therapy fails or if symptoms progress despite medical therapy.


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InternalMed_Harrison. Prostate cancer is the most common malignancy in American men, accounting for 29% of all diagnosed cancers and approximately 13% of all cancer deaths; its incidence is on the rise, partly due to increased screening with PSA. In 2013, approximately 233,000 new cases of prostate cancer were diagnosed in the United States and there were 29,480 deaths related to prostate cancer. The majority of these men have low-grade, organ-confined prostate cancer and excellent prospects of long-term survival. Substantial improvement in survival in men with prostate cancer has focused attention on the high prevalence of sexual dysfunction, physical dysfunction, and low vitality, which are important contributors to poor quality of life among patients treated for prostate cancer. The pathophysiology of these symptoms after radical prostatectomy is multifactorial, but denervation and androgen deficiency are important contributors to these symptoms.


InternalMed_Harrison

InternalMed_Harrison. Androgen deficiency is common in men with prostate cancer. Testosterone levels decline with age, and men with prostate cancer are at risk of having low testosterone levels simply by virtue of their age.


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InternalMed_Harrison. However, total and free testosterone levels are even lower in men with prostate cancer, who have undergone prostatectomy, when compared with age-matched controls without cancer. Androgen deficiency in men with prostate cancer is associated with distressing symptoms such as fatigue, sexual dysfunction, hot flushes, mobility limitation, and decreased physical function. Even with a bilateral nerve-sparing procedure, more than 50% of men develop sexual dysfunction after surgery. Although there is some recovery of sexual function with passage of time, 40–50% of men undergoing radical prostatectomy find their sexual performance to be problematic 18 months after surgery. Sexual performance problems are a source of psychosocial distress in men with localized prostate cancer. In addition to its causal contribution to distressing symptoms, androgen deficiency in men with prostate cancer increases the risk of bone fractures, diabetes, coronary heart disease, and frailty.


InternalMed_Harrison

InternalMed_Harrison. Testosterone Therapy in Men with History of Prostate Cancer A history of prostate cancer has historically been considered a contraindication for testosterone therapy. This guidance is based on observations that testosterone promotes the growth of metastatic prostate cancer. Metastatic prostate cancer generally regresses after orchidectomy and androgen deprivation therapy. Androgen receptor signaling plays a central role in maintaining growth of normal prostate and prostate cancer. PSA levels are lower in hypogonadal men and increase after testosterone therapy. Prostate volume is lower in hypogonadal men and increases after testosterone therapy to levels seen in age-matched controls.


InternalMed_Harrison

InternalMed_Harrison. However, the role of testosterone in prostate cancer is complex. Epidemiologic studies have not revealed a consistent relationship between serum testosterone and prostate cancer. In a landmark randomized trial, testosterone therapy of older men with low testosterone did not affect intraprostatic androgen levels or the expression of androgen-dependent prostatic genes. The suppression of circulating testosterone levels by a gonadotropin-releasing hormone (GnRH) antagonist also does not affect intraprostatic androgen concentrations. Open-label trials and retrospective analyses of testosterone therapy in men with prostate cancer, who have undergone radical prostatectomy 7e-5 and have undetectable PSA levels after radical prostatectomy, have found very low rates of PSA recurrence. Even in men with high-grade prostatic intraepithelial neoplasia (HGPIN)—a group at high risk of developing prostate cancer—testosterone therapy for 1 year did not increase PSA or rates of prostate cancer.


InternalMed_Harrison

InternalMed_Harrison. After radical prostatectomy, in the absence of residual cancer, PSA becomes undetectable within a month. An undetectable PSA after radical prostatectomy is a good indicator of biochemical recurrence-free survival at 5 years. Therefore, men with organ-confined prostate cancer (pT2), Gleason score ≤6, and a preoperative PSA of <10 ng/mL, who have had undetectable PSA levels (<0.1 ng/mL) for >2 years after radical prostatectomy, have very low risk of disease recurrence (<0.5% at 10 years) and may be considered for testosterone therapy on an individualized basis. If testosterone therapy is instituted, it should be associated with careful monitoring of PSA levels and done in consultation with a urologist.


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InternalMed_Harrison. In patients with prostate cancer and distant metastases, androgen deprivation therapy (ADT) improves survival. In patients with locally advanced disease, ADT in combination with external-beam radiation or as an adjuvant therapy (after prostatectomy and pelvic lymphadenectomy) also has been shown to improve survival. However, ADT is being increasingly used as primary therapy in men with localized disease and in men encountering biochemical recurrence without clear evidence of survival advantage. Because most men with prostate cancer die of conditions other than their primary malignancy, recognition and management of these adverse effects is paramount.


InternalMed_Harrison

InternalMed_Harrison. Profound hypogonadism resulting from ADT is associated with sexual dysfunction, vasomotor symptoms, gynecomastia, decreased muscle mass and strength, frailty, increased fat mass, anemia, fatigue, bone loss, loss of body hair, depressive symptoms, and reduced quality of life. Diabetes and cardiovascular disease have recently been added to the list of these complications (Fig. 7e-3). Treatment with GnRH Any fracture (1.54) Shahinian et al. 2005, NEJM Fracture requiring hospitalization (1.66) Diabetes (1.44) Keating et al. 2006, JCO Myocardial infarction (1.11) Peripheral vascular disease (1.16) Keating et al. 2006, JCO Coronary heart disease (1.16) Hu et al. 2012, Eur Urol Sudden death (1.16)


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InternalMed_Harrison. Keating et al. 2006, JCO Myocardial infarction (1.11) Peripheral vascular disease (1.16) Keating et al. 2006, JCO Coronary heart disease (1.16) Hu et al. 2012, Eur Urol Sudden death (1.16) FIGURE 7e-3 Adverse cardiometabolic and skeletal effects of androgen deprivation therapy (ADT) in men receiving ADT for prostate cancer. Administration of ADT has been associated with increased risk of thromboembolic events, fractures, and diabetes. Some, but not all, studies have reported increased risk of cardiovascular events in men receiving ADT. (Data on relative risk were derived from VB Shahinian et al: N Engl J Med 352:154, 2005; NL Keating et al: J Clin Oncol 24:4448, 2006; and JC Hu et al: Eur Urol 61:1119, 2012.) 1. Weigh the risks and benefits of ADT and whether intermittent ADT is a feasible and safe option. 2. Perform a baseline assessment including fasting glucose, plasma lipids, blood pressure, bone mineral density, and FRAX® score.


InternalMed_Harrison

InternalMed_Harrison. 2. Perform a baseline assessment including fasting glucose, plasma lipids, blood pressure, bone mineral density, and FRAX® score. 3. Optimize calcium and vitamin D intake, encourage structured physical activity and exercise, and consider pharmacologic therapy in men with a previous minimal trauma fracture and those with a 10-year risk of a major osteoporotic fracture >20%, unless contraindicated. 4. Monitor body weight, fasting glucose, plasma lipids, blood pressure, and bone mineral density, and encourage smoking cessation and physical activity. 5. In men who are receiving ADT and who experience bothersome hot flushes, as indicated by sleep disturbance or interference with work or activities of daily living, consider initial therapy with venlafaxine. If in effective, add medroxyprogesterone acetate. 6. In men who experience painful breast enlargement, consider therapy with an estrogen receptor antagonist, such as tamoxifen.


InternalMed_Harrison

InternalMed_Harrison. 6. In men who experience painful breast enlargement, consider therapy with an estrogen receptor antagonist, such as tamoxifen. agonists in men with prostate cancer is associated with rapid induction of insulin resistance, hyperinsulinemia, and a significant increase in the risk of incident diabetes. Metabolic syndrome is prevalent in over 50% of men undergoing long-term ADT. Some but not all studies have reported an increased risk of cardiovascular events, death due to cardiovascular events, and peripheral vascular disease in men undergoing ADT. Men receiving ADT are also at increased risk of thromboembolic events. The rates of acute kidney injury are higher in men currently receiving ADT than in men not receiving ADT; the increased risk appears to be particularly associated with the use of combined regimens of a GnRH agonist plus an antiandrogen. ADT also is associated with substantially increased risk of osteoporosis and bone fractures. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. The benefits of ADT in treating nonmetastatic prostate cancer should be carefully weighed against the risks of ADT-induced adverse events (Table 7e-4). If ADT is medically indicated, consider whether intermittent ADT is a feasible option. Men being considered for ADT should undergo assessment of cardiovascular, diabetes, and fracture risk; this assessment may include measurement of blood glucose, plasma lipids, and bone mineral density (BMD) by dual-energy x-ray absorptiometry. Institute measures to prevent bone loss, including physical activity, adequate calcium and vitamin D intake, and pharmacologic therapy in men with a previous minimal trauma fracture and those with a 10-year risk of a major osteoporotic fracture >20%, unless contraindicated. Men with prostate cancer who are receiving ADT should be monitored for weight gain and diabetes. Encourage lifestyle interventions, including physical activity and exercise, and attention to weight, blood pressure, lipid profile, blood


InternalMed_Harrison

InternalMed_Harrison. ADT should be monitored for weight gain and diabetes. Encourage lifestyle interventions, including physical activity and exercise, and attention to weight, blood pressure, lipid profile, blood glucose, and smoking cessation, to reduce the risk of cardiometabolic complications. In randomized trials, medroxyprogesterone, cyproterone acetate, and the selective serotonin reuptake inhibitor venlafaxine have been shown to be more efficacious than placebo in alleviating hot flushes. The side effects of these medications, including increased appetite and weight gain with medroxyprogesterone, gynecomastia with estrogenic compounds, and dry mouth with venlafaxine, should be weighed against their relative efficacy. Acupuncture, soy products, vitamin E, and herbal medicines have been used empirically for the treatment of vasomotor symptoms without clear evidence of efficacy. Gynecomastia can be prevented by local radiation therapy or the use of an antiestrogen or an aromatase inhibitor; these


InternalMed_Harrison

InternalMed_Harrison. for the treatment of vasomotor symptoms without clear evidence of efficacy. Gynecomastia can be prevented by local radiation therapy or the use of an antiestrogen or an aromatase inhibitor; these therapies are effective in alleviating pain and tenderness but are less effective in reducing established gynecomastia.


InternalMed_Harrison

InternalMed_Harrison. Chapter 8 Medical Disorders During Pregnancy Medical disorders during pregnancy Robert L. Barbieri, John T. Repke Each year, approximately 4 million births occur in the United States, and more than 130 million births occur worldwide. A significant 8 proportion of births are complicated by medical disorders. In the past, many medical disorders were contraindications to pregnancy. Advances in obstetrics, neonatology, obstetric anesthesiology, and medicine have increased the expectation that pregnancy will result in a positive outcome for both mother and fetus despite most of these conditions. A successful pregnancy requires important physiologic adaptations, such as a marked increase in cardiac output. Medical problems that interfere with the physiologic adaptations of pregnancy increase the risk for poor pregnancy outcome; conversely, in some instances, pregnancy may adversely impact an underlying medical disorder.


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InternalMed_Harrison. (See also Chap. 298) In pregnancy, cardiac output increases by 40%, with most of the increase due to an increase in stroke volume. Heart rate increases by ~10 beats/min during the third trimester. In the second trimester, systemic vascular resistance decreases, and this decline is associated with a fall in blood pressure. During pregnancy, a blood pressure of 140/90 mmHg is considered to be abnormally elevated and is associated with an increase in perinatal morbidity and mortality. In all pregnant women, the measurement of blood pressure should be performed in the sitting position, because the lateral recumbent position may result in a blood pressure lower than that recorded in the sitting position. The diagnosis of hypertension requires the measurement of two elevated blood pressures at least 6 h apart. Hypertension during pregnancy is usually caused by preeclampsia, chronic hypertension, gestational hypertension, or renal disease.


InternalMed_Harrison

InternalMed_Harrison. Approximately 5–7% of all pregnant women develop preeclampsia, the new onset of hypertension (blood pressure >140/90 mmHg) and proteinuria (either a 24 hour urinary protein >300 mg/24 h, or a protein-creatinine ratio ≥0.3) after 20 weeks of gestation. Although the precise pathophysiology of preeclampsia remains unknown, recent studies show excessive placental production of antagonists to both vascular epithelial growth factor (VEGF) and transforming growth factor β (TGF-β). These antagonists to VEGF and TGF-β disrupt endothelial and renal glomerular function resulting in edema, hypertension, and proteinuria. The renal histological feature of preeclampsia is glomerular endotheliosis. Glomerular endothelial cells are swollen and encroach on the vascular lumen. Preeclampsia is associated with abnormalities of cerebral circulatory autoregulation, which increase the risk of stroke at mildly and moderately elevated blood pressures. Risk factors for the development of preeclampsia include


InternalMed_Harrison

InternalMed_Harrison. abnormalities of cerebral circulatory autoregulation, which increase the risk of stroke at mildly and moderately elevated blood pressures. Risk factors for the development of preeclampsia include nulliparity, diabetes mellitus, a history of renal disease or chronic hypertension, a prior history of preeclampsia, extremes of maternal age (>35 years or <15 years), obesity, antiphospholipid antibody syndrome, and multiple gestation. Low-dose aspirin (81 mg daily, initiated at the end of the first trimester) may reduce the risk of preeclampsia in pregnant women at high risk of developing the disease.


InternalMed_Harrison

InternalMed_Harrison. In December, 2013 The American College of Obstetricians and Gynecologists issued a report summarizing the findings and recommendations of their Task Force on Hypertension in Pregnancy. With respect to preeclampsia several pertinent revisions to the diagnostic criteria were made including: proteinuria is no longer an absolute requirement for making the diagnosis; the terms mild and severe preeclampsia have been replaced, and the disease is now termed preeclampsia either with or without severe features; removal of fetal growth restriction as a defining criterion for severe preeclampsia.


InternalMed_Harrison

InternalMed_Harrison. Preeclampsia with severe features is the presence of new-onset hypertension and proteinuria accompanied by end-organ damage. Features may include severe elevation of blood pressure (>160/110 mmHg), evidence of central nervous system (CNS) dysfunction (headaches, blurred vision, seizures, coma), renal dysfunction (oliguria or creatinine >1.5 mg/dL), pulmonary edema, hepatocellular injury (serum alanine aminotransferase level more than twofold the upper limit of normal), hematologic dysfunction (platelet count <100,000/L or disseminated intravascular coagulation [DIC]). The HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) is a special subtype of severe preeclampsia and is a major cause of morbidity and mortality in this disease. Platelet dysfunction and coagulation disorders further increase the risk of stroke.


InternalMed_Harrison

InternalMed_Harrison. Preeclampsia resolves within a few weeks after delivery. For pregnant women with preeclampsia prior to 37 weeks of gestation, delivery reduces the mother’s morbidity but exposes the fetus to the risk of premature birth. The management of preeclampsia is challenging because it requires the clinician to balance the health of the mother and fetus simultaneously. In general, prior to term, women with mild preeclampsia without severe features may be managed conservatively with limited physical activity, although bed rest is not recommended, close monitoring of blood pressure and renal function, and careful fetal surveillance. For women with preeclampsia with severe features, delivery is recommended unless the patient is eligible for expectant management in a tertiary hospital setting. Expectant management of preeclampsia with severe features remote from term affords some benefits for the fetus but significant risks for the mother.


InternalMed_Harrison

InternalMed_Harrison. The definitive treatment of preeclampsia is delivery of the fetus and placenta. For women with preeclampsia with severe features, aggressive management of blood pressures >160/110 mmHg reduces the risk of cerebrovascular accidents. IV labetalol or hydralazine is most commonly used to acutely manage severe hypertension in preeclampsia; labetalol is associated with fewer episodes of maternal hypotension. Oral nifedipine and labetalol are commonly used to manage hypertension in pregnancy. Elevated arterial pressure should be reduced slowly to avoid hypotension and a decrease in blood flow to the fetus. Angiotensin-converting enzyme (ACE) inhibitors as well as angiotensin-receptor blockers should be avoided in the second and third trimesters of pregnancy because of their adverse effects on fetal development.


InternalMed_Harrison

InternalMed_Harrison. Magnesium sulfate is the preferred agent for the prevention and treatment of eclamptic seizures. Large, randomized clinical trials have demonstrated the superiority of magnesium sulfate over phenytoin and diazepam in reducing the risk of seizure and, possibly, the risk of maternal death. Magnesium may prevent seizures by interacting with N-methyl-D-aspartate (NMDA) receptors in the CNS. Given the difficulty of predicting eclamptic seizures on the basis of disease severity, once the decision to proceed with delivery is made, most patients carrying a diagnosis of preeclampsia should be treated with magnesium sulfate. Women who have had preeclampsia appear to be at increased risk of cardiovascular and renal disease later in life. Pregnancy complicated by chronic essential hypertension is associated with intrauterine growth restriction and increased perinatal mortality.


InternalMed_Harrison

InternalMed_Harrison. Pregnant women with chronic hypertension are at increased risk for superimposed preeclampsia and abruptio placentae. Women with chronic hypertension should have a thorough prepregnancy evaluation, both to identify remediable causes of hypertension and to ensure that the prescribed antihypertensive agents (e.g., ACE inhibitors, angiotensin-receptor blockers) are not associated with an adverse outcome of pregnancy. α-Methyldopa, labetalol, and nifedipine are the most commonly used medications for the treatment of chronic hypertension in pregnancy. The target blood pressure is in the range of 130–150 mmHg systolic and 80–100 mmHg diastolic. Should hypertension worsen during pregnancy, baseline evaluation of renal function (see below) is necessary to help differentiate the effects of chronic hypertension from those of superimposed preeclampsia. There are no convincing data that the treatment of mild chronic hypertension improves perinatal outcome.


InternalMed_Harrison

InternalMed_Harrison. The development of elevated blood pressure during pregnancy or in the first 24 h post-partum in the absence of preexisting chronic hypertension or proteinuria is referred to as gestational hypertension. Mild gestational hypertension that does not progress to preeclampsia has not been associated with adverse pregnancy outcome or adverse long-term prognosis.


InternalMed_Harrison

InternalMed_Harrison. (See also Chaps. 333 and 341) Normal pregnancy is characterized by an increase in glomerular filtration rate and creatinine clearance. This increase occurs secondary to a rise in renal plasma flow and increased glomerular filtration pressures. Patients with underlying renal disease and hypertension may expect a worsening of hypertension during pregnancy. If superimposed preeclampsia develops, the additional endothelial injury results in a capillary leak syndrome that may make management challenging. In general, patients with underlying renal disease and hypertension benefit from aggressive management of blood pressure. Preconception counseling is also essential for these patients so that accurate risk assessment and medication changes can occur prior to pregnancy. In general, a prepregnancy serum creatinine level <133 μmol/L (<1.5 mg/dL) is associated with a favorable prognosis. When renal disease worsens during pregnancy, close collaboration between the internist and the


InternalMed_Harrison

InternalMed_Harrison. a prepregnancy serum creatinine level <133 μmol/L (<1.5 mg/dL) is associated with a favorable prognosis. When renal disease worsens during pregnancy, close collaboration between the internist and the maternal-fetal medicine specialist is essential so that decisions regarding delivery can be weighed to balance the sequelae of prematurity for the neonate versus long-term sequelae for the mother with respect to future renal function.


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InternalMed_Harrison. (See also Chaps. 283–286) Valvular heart disease is the most common cardiac problem complicating pregnancy.


InternalMed_Harrison

InternalMed_Harrison. Mitral Stenosis This is the valvular disease most likely to cause death during pregnancy. The pregnancy-induced increase in blood volume, cardiac output, and tachycardia can increase the transmitral pressure gradient and cause pulmonary edema in women with mitral stenosis. Women with moderate to severe mitral stenosis who are planning pregnancy and have either symptomatic disease or pulmonary hypertension should undergo valvuloplasty prior to conception. Pregnancy associated with long-standing mitral stenosis may result in pulmonary hypertension. Sudden death has been reported when hypovolemia occurs. Careful control of heart rate, especially during labor and delivery, minimizes the impact of tachycardia and reduced ventricular filling times on cardiac function. Pregnant women with mitral stenosis are at increased risk for the development of atrial fibrillation and other tachyarrhythmias. Medical management of severe mitral stenosis and atrial fibrillation with digoxin and beta


InternalMed_Harrison

InternalMed_Harrison. mitral stenosis are at increased risk for the development of atrial fibrillation and other tachyarrhythmias. Medical management of severe mitral stenosis and atrial fibrillation with digoxin and beta blockers is recommended. Balloon valvulotomy can be carried out during pregnancy. The immediate postpartum period is a time of particular concern secondary to rapid volume shifts. Careful monitoring of cardiac and fluid status should be observed.


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InternalMed_Harrison. Mitral Regurgitation and Aortic Regurgitation and Stenosis The pregnancy-induced decrease in systemic vascular resistance reduces the risk of cardiac failure with these conditions. As a rule, mitral valve prolapse does not present problems for the pregnant patient, and aortic stenosis, unless very severe, is well tolerated. In the most severe cases of aortic stenosis, limitation of activity or balloon valvuloplasty may be indicated.


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InternalMed_Harrison. (See also Chap. 282) Reparative surgery has markedly increased the number of women with surgically repaired congenital heart disease. Maternal morbidity and mortality are greater among these women than among those without surgical repairs. When pregnant, these patients should be jointly managed by a cardiologist and an obstetrician familiar with these problems. The presence of a congenital cardiac lesion in the mother increases the risk of congenital cardiac disease in the newborn. Prenatal screening of the fetus for congenital cardiac disease with ultrasound is recommended. Atrial or ventricular septal defect is usually well tolerated during pregnancy in the absence of pulmonary hypertension, provided that the woman’s prepregnancy cardiac status is favorable. Use of air filters on IV sets during labor and delivery in patients with intracardiac shunts is recommended.


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InternalMed_Harrison. Supraventricular tachycardia (Chap. 276) is a common cardiac complication of pregnancy. Treatment is the same as in the nonpregnant patient, and fetal tolerance of medications such as adenosine and calcium channel blockers is acceptable. When necessary, pharmacologic or electric cardioversion may be performed to improve cardiac performance and reduce symptoms. This intervention is generally well tolerated by mother and fetus. Peripartum cardiomyopathy (Chap. 287) is an uncommon disorder of pregnancy associated with myocarditis, and its etiology remains unknown. Treatment is directed toward symptomatic relief and improvement of cardiac function. Many patients recover completely; others are left with progressive dilated cardiomyopathy. Recurrence in a subsequent pregnancy has been reported, and women who do not have normal baseline left-ventricular function after an episode of peripartum cardiomyopathy should be counseled to avoid pregnancy.


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InternalMed_Harrison. SPECIFIC HIgH-RISK CARdIAC LESIoNS Marfan Syndrome (See also Chap. 427) This autosomal dominant disease is associated with a high risk of maternal morbidity. Approximately 15% of pregnant women with Marfan syndrome develop a major cardiovascular manifestation during pregnancy, with almost all women surviving. An aortic root diameter <40 mm is associated with a favorable outcome of pregnancy. Prophylactic therapy with beta blockers has been advocated, although large-scale clinical trials in pregnancy have not been performed. Ehlers-Danlos syndrome (EDS) may be associated with premature labor, and in type IV EDS there is increased risk of organ or vascular rupture that may cause death.


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InternalMed_Harrison. Pulmonary Hypertension (See also Chap. 304) Maternal mortality in the setting of severe pulmonary hypertension is high, and primary pulmonary hypertension is a contraindication to pregnancy. Termination of pregnancy may be advisable in these circumstances to preserve the life of the mother. In the Eisenmenger syndrome, i.e., the combination of pulmonary hypertension with right-to-left shunting due to congenital abnormalities (Chap. 282), maternal and fetal deaths occur frequently. Systemic hypotension may occur after blood loss, prolonged Valsalva maneuver, or regional anesthesia; sudden death secondary to hypotension is a dreaded complication. Management of these patients is challenging, and invasive hemodynamic monitoring during labor and delivery is recommended in severe cases. In patients with pulmonary hypertension, vaginal delivery is less stressful hemodynamically than cesarean section, which should be reserved for accepted obstetric indications.


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InternalMed_Harrison. (See also Chap. 300) A hypercoagulable state is characteristic of pregnancy, and deep venous thrombosis (DVT) occurs in about 1 in 500 pregnancies. In pregnant women, most unilateral DVTs occur in the left leg because the left iliac vein is compressed by the right iliac artery and the uterus compresses the inferior vena cava. Pregnancy is associated with an increase in procoagulants such as factors V and VII and a decrease in anticoagulant activity, including proteins C and S. Pulmonary embolism is one of the most common causes of maternal death in the United States. Activated protein C resistance caused by the factor V Leiden mutation increases the risk for DVT and pulmonary embolism during pregnancy. Approximately 25% of women with DVT during pregnancy carry the factor V Leiden allele. Additional genetic mutations associated with DVT during pregnancy include the prothrombin G20210A mutation (heterozygotes and homozygotes) and the methylenetetrahydrofolate reductase C677T mutation


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InternalMed_Harrison. Additional genetic mutations associated with DVT during pregnancy include the prothrombin G20210A mutation (heterozygotes and homozygotes) and the methylenetetrahydrofolate reductase C677T mutation (homozygotes).


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InternalMed_Harrison. Aggressive diagnosis and management of DVT and suspected pulmonary embolism optimize the outcome for mother and fetus. In general, all diagnostic and therapeutic modalities afforded the non-pregnant patient should be utilized in pregnancy except for D-dimer measurement, in which values are elevated in normal pregnancy. Anticoagulant therapy with low-molecular-weight heparin (LMWH) or unfractionated heparin is indicated in pregnant women with DVT. LMWH may be associated with an increased risk of epidural hematoma in women receiving an epidural anesthetic in labor. Four weeks prior to anticipated delivery, LMWH should be switched to unfractionated heparin. Warfarin therapy is contraindicated in the first trimester due to its association with fetal chondrodysplasia punctata. In the second and third trimesters, warfarin may cause fetal optic atrophy and mental retardation. When DVT occurs in the postpartum period, LMWH therapy for 7–10 days may be followed by warfarin therapy for 3–6


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InternalMed_Harrison. and third trimesters, warfarin may cause fetal optic atrophy and mental retardation. When DVT occurs in the postpartum period, LMWH therapy for 7–10 days may be followed by warfarin therapy for 3–6 months. Warfarin is not contraindicated in breast-feeding women. For women at moderate or high risk of DVT who have a cesarean delivery, mechanical and/or pharmacologic prophylaxis is warranted.


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InternalMed_Harrison. (See also Chaps. 417–419) In pregnancy, the fetoplacental unit induces major metabolic changes, the purpose of which is to shunt glucose and amino acids to the fetus while the mother uses ketones and triglycerides to fuel her metabolic needs. These metabolic changes are accompanied by maternal insulin resistance caused in part by placental production of steroids, a growth hormone variant, and placental lactogen. Although pregnancy has been referred to as a state of “accelerated starvation,” it is better characterized as “accelerated ketosis.” In pregnancy, after an overnight fast, plasma glucose is lower by 0.8–1.1 mmol/L (15–20 mg/dL) than in the nonpregnant state. This difference is due to the use of glucose by the fetus. In early pregnancy, fasting may result in circulating glucose concentrations in the range of 2.2 mmol/L (40 mg/dL) and may be associated with symptoms of hypoglycemia. In contrast to the decrease in maternal glucose concentration, plasma hydroxybutyrate and


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InternalMed_Harrison. concentrations in the range of 2.2 mmol/L (40 mg/dL) and may be associated with symptoms of hypoglycemia. In contrast to the decrease in maternal glucose concentration, plasma hydroxybutyrate and acetoacetate levels rise to two to four times normal after a fast.


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InternalMed_Harrison. Pregnancy complicated by diabetes mellitus is associated with higher maternal and perinatal morbidity and mortality rates. Preconception counseling and treatment are important for the diabetic patient contemplating pregnancy and can reduce the risk of congenital malformations and improve pregnancy outcome. Folate supplementation reduces the incidence of fetal neural tube defects, which occur with greater frequency in fetuses of diabetic mothers. In addition, optimizing glucose control during key periods of organogenesis reduces other congenital anomalies, including sacral agenesis, caudal dysplasia, renal agenesis, and ventricular septal defect.


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InternalMed_Harrison. Once pregnancy is established, glucose control should be managed more aggressively than in the nonpregnant state. In addition to dietary changes, this enhanced management requires more frequent blood glucose monitoring and often involves additional injections of insulin or conversion to an insulin pump. Fasting blood glucose levels should be maintained at <5.8 mmol/L (<105 mg/dL), with avoidance of values >7.8 mmol/L (140 mg/dL). Commencing in the third trimester, regular surveillance of maternal glucose control as well as assessment of fetal growth (obstetric sonography) and fetoplacental oxygenation (fetal heart rate monitoring or biophysical profile) optimize pregnancy outcome. Pregnant diabetic patients without vascular disease are at greater risk for delivering a macrosomic fetus, and attention to fetal growth via clinical and ultrasound examination is important. Fetal macrosomia is associated with an increased risk of maternal and fetal birth trauma, including permanent newborn


InternalMed_Harrison

InternalMed_Harrison. attention to fetal growth via clinical and ultrasound examination is important. Fetal macrosomia is associated with an increased risk of maternal and fetal birth trauma, including permanent newborn Erb’s palsy. Pregnant women with diabetes have an increased risk of developing preeclampsia, and those with vascular disease are at greater risk for developing intrauterine growth restriction, which is associated with an increased risk of fetal and neonatal death. Excellent pregnancy outcomes in patients with diabetic nephropathy and proliferative retinopathy have been reported with aggressive glucose control and intensive maternal and fetal surveillance.


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InternalMed_Harrison. As pregnancy progresses, glycemic control may become more difficult to achieve due to an increase in insulin resistance. Because of delayed pulmonary maturation of the fetuses of diabetic mothers, early delivery should be avoided unless there is biochemical evidence of fetal lung maturity. In general, efforts to control glucose and avoid preterm delivery result in the best overall outcome for both mother and newborn. Preterm delivery is generally performed only for the usual obstetric indications (e.g., preeclampsia, fetal growth restriction, non-reassuring fetal testing) or for worsening maternal renal or active proliferative retinopathy.


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InternalMed_Harrison. Gestational diabetes occurs in approximately 4% of pregnancies. All pregnant women should be screened for gestational diabetes unless they are in a low-risk group. Women at low risk for gestational diabetes are those <25 years of age; those with a body mass index <25 kg/m2, no maternal history of macrosomia or gestational diabetes, and no diabetes in a first-degree relative; and those who are not members of a high-risk ethnic group (African American, Hispanic, Native American). A typical two-step strategy for establishing the diagnosis of gestational diabetes involves administration of a 50-g oral glucose challenge with a single serum glucose measurement at 60 min. If the plasma glucose is <7.8 mmol/L (<130 mg/dL), the test is considered normal. Plasma glucose >7.8 mmol/L (>130 mg/dL) warrants administration of a 100-g oral glucose challenge with plasma glucose measurements obtained in the fasting state and at 1, 2, and 3 h. Normal plasma glucose concentrations at these time points


InternalMed_Harrison

InternalMed_Harrison. administration of a 100-g oral glucose challenge with plasma glucose measurements obtained in the fasting state and at 1, 2, and 3 h. Normal plasma glucose concentrations at these time points are <5.8 mmol/L (<105 mg/dL), 10.5 mmol/L (190 mg/dL), 9.1 mmol/L (165 mg/dL), and 8.0 mmol/L (145 mg/dL), respectively. Some centers have adopted more sensitive criteria, using values of <5.3 mmol/L (<95 mg/dL), <10 mmol/L (<180 mg/dL), <8.6 mmol/L (<155 mg/dL), and <7.8 mmol/L (<140 mg/dL) as the upper norms for a 3-h glucose tolerance test. Two elevated glucose values indicate a positive test. Adverse pregnancy outcomes for mother and fetus appear to increase with glucose as a continuous variable; thus it is challenging to define the optimal threshold for establishing the diagnosis of gestational diabetes.


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InternalMed_Harrison. Pregnant women with gestational diabetes are at increased risk of stillbirth, preeclampsia, and delivery of infants who are large for their gestational age, with resulting birth lacerations, shoulder dystocia, and birth trauma including brachial plexus injury. These fetuses are at risk of hypoglycemia, hyperbilirubinemia, and polycythemia. Tight control of blood sugar during pregnancy and labor can reduce these risks.


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InternalMed_Harrison. Treatment of gestational diabetes with a two-step strategy—dietary intervention followed by insulin injections if diet alone does not adequately control blood sugar [fasting glucose <5.6 mmol/L (<100 mg/dL) and 2-h postprandial glucose <7.0 mmol/L (<126 mg/dL)]— is associated with a decreased risk of birth trauma for the fetus. Oral hypoglycemic agents such as glyburide and metformin have become more commonly utilized for managing gestational diabetes refractory to nutritional management, but many experts favor insulin therapy. For women with gestational diabetes, there is a 40% risk of being diagnosed with diabetes within the 10 years after the index pregnancy. In women with a history of gestational diabetes, exercise, weight loss, and treatment with metformin reduce the risk of developing diabetes. All women with a history of gestational diabetes should be counseled about prevention strategies and evaluated regularly for diabetes.


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InternalMed_Harrison. (See also Chap. 416) Pregnant women who are obese have an increased risk of stillbirth, congenital fetal malformations, gestational diabetes, preeclampsia, urinary tract infections, post-date delivery, and cesarean delivery. Women contemplating pregnancy should attempt to attain a healthy weight prior to conception. For morbidly obese women who have not been able to lose weight with lifestyle changes, bariatric surgery may result in weight loss and improve pregnancy outcomes. Following bariatric surgery, women should delay conception for 1 year to avoid pregnancy during an interval of rapid metabolic changes. (See also Chap. 405) In pregnancy, the estrogen-induced increase in thyroxine-binding globulin increases circulating levels of total T3 and total T4. The normal range of circulating levels of free T4, free T3, and thyroid-stimulating hormone (TSH) remain unaltered by pregnancy.


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InternalMed_Harrison. The thyroid gland normally enlarges during pregnancy. Many physiologic adaptations to pregnancy may mimic subtle signs of hyperthyroidism. Maternal hyperthyroidism occurs at a rate of ~2 per 1000 pregnancies and is generally well tolerated by pregnant women. Clinical signs and symptoms should alert the physician to the occurrence of this condition. Hyperthyroidism in pregnancy is most commonly caused by Graves’ disease, but autonomously functioning nodules and gestational trophoblastic disease should also be considered. Although pregnant women are able to tolerate mild hyperthyroidism without adverse sequelae, more severe hyperthyroidism can cause spontaneous abortion or premature labor, and thyroid storm is associated with a significant risk of maternal death.


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InternalMed_Harrison. Testing for hypothyroidism using TSH measurements before or early in pregnancy may be warranted in symptomatic women and in women with a personal or family history of thyroid disease. With use of this case-finding approach, about 30% of pregnant women with mild hypothyroidism remain undiagnosed, leading some to recommend universal screening. Children born to women with an elevated serum TSH (and a normal total thyroxine) during pregnancy may have impaired performance on neuropsychologic tests.


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InternalMed_Harrison. Methimazole crosses the placenta to a greater degree than propylthiouracil and has been associated with fetal aplasia cutis. However, propylthiouracil can be associated with liver failure. Some experts recommend propylthiouracil in the first trimester and methimazole thereafter. Radioiodine should not be used during pregnancy, either for scanning or for treatment, because of effects on the fetal thyroid. In emergent circumstances, additional treatment with beta blockers may be necessary. Hyperthyroidism is most difficult to control in the first trimester of pregnancy and easiest to control in the third trimester.


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InternalMed_Harrison. The goal of therapy for hypothyroidism is to maintain the serum TSH in the normal range, and thyroxine is the drug of choice. During pregnancy, the dose of thyroxine required to keep the TSH in the normal range rises. In one study, the mean replacement dose of thyroxine required to maintain the TSH in the normal range was 0.1 mg daily before pregnancy and increased to 0.15 mg daily during pregnancy. Since the increased thyroxine requirement occurs as early as the fifth week of pregnancy, one approach is to increase the thyroxine dose by 30% (two additional pills weekly) as soon as pregnancy is diagnosed and then adjust the dose by serial measurements of TSH. Pregnancy has been described as a state of physiologic anemia. Part of the reduction in hemoglobin concentration is dilutional, but iron and folate deficiencies are major causes of correctable anemia during pregnancy.


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InternalMed_Harrison. In populations at high risk for hemoglobinopathies (Chap. 127), hemoglobin electrophoresis should be performed as part of the prenatal screen. Hemoglobinopathies can be associated with increased maternal and fetal morbidity and mortality. Management is tailored to the specific hemoglobinopathy and is generally the same for both pregnant and nonpregnant women. Prenatal diagnosis of hemoglobinopathies in the fetus is readily available and should be discussed with prospective parents either prior to or early in pregnancy.


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InternalMed_Harrison. Thrombocytopenia occurs commonly during pregnancy. The majority of cases are benign gestational thrombocytopenias, but the differential diagnosis should include immune thrombocytopenia (Chap. 140), thrombotic thrombocytopenic purpura, and preeclampsia. Maternal thrombocytopenia may also be caused by DIC, which is a consumptive coagulopathy characterized by thrombocytopenia, prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), elevated fibrin degradation products, and a low fibrinogen concentration. Several catastrophic obstetric events are associated with the development of DIC, including retention of a dead fetus, sepsis, abruptio placentae, and amniotic fluid embolism.


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InternalMed_Harrison. Headache appearing during pregnancy is usually due to migraine (Chap. 21), a condition that may worsen, improve, or be unaffected by pregnancy. A new or worsening headache, particularly if associated with visual blurring, may signal eclampsia (above) or pseudotumor cerebri (benign intracranial hypertension); diplopia due to a sixth-nerve palsy suggests pseudotumor cerebri (Chap. 39). The risk of seizures in patients with epilepsy increases in the postpartum period but not consistently during pregnancy; management is discussed in Chap. 445. The risk of stroke is generally thought to increase during pregnancy because of a hypercoagulable state; however, studies suggest that the period of risk occurs primarily in the postpartum period and that both ischemic and hemorrhagic strokes may occur at this time. Guidelines for use of heparin therapy are summarized above (see “Deep Venous Thrombosis and Pulmonary Embolism”); warfarin is teratogenic and should be avoided.


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InternalMed_Harrison. The onset of a new movement disorder during pregnancy suggests chorea gravidarum, a variant of Sydenham’s chorea associated with rheumatic fever and streptococcal infection (Chap. 381); the chorea may recur with subsequent pregnancies. Patients with preexisting multiple sclerosis (Chap. 458) experience a gradual decrease in the risk of relapses as pregnancy progresses and, conversely, an increase in attack risk during the postpartum period. Disease-modifying agents, including interferon β, should not be administered to pregnant multiple sclerosis patients, but moderate or severe relapses can be safely treated with pulse glucocorticoid therapy. Finally, certain tumors, particularly pituitary adenoma and meningioma (Chap. 403), may manifest during pregnancy because of accelerated growth, possibly driven by hormonal factors.


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InternalMed_Harrison. Peripheral nerve disorders associated with pregnancy include Bell’s palsy (idiopathic facial paralysis) (Chap. 459), which is approximately threefold more likely to occur during the third trimester and immediate postpartum period than in the general population. Therapy with glucocorticoids should follow the guidelines established for non-pregnant patients. Entrapment neuropathies are common in the later stages of pregnancy, presumably as a result of fluid retention. Carpal tunnel syndrome (median nerve) presents first as pain and paresthesia in the hand (often worse at night) and later with weakness in the thenar muscles. Treatment is generally conservative; wrist splints may be helpful, and glucocorticoid injections or surgical section of the carpal tunnel can usually be postponed. Meralgia paresthetica (lateral femoral cutaneous nerve entrapment) consists of pain and numbness in the lateral aspect of the thigh without weakness. Patients are usually reassured to learn that these


InternalMed_Harrison

InternalMed_Harrison. paresthetica (lateral femoral cutaneous nerve entrapment) consists of pain and numbness in the lateral aspect of the thigh without weakness. Patients are usually reassured to learn that these symptoms are benign and can be expected to remit spontaneously after the pregnancy has been completed. Restless leg syndrome is the most common peripheral nerve and movement disorder in pregnancy. Disordered iron metabolism is the suspected etiology. Management is expectant in most cases.


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InternalMed_Harrison. Up to 90% of pregnant women experience nausea and vomiting during the first trimester of pregnancy. Hyperemesis gravidarum is a severe form that prevents adequate fluid and nutritional intake and may require hospitalization to prevent dehydration and malnutrition. Crohn’s disease may be associated with exacerbations in the second and third trimesters. Ulcerative colitis is associated with disease exacerbations in the first trimester and during the early postpartum period. Medical management of these diseases during pregnancy is similar to management in the nonpregnant state (Chap. 351).


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InternalMed_Harrison. Exacerbation of gallbladder disease is common during pregnancy. In part, this aggravation may be due to pregnancy-induced alteration in the metabolism of bile and fatty acids. Intrahepatic cholestasis of pregnancy is generally a third-trimester event. Profound pruritus may accompany this condition, and it may be associated with increased fetal mortality. Placental bile salt deposition may contribute to progressive uteroplacental insufficiency. Therefore, regular fetal surveillance should be undertaken once the diagnosis of intrahepatic cholestasis is made, and delivery should be planned once the fetus reaches about 37 weeks of gestation. Favorable results with ursodiol have been reported.


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InternalMed_Harrison. Acute fatty liver is a rare complication of pregnancy. Frequently confused with the HELLP syndrome (see “Preeclampsia” above) and severe preeclampsia, the diagnosis of acute fatty liver of pregnancy may be facilitated by imaging studies and laboratory evaluation. Acute fatty liver of pregnancy is generally characterized by markedly increased serum levels of bilirubin and ammonia and by hypoglycemia. Management of acute fatty liver of pregnancy is supportive; recurrence in subsequent pregnancies has been reported. All pregnant women should be screened for hepatitis B. This information is important for pediatricians after delivery of the infant. All infants receive hepatitis B vaccine. Infants born to mothers who are carriers of hepatitis B surface antigen should also receive hepatitis B immune globulin as soon after birth as possible and preferably within the first 72 h. Screening for hepatitis C is recommended for individuals at high risk for exposure.


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InternalMed_Harrison. Other than bacterial vaginosis, the most common bacterial infections during pregnancy involve the urinary tract (Chap. 162). Many pregnant women have asymptomatic bacteriuria, most likely due to stasis caused by progestational effects on ureteral and bladder smooth muscle and later in pregnancy due to compression effects of the enlarging uterus. In itself, this condition is not associated with an adverse outcome of pregnancy. However, if asymptomatic bacteriuria is left untreated, symptomatic pyelonephritis may occur. Indeed, ~75% of pregnancy-associated pyelonephritis cases are the result of untreated asymptomatic bacteriuria. All pregnant women should be screened with a urine culture for asymptomatic bacteriuria at the first prenatal visit. Subsequent screening with nitrite/leukocyte esterase strips is indicated for high-risk women, such as those with sickle cell trait or a history of urinary tract infections. All women with positive screens should be treated. Pregnant women who


InternalMed_Harrison

InternalMed_Harrison. esterase strips is indicated for high-risk women, such as those with sickle cell trait or a history of urinary tract infections. All women with positive screens should be treated. Pregnant women who develop pyelonephritis need careful monitoring, including inpatient IV antibiotic administration due to the elevated risk of urosepsis and acute respiratory distress syndrome in pregnancy.


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InternalMed_Harrison. Abdominal pain and fever during pregnancy create a clinical dilemma. The diagnosis of greatest concern is intrauterine amniotic infection. While amniotic infection most commonly follows rupture of the membranes, this is not always the case. In general, antibiotic therapy is not recommended as a temporizing measure in these circumstances. If intrauterine infection is suspected, induced delivery with concomitant antibiotic therapy is generally indicated. Intrauterine amniotic infection is most often caused by pathogens such as Escherichia coli and group B Streptococcus (GBS). In high-risk patients at term or in preterm patients, routine intrapartum prophylaxis of GBS disease is recommended. Penicillin G and ampicillin are the drugs of choice. In penicillin-allergic patients with a low risk of anaphylaxis, cefazolin is recommended. If the patient is at high risk of anaphylaxis, vancomycin is recommended. If the organism is known to be sensitive to clindamycin, this antibiotic may be


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InternalMed_Harrison. of anaphylaxis, cefazolin is recommended. If the patient is at high risk of anaphylaxis, vancomycin is recommended. If the organism is known to be sensitive to clindamycin, this antibiotic may be used. For the reduction of neonatal morbidity due to GBS, universal screening of pregnant women for GBS between 35 and 37 weeks of gestation, with intrapartum antibiotic treatment of infected women, is recommended.


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InternalMed_Harrison. Postpartum infection is a significant cause of maternal morbidity and mortality. Postpartum endomyometritis is more common after cesarean delivery than vaginal delivery and develops in 2% of women after elective repeat cesarean section and in up to 10% after emergency cesarean section following prolonged labor. To reduce the risk of endomyometritis, prophylactic antibiotics should be given to all patients undergoing cesarean section, and administration 30–60 min prior to skin incision is preferable to administration at the time of umbilical cord clamping. As most cases of postpartum endomyometritis are polymicrobial, broad-spectrum antibiotic coverage with a penicillin, an aminoglycoside, and metronidazole is recommended (Chap. 201). Most cases resolve within 72 h. Women who do not respond to antibiotic treatment for postpartum endomyometritis should be evaluated for septic pelvic thrombophlebitis. Imaging studies may be helpful in establishing the diagnosis, which is primarily a


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InternalMed_Harrison. to antibiotic treatment for postpartum endomyometritis should be evaluated for septic pelvic thrombophlebitis. Imaging studies may be helpful in establishing the diagnosis, which is primarily a clinical diagnosis of exclusion. Patients with septic pelvic thrombophlebitis generally have tachycardia out of proportion to their fever and respond rapidly to IV administration of heparin.


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InternalMed_Harrison. All pregnant patients are screened prenatally for gonorrhea and chlamydial infections, and the detection of either should result in prompt treatment. Ceftriaxone and azithromycin are the agents of choice (Chaps. 181 and 213). VIRAL INFECTIoNS Influenza (See also Chap. 224) Pregnant women with influenza are at increased risk of serious complications and death. All women who are pregnant or plan to become pregnant in the near future should receive inactivated influenza vaccine. The prompt initiation of antiviral treatment is recommended for pregnant women in whom influenza is suspected. Treatment can be reconsidered once the results of high-sensitivity tests are available. Prompt initiation of treatment lowers the risk of admission to an intensive care unit and death.


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InternalMed_Harrison. Cytomegalovirus Infection The most common cause of congenital viral infection in the United States is cytomegalovirus (CMV) (Chap. 219). As many as 50–90% of women of childbearing age have antibodies to CMV, but only rarely does CMV reactivation result in neonatal infection. More commonly, primary CMV infection during pregnancy creates a risk of congenital CMV. No currently accepted treatment of CMV infection during pregnancy has been demonstrated to protect the fetus effectively. Moreover, it is difficult to predict which fetus will sustain a life-threatening CMV infection. Severe CMV disease in the newborn is characterized most often by petechiae, hepatosplenomegaly, and jaundice. Chorioretinitis, microcephaly, intracranial calcifications, hepatitis, hemolytic anemia, and purpura may also develop. CNS involvement, resulting in the development of psychomotor, ocular, auditory, and dental abnormalities over time, has been described.


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InternalMed_Harrison. Rubella (See also Chap. 230e) Rubella virus is a known teratogen; first-trimester rubella carries a high risk of fetal anomalies, though the risk significantly decreases later in pregnancy. Congenital rubella may be diagnosed by percutaneous umbilical-blood sampling with the detection of IgM antibodies in fetal blood. All pregnant women and all women of childbearing age should be tested for their immune status to rubella. All nonpregnant women who are not immune to rubella should be vaccinated. The incidence of congenital rubella in the United States is extremely low.


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InternalMed_Harrison. Herpesvirus Infection (See also Chap. 216) The acquisition of genital herpes during pregnancy is associated with spontaneous abortion, prematurity, and congenital and neonatal herpes. A cohort study of pregnant women without evidence of previous herpesvirus infection demonstrated that ~2% acquired a new herpesvirus infection during the pregnancy. Approximately 60% of the newly infected women had no clinical symptoms. Infection occurred with equal frequency in all three trimesters. If herpesvirus seroconversion occurred early in pregnancy, the risk of transmission to the newborn was very low. In women who acquired genital herpes shortly before delivery, the risk of transmission was high. The risk of active genital herpes lesions at term can be reduced by prescribing acyclovir for the last 4 weeks of pregnancy to women who have had their first episode of genital herpes during the pregnancy.


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InternalMed_Harrison. Herpesvirus infection in the newborn can be devastating. Disseminated neonatal herpes carries with it high mortality and morbidity rates from CNS involvement. It is recommended that pregnant women with active genital herpes lesions at the time of presentation in labor be delivered by cesarean section. Parvovirus Infection (See also Chap. 221) Parvovirus infection (caused by human parvovirus B19) may occur during pregnancy. It rarely causes sequelae, but susceptible women infected during pregnancy may be at risk for fetal hydrops secondary to erythroid aplasia and profound anemia.


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InternalMed_Harrison. HIV Infection (See also Chap. 226) The predominant cause of HIV infection in children is transmission of the virus from mother to newborn during the perinatal period. All pregnant women should be screened for HIV infection. Factors that increase the risk of mother-to-newborn transmission include high maternal viral load, low maternal CD4+ T cell count, prolonged labor, prolonged duration of membrane rupture, and the presence of other genital tract infections, such as syphilis or herpes. Prior to the widespread use of antiretroviral treatment, the perinatal transmission rate was in the range of 20%. In women with a good response to antiretroviral treatment, the transmission rate is about 1%. Measurement of maternal plasma HIV RNA copy number guides the decision for vaginal versus cesarean delivery. For women with <1000 copies of plasma HIV RNA/ml who are receiving combination antiretroviral therapy, the risk of transmission to the newborn is approximately 1% regardless of mode of


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InternalMed_Harrison. delivery. For women with <1000 copies of plasma HIV RNA/ml who are receiving combination antiretroviral therapy, the risk of transmission to the newborn is approximately 1% regardless of mode of delivery or duration of membrane rupture. These women may elect to attempt a vaginal birth following the spontaneous onset of labor. For women with a viral load of ≥1000 copies/ml prior to 38 weeks of gestation, a scheduled prelabor cesarean at 38 weeks is recommended to reduce the risk of HIV transmission to the newborn. To reduce the risk of mother-to-newborn transmission, women with >400 copies of HIV RNA/ml should be treated during the intrapartum interval with zidovudine. All newborns of HIV-infected mothers should be treated with zidovudine for 6 months after birth. Women who are HIV-positive may transmit the virus through their breast milk. In developed countries, HIV-infected mothers are advised not to breast-feed.


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InternalMed_Harrison. (See also Chap. 148) For rubella-nonimmune individuals contemplating pregnancy, measles-mumps-rubella vaccine should be administered, ideally at least 3 months prior to conception but otherwise in the immediate postpartum period. In addition, pregnancy is not a contraindication for vaccination against influenza, tetanus, diphtheria, and pertussis (Tdap), and these vaccines are recommended for appropriate individuals.


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InternalMed_Harrison. Maternal death is defined as death occurring during pregnancy or within 42 days of completion of pregnancy from a cause related to or aggravated by pregnancy, but not due to accident or incidental causes. From 1935 to 2007, the U.S. maternal death rate decreased from nearly 600/100,000 births to 12.7/100,000 births. There are significant health disparities in the maternal mortality rate, with the highest rates among non-Hispanic black women. In 2007, maternal mortality rates (per 100,000) by race were 10.5 among non-Hispanic white women, 8.9 among Hispanic women, and 28.4 among non-Hispanic black women. The most common causes of maternal death in the United States today are pulmonary embolism, obstetric hemorrhage, hypertension, sepsis, cardiovascular conditions (including peripartum cardiomyopathy), and ectopic pregnancy. As stated above, the maternal mortality rate in the United States is about 12.7/100,00 births. In some countries in sub-


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InternalMed_Harrison. As stated above, the maternal mortality rate in the United States is about 12.7/100,00 births. In some countries in sub- Saharan Africa and southern Asia, the maternal mortality rate is about 500/100,000 live births. The most common cause of maternal death in these countries is maternal hemorrhage. The high maternal death rates are due in part to inadequate contraceptive and family-planning services, an insufficient number of skilled birth attendants, and difficulty in accessing birthing centers and emergency obstetrical care units. Maternal death is a global public-health tragedy that could be mitigated with the application of modest resources.


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InternalMed_Harrison. With improved diagnostic and therapeutic modalities as well as advances in the treatment of infertility, more patients with medical complications will be seeking and will require complex obstetric care. Improved outcomes of pregnancy in these women will be best attained by a team of internists, maternal-fetal medicine (high-risk obstetrics) specialists, and anesthesiologists assembled to counsel these patients about the risks of pregnancy and to plan their treatment prior to conception. The importance of preconception counseling cannot be overstated. It is the responsibility of all physicians caring for women in the reproductive age group to assess their patients’ reproductive plans as part of their overall health evaluation. 9 Medical evaluation of the surgical patient Wei C. Lau, Kim A. Eagle


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InternalMed_Harrison. Medical evaluation of the surgical patient Wei C. Lau, Kim A. Eagle Cardiovascular and pulmonary complications continue to account for major morbidity and mortality in patients undergoing noncardiac surgery. Emerging evidence-based practices dictate that the internist should perform an individualized evaluation of the surgical patient to provide an accurate preoperative risk assessment and stratification that will guide optimal perioperative risk-reduction strategies. This chapter reviews cardiovascular and pulmonary preoperative risk assessment, targeting intermediateand high-risk patients with the goal of improving outcome. It also reviews perioperative management and prophylaxis of diabetes mellitus, endocarditis, and venous thromboembolism. Simple, standardized preoperative screening questionnaires, such as the one shown in Table 9-1, have been developed for the purpose of identifying patients at intermediate or high risk who may benefit 1. Age, weight, height 2.


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InternalMed_Harrison. Age, weight, height 2. Are you: Female and 55 years of age or older or male and 45 years of age of older? If yes, are you 70 years of age or older? 3. Do you take anticoagulant medications (“blood thinners”)? 4. Do you have or have you had any of the following heart-related conditions? Heart disease Heart attack within the last 6 months Angina (chest pain) 5. Do you have or have you ever had any of the following? Rheumatoid arthritis Kidney disease Liver disease Diabetes 6. Do you get short of breath when you lie flat? 7. Are you currently on oxygen treatment? 8. Do you have a chronic cough that produces any discharge or fluid? 9. Do you have lung problems or diseases? 10. Have you or any blood member of your family ever had a problem other than nausea with any anesthesia? If yes, describe: 11.


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InternalMed_Harrison. 9. Do you have lung problems or diseases? 10. Have you or any blood member of your family ever had a problem other than nausea with any anesthesia? If yes, describe: 11. If female, is it possible that you are pregnant? Pregnancy test: Please list date of last menstrual period: aUniversity of Michigan Health System patient information report. Patients who answer yes to any of questions 2–9 should receive a more detailed clinical evaluation. Source: Adapted from KK Tremper, P Benedict: Anesthesiology 92:1212, 2000; with permission.


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InternalMed_Harrison. Source: Adapted from KK Tremper, P Benedict: Anesthesiology 92:1212, 2000; with permission. from a more detailed clinical evaluation. Evaluation of such patients for surgery should always begin with a thorough history and physical examination and with a 12-lead resting electrocardiogram (ECG), in accordance with the American College of Cardiology/American Heart Association (ACC/AHA) guidelines. The history should focus on symptoms of occult cardiac or pulmonary disease. The urgency of the surgery should be determined, as true emergency procedures are associated with unavoidably higher morbidity and mortality risk. Preoperative laboratory testing should be carried out only for specific clinical conditions, as noted during clinical examination. Thus, healthy patients of any age who are undergoing elective surgical procedures without coexisting medical conditions should not require any testing unless the degree of surgical stress may result in unusual changes from the baseline state.


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InternalMed_Harrison. A stepwise approach to cardiac risk assessment and stratification in patients undergoing noncardiac surgery is illustrated in Fig. 9-1. Assessment of exercise tolerance in the prediction of in-hospital perioperative risk is most helpful in patients who self-report worsening exercise-induced cardiopulmonary symptoms; those who may benefit from noninvasive or invasive cardiac testing regardless of a scheduled surgical procedure; and those with known coronary artery disease (CAD) or with multiple risk factors who are able to exercise. For predicting perioperative events, poor exercise tolerance has been defined as the inability to walk four blocks or climb two flights of stairs at a normal pace or to meet a metabolic equivalent (MET) level of 4 (e.g., carrying objects of 15–20 lb or playing golf or doubles tennis) because of the development of dyspnea, angina, or excessive fatigue (Table 9-2).


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InternalMed_Harrison. Previous studies have compared several cardiac risk indices. The American College of Surgeons’ National Surgical Quality Improvement Chapter 9 Medical Evaluation of the Surgical Patient SurgeryCoronary revascularizationwithin 5 yearsIf yes, and no recurrentsymptoms2SurgeryCoronary revascularization within 5 years If yes, and no recurrent symptoms2 Recent coronary evaluation3If no, or recurrent symptomsRecent coronary evaluation3 If no, or recurrent symptoms No Clinical assessment --Age >70, <4 METs --Signs of CHF, AS --EKG changes ischemic or infarct


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InternalMed_Harrison. Clinical assessment --Age >70, <4 METs --Signs of CHF, AS --EKG changes ischemic or infarct SurgerySurgeryPositive stress testNon invasive cardiac testInitiate and/orcontinue optimalpreventive medicaltherapy treatmentNegative stress testIdentify, initiate treatment inpatients requiring preventiveor continue long termmedical preventive therapySurgery Surgery Positive stress test Coronary revascularization ACC/AHA guidelines Non invasive cardiac test Initiate and/or continue optimal preventive medical therapy treatment Negative stress test Identify, initiate treatment in patients requiring preventive or continue long term medical preventive therapy Poor functional capacity, history of angina Yes No


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InternalMed_Harrison. FIgURE 9-1 Composite algorithm for cardiac risk assessment and stratification in patients undergoing noncardiac surgery. Stepwise clinical evaluation: [1] emergency surgery; [2] prior coronary revascularization; [3] prior coronary evaluation; [4] clinical assessment; [5] RCRI; [6] risk modification strategies. Preventive medical therapy = beta blocker and statin therapy. RCRI, revised cardiac risk index. (Adapted from LA Fleisher et al: Circulation 116:1971, 2007, with permission.) Program prospective database has identified five predictors of perioperative myocardial infarction (MI) and cardiac arrest based on increasing age, American Society of Anesthesiologists class, type of surgery, dependent functional status, and abnormal serum creatinine level. However, given its accuracy and simplicity, the revised cardiac risk assessMent of CardIaC rIsk By funCtIonaL status


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InternalMed_Harrison. Higher • Has difficulty with adult activities of daily living • Cannot walk four blocks or up two flights of stairs or does not meet a MET level of 4 active: easily does vigorous tasks Lower • Performs regular vigorous exercises Source: From LA Fleisher et al: Circulation 116:1971, 2007.


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InternalMed_Harrison. index (RCRI) (Table 9-3) is favored. The RCRI relies on the presence or absence of six identifiable predictive factors: high-risk surgery, ischemic heart disease, congestive heart failure, cerebrovascular disease, diabetes mellitus, and renal dysfunction. Each of these predictors is assigned one point. The risk of major cardiac events—defined as myocardial infarction, pulmonary edema, ventricular fibrillation or primary cardiac arrest, and complete heart block—can then be predicted. Based on the presence of none, one, two, three, or more of these clinical predictors, the rate of development of one of these four major cardiac events is estimated to be 0.4, 0.9, 7, and 11%, respectively (Fig. 9-2). An RCRI score of 0 signifies a 0.4–0.5% risk of cardiac events; RCRI 1, 0.9–1.3%; RCRI 2, 4–7%; and RCRI ≥3, 9–11%. The clinical utility of the RCRI is to identify patients with three or more predictors who are at very high risk (≥11%) for cardiac complications and who may benefit from


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InternalMed_Harrison. 2, 4–7%; and RCRI ≥3, 9–11%. The clinical utility of the RCRI is to identify patients with three or more predictors who are at very high risk (≥11%) for cardiac complications and who may benefit from further risk stratification with noninvasive cardiac testing or initiation of preoperative preventive medical management.


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InternalMed_Harrison. History of myocardial infarction Current angina considered to be ischemic Requirement for sublingual nitroglycerin Positive exercise test Pathological Q-waves on ECG History of PCI and/or CABG with current angina considered to be ischemic Left ventricular failure by physical examination History of paroxysmal nocturnal dyspnea History of pulmonary edema S3 gallop on cardiac auscultation Bilateral rales on pulmonary auscultation Pulmonary edema on chest x-ray History of transient ischemic attack History of cerebrovascular accident Treatment with insulin Abbreviations: CABG, coronary artery bypass grafting; ECG, electrocardiogram; PCI, percutaneous coronary interventions. Source: Adapted from TH Lee et al: Circulation 100:1043, 1999.


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InternalMed_Harrison. Abbreviations: CABG, coronary artery bypass grafting; ECG, electrocardiogram; PCI, percutaneous coronary interventions. Source: Adapted from TH Lee et al: Circulation 100:1043, 1999. There is little evidence to support widespread application of preoperative noninvasive cardiac testing for all patients undergoing major surgery. Rather, a discriminative approach based on clinical risk categorization appears to be both clinically useful and cost-effective. There is potential benefit in identifying asymptomatic but high-risk patients, such as those with left main or left main–equivalent CAD or those with three-vessel CAD and poor left ventricular function, who may benefit from coronary revascularization (Chap. 293). However, evidence does not support aggressive attempts to identify patients at intermediate risk who have asymptomatic but advanced coronary artery disease, in whom coronary revascularization appears to offer little advantage over medical therapy.


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InternalMed_Harrison. RCRI 0 1 2 ˜3 Event Rate 0.50% 1.30% 6.00% 11% An RCRI score ≥3 in patients with severe myocardial ischemia on stress testing should lead to consideration of coronary revascularization prior to noncardiac surgery. Noninvasive cardiac testing is most appropriate if it is anticipated that, in the event of a strongly positive test, a patient will meet guidelines for coronary angiography and coronary revascularization. Pharmacologic stress tests are more useful than exercise testing in patients with functional limitations. Dobutamine echocardiography and persantine, adenosine, or dobutamine nuclear perfusion testing (Chap. 270e) have excellent negative predictive values (near 100%) but poor positive predictive values (<20%) in the identification of patients at risk for perioperative MI or death. Thus, a negative study is reassuring, but a positive study is a relatively weak predictor of a “hard” perioperative cardiac event.


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InternalMed_Harrison. RISK ModIFICATIoN: PREVENTIVE STRATEgIES To REdUCE CARdIAC RISK Perioperative Coronary Revascularization Currently, potential options for reducing perioperative cardiovascular risk include coronary artery revascularization and/or perioperative preventive medical therapies (Chap. 293). Prophylactic coronary revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) provides no shortor midterm survival benefit for patients without left main CAD or three-vessel CAD in the presence of poor left ventricular systolic function and is not recommended for patients with stable CAD before noncardiac surgery. Although PCI is associated with lower procedural risk than is CABG in the perioperative setting, the placement of a coronary artery stent soon before noncardiac surgery may increase the risk of bleeding during surgery if dual antiplatelet therapy (aspirin and thienopyridine) is administered; moreover, stent placement shortly before


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InternalMed_Harrison. soon before noncardiac surgery may increase the risk of bleeding during surgery if dual antiplatelet therapy (aspirin and thienopyridine) is administered; moreover, stent placement shortly before noncardiac surgery increases the perioperative risk of MI and cardiac death due to stent thrombosis if such therapy is withdrawn prematurely (Chap. 296e). It is recommended that, if possible, noncardiac surgery be delayed 30–45 days after placement of a bare metal coronary stent and for 365 days after a drug-eluting stent. For patients who must undergo noncardiac surgery early (>14 days) after PCI, balloon angioplasty without stent placement appears to be a reasonable alternative because dual antiplatelet therapy is not necessary in such patients. One recent clinical trial further suggests that after 6 months, bare metal and drug eluting stents may not pose a threat.


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InternalMed_Harrison. perIoperatIve preventIve medIcal therapIes The goal of perioperative preventive medical therapies with β-adrenergic antagonists, HMG-CoA reductase inhibitors (statins), antiplatelet agents, and α2 agonists is to reduce perioperative adrenergic stimulation, ischemia, and inflammation, which are triggered during the perioperative period. β-adrenergIc antagonIsts The use of perioperative beta blockade should be based on a thorough assessment of a patient’s perioperative clinical and surgery-specific cardiac risk (RCRI ≥2). For patients with or without mild to moder- Chapter 9 Medical Evaluation of the Surgical Patient 10% 15% 4–7 9–11 0% 5%Risk of cardiac events0.9–1.30.4–0.5


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InternalMed_Harrison. Chapter 9 Medical Evaluation of the Surgical Patient 10% 15% 4–7 9–11 0% 5%Risk of cardiac events0.9–1.30.4–0.5 The POISE trial highlights the importance of a clear risk-and-benefit assessment, with careful initiation and titration to therapeutic efficacy of preoperative beta blockers in patients undergoing noncardiac surgery. A recent meta-analysis which included the POISE study further supports that excessive beta blocker dosing is, in fact, harmful. The ACC/AHA guidelines recommend the following: (1) Beta blockers should be continued in patients with active cardiac conditions who are undergoing surgery and are receiving beta blockers. (2) Beta blockers titrated to heart rate and blood pressure are probably recommended for patients undergoing vascular surgery who are at high cardiac risk defined by CAD or cardiac ischemia on preoperative testing.


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InternalMed_Harrison. (3) Beta blockers are reasonable for high-risk patients (RCRI ≥2) who undergo vascular surgery. (4) Beta blockers are reasonable for patients with known CAD or high risk (RCRI ≥2) who undergo intermediate-risk surgery. (5) Nondiscriminant administration of high-dose beta blockers without dose titration to effectiveness is contraindicated for patients who have never been treated with a beta blocker.


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InternalMed_Harrison. hmg-coa reductase InhIbItors (statIns) A number of prospective and retrospective studies support the perioperative prophylactic use of statins for reduction of cardiac complications in patients with established atherosclerosis. The ACC/AHA Guidelines support the protective efficacy of perioperative statins on cardiac complications in intermediate risk patients undergoing major noncardiac surgery. For patients undergoing noncardiac surgery and currently taking statins, statin therapy should be continued to reduce perioperative cardiac risk. Statins are reasonable for patients undergoing vascular surgery with or without clinical risk factors (RCRI ≥1). angIotensIn-convertIng enzyme (ace) InhIbItors Evidence supports the discontinuation of ACE inhibitors and angiotensin receptor blockers for 24 h prior to noncardiac surgery due to adverse circulatory effects after induction of anesthesia.


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InternalMed_Harrison. oral antIplatelet agents Evidence-based recommendations regarding perioperative use of aspirin and/or thienopyridine to reduce cardiac risk currently lack clarity. A substantial increase in perioperative bleeding and in the need for transfusion in patients receiving dual antiplatelet therapy has been observed. The discontinuation of thienopyridine and aspirin for 5–7 days prior to major surgery to minimize the risk of perioperative bleeding and transfusion must be balanced with the potential increased risk of an acute coronary syndrome and of subacute stent thrombosis in patients with recent coronary stent implantation. If clinicians elect to withhold antiplatelet agents prior to surgery, these agents should be restarted as soon as possible postoperatively.


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InternalMed_Harrison. α2 agonIsts Several prospective and retrospective meta-analyses of perioperative α2 agonists (clonidine and mivazerol) demonstrated a reduction of cardiac death rates among patients with known coronary artery disease who underwent noncardiac surgery. α2 agonists thus may be considered for perioperative control of hypertension in patients with known coronary artery disease or an RCRI score ≥2. calcIum channel blockers Evidence is lacking to support the use of calcium channel blockers as a prophylactic strategy to decrease perioperative risk in major noncardiac surgery.


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InternalMed_Harrison. anesthetIcs Mortality risk is low with safe delivery of modern anesthesia, especially among low-risk patients undergoing low-risk surgery (Table 9-4). Inhaled anesthetics have predictable circulatory and respiratory effects: all decrease arterial pressure in a dose-dependent manner by reducing sympathetic tone and causing systemic vasodilation, myocardial depression, and decreased cardiac output. Inhaled anesthetics also cause respiratory depression, with diminished responses to both hypercapnia and hypoxemia, in a dose-dependent manner; in addition, these agents have a variable effect on heart rate. Prolonged residual neuromuscular blockade also increases the risk of postoperative pulmonary complications due to reduction in functional residual lung capacity, loss of diaphragmatic and intercostal muscle function, atelectasis, and arterial hypoxemia from ventilation-perfusion mismatch.


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InternalMed_Harrison. Higher • Emergent major operations, especially in the elderly • Prolonged surgery associated with large fluid shift and/or • Prostate surgery Lower • Eye, skin, and superficial surgery Source: From LA Fleisher et al: Circulation 116:1971, 2007, with permission. Several meta-analyses have shown that rates of pneumonia and respiratory failure are lower among patients receiving neuroaxial anesthesia (epidural or spinal) rather than general anesthesia (inhaled). However, there were no significant differences in cardiac events between the two approaches. Evidence from a meta-analysis of randomized controlled trials supports postoperative epidural analgesia for >24 h for the purpose of pain relief. However, the risk of epidural hematoma in the setting of systemic anticoagulation for venous thromboembolism prophylaxis (see below) and postoperative epidural catheterization must be considered.


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InternalMed_Harrison. Perioperative pulmonary complications occur frequently and lead to significant morbidity and mortality. The guidelines from the American College of Physicians recommend the following: 1. All patients undergoing noncardiac surgery should be assessed for risk of pulmonary complications (Table 9-5). 2. Patients undergoing emergency or prolonged (3to 4-h) surgery; aortic aneurysm repair; vascular surgery; major abdominal, thoracic, neurologic, head, or neck surgery; and general anesthesia 1. Upper respiratory tract infection: cough, dyspnea 2. 3. 4. 5. American Society of Anesthesiologists Class ≥2 6. 7. 8. Serum albumin <3.5 g/dL 9. 10. Impaired sensorium (confusion, delirium, or mental status changes) 11. 12. 13. 14. Spirometry threshold before lung resection a. FEV1 <2 L b. MVV <50% of predicted c. PEF <100 L or 50% predicted value d. PCO2 ≥45 mmHg e. PO2 ≤50 mmHg