In type 1 women, early pregnancy is a cause of falling insulin require- ments and recurrent hypoglycemia. It has been suggested that up to 40% of women with type 1 diabetes will expe rience signi \201 cant hypoglycemic episodes when pregnant and hypoglycemic awareness may alter. Advice regarding care with driving and other potentially hazardous pursuits is there fore needed early in pregnancy, if not before conception. Type 2 women requiring insulin usually need 0.9 units/kg/day initially and 1.6 units/kg/day later in the pregnancy. Monitoring of diabetic complications during pregnancy Certain diabetic complications are kn own to worsen during pregnancy. Screening for nephropathy and retinopathy in particular is advised at least each trimester. Fetal monitoring Scanning of the fetus is performed at 10 \200\22312 weeks to look for cong enital abnormalities and to con \201 rm dates. Repeat scanning is used to check for excessive growth or macrosomia at 18 \200\22320 weeks, 28 weeks, 32 weeks, and 36 weeks, although the exact timing and frequency can vary between centers. Management of delivery At delivery, most units have set protocols (see Box 110.2 ). In gene ral, induc- tion soon after 38 weeks \200\231 gestation (or not later than the expected del ivery date) and use of a continuous insulin infusion with a separate dextrose and potassium infusion to maintain stable blood glucose levels are advisable. This infusion is important, as maternal hyperglycemia during delivery can be associated wit h neonatal hypoglycemia and an adverse neurological outcome in the infant. The infant respo nds to a hyperglycemic environ- ment in utero by increasing its own insulin production. After delivery Monitoring of the infant \200\231s capillary blood glucose levels post-deliv ery is also often performed. The i potential for hypoglycemia in the mother 110-Draznin-Chap110.indd 643 3/31/2011 5:33:18 PM CHAPTER 110 Diabetes and pregnancy 644 Box 110.2 Treatment regimen for labor and delivery \200 If labor is induced, omit the pre vious evening \200\231s long-acting insulin. \200 Infuse 10% glucose at 75 \200\223125 mL /h (with 20 mmol potassium per 500 mL bag). Infuse via syringe driver 2 \200\2234 units/h o f soluble insulin initially (usually made as 50 mL soluble insulin in 50 mL of 0.9% saline in a 50 mL syringe). Monitor capillary blood glucose levels hourly and adjust infusion rate of the insulin to keep blood glucose levels in the 110 \200\223150 mg/dL range. Monitor \202 uid balance carefully (especially if oxytocin is also being given). oxytocin) Check serum sodium if labor lasts over 24 hours (or 8 hours with and the baby if breast-feeding also needs to be watched for. Extra car- bohydrate snacks fo r the mother are often needed, along with a 20 \200\22325% reduction in pre-conception insu lin requirements. One day \200\231s worth of breast milk contains about 50 g of carbohydrate. Also consider m onitoring thyroid function at 3 and 6 months post- delivery. After delivery \200 Halve the IV insulin infusion rate. \200 Continue to monitor capill ary blood glucose hourly for at least 4 hours then every 2 \200\2234 hours until the mother is eating normally. Return to the pre-pregnancy regimen when the mother is eating normally, but be careful, as insulin requirements can be low for the \201 rst 24 hours. Gestational diabetes Epidemiology Pregnancy induces a state of insulin resistance with increases in the levels o f growth hormone, placental growth hormone, progesterone, placental lactogen, and cortisol. This can result in altered glucose handling. Impaired glucose tolerance during pregnancy occurs in up to 2 \200\2233% of pregnant women and may be associated with an i risk of subsequent type 2 diabetes in 20 \200\22350% of pat ients. Worsening maternal insulin resistance and associated hyperglycemia usually becomes e vident from the second trimester on if it is going to occur. As with women previously known to have diabetes, there is an associa- tion with worsening c arbohydrate intolerance and a worse maternal and fetal outcome. Untreated gestational diabetes has a perinatal mortality of 4.4 \200\2236.4% com- pared to 0.5 \200\2231.5% in a similar ethnic normoglycemic population. Intensive insulin treatment has been shown to reduce such complications. This is the rationale for careful multidiscipl inary care of these patients. 110-Draznin-Chap110.indd 644 3/31/2011 5:33:18 PM GESTATIONAL DIABETES 645 Treatment Initial treatment is with dietary advice; in 10 \200\22330%, insulin is also requ ired. Insulin therapy should be considered if fasting blood glucoses are >110 mg/dL or post prandial levels are >150 mg/dL. Obesity is not uncommon in these patients. The importance of post- delivery dietary modi \201 cation and weight reduction, to reduce the risk of future type 2 diabetes, should also be reinforced. The varying insulin requirements during pregnancy occur as in those with previously known d iabetes, and most (but not all) patients will not need insulin treatment following delivery . Monitoring is with home capil- lary blood glucose measurements, daily if on diet alone an d more fre- quently if on insulin therapy. The frequency needed depends on the results obtained, with the aim of keeping all readings <126 mg/dL. If diet alone fails, a basal bolus insulin regimen as used in the known diabeti c is usually required. The total ini- tial daily dose is determined on the basis of the deg ree of hyperglycemia present; 4 \200\2236 units per bolus is usual. As with the previously known diabetic mother, the aim is to have a nor- mal delivery, more often at 38 weeks to term, depending on fetal growth. An oral glucose tolerance test (OGTT) should be performed 6 weeks after delivery in all patients not requiring insulin post-deli very, to con \201 rm a return to normal glucose metabolism. A further reinforcement of die t and weight advice at this time is also usual practice. Whether these patients should be followed up because of their i risk of diabetes is unclear , although annual fasting blood glucose levels in asymptomatic women with a normal 6-week p ostpartum OGTT is often advised. More careful review is suggested for those with abnormal O GTTs. High-risk groups Most women with gestational diabetes are found on routine screening at abo ut 30 weeks, but certain high-risk groups should be screened earlier (see Box 110.3 for scr eening methods). These risk factors include the following: Previous gestational diabetes \200 A large baby in their last pregnancy, e.g., >4.0 kg at term \200 A previous unexplained stillbirth or perinatal death \200 Maternal obesity \200 Family history of diabetes ( \201 rst-degree relatives) \200 Polyhydramnios Contraception and diabetes Oral contraceptives The early combined oral contraceptive pills (OCP) impaired glucose tole r- ance and so were not advised in patients with diabetes. The use of third- generation low -dose estrogen-containing combined OCPs (e.g., 20 mcg ethinylestradiol) is safe in women <3 5 years of age. Third-generation OCPs are advised, as they have a better risk pro \201 le for arterial disease and only occasionally increase insulin requirements. 110-Draznin-Chap110.indd 645 3/31/2011 5:33:18 PM CHAPTER 110 Diabetes and pregnancy 646 Box 110.3 Methods of screening \200 Urine dip testing for glucose should be performed on every pregnant woman at every antenatal visit. If glycosuria is found, a fasting glucose test is performed, and if >110 mg/dL, a 75 g OGTT is needed (see Table 110.1). Routine screening at 28 \200\22332 weeks is also often done, either with random blood gluco se tests or a fasting blood glucose level. If a fasting level is >110 mg/dL or a postprandi al level is >126 mg/dL, an OGTT is required. The diagnostic criteria for diabetes are no different from those in the nonpregnant populat ion. A diagnosis of gestational diabetes or gestational IGT is made if the fasting glucose is 110 \200\223140 mg/dL and/ or the 2-hour postprandial level is 160 \200\223200 mg/dL by St. Vincent de \201 nition. The WHO de \201 nition has a fasting level of 140 mg/dL and/ or a 2-hour postprandial level of 140 \200\223200 mg/dL. Table 110.1 Interpretation of 75 g oral glucose tolerance test during pregnancy Plasma glucose (mg/dL) Diabetes Fasting >126 2-hour postprandial level >200 Gestational IGT 110 \200\223140 160 \200\223199 Normal <109 160 As in the nondiabetic population, standard advice regarding the pill should be given. Its u se should be avoided in at-risk groups such as over- weight smokers with a family history o f thromboembolism and coronary heart disease. There is an i risk of cerebral thromboembolis m in type 1 patients, but the OCP dose not increase this. In those with microvascular disease or coronary risk factors, the pro- gesterone-only \200 \234mini-pill \200\235 (POP) is safer than the combined OCP, as it has no signi \201 cant adverse effects on lipid metabolism, clotting, platelet aggregation, or \201 brinolytic a ctivity. It has been suggested that levonorgestrel- and norethisterone-contain- ing POPs may reduce HDL 2 cholesterol subfractions. The avoidance of POPs in those with established arterial di sease is advised. Barrier methods The condom and the diaphragm were historically the contraceptive method of choice in people with diabetes and do not have the metabolic risks of the oral contraceptiv es described above. But both are less effective forms of contraception with a failure rate of 0.7 \200\2233.6/1 00 couple years for the condom and 2/100 couple years for the diaphragm, compared to nearly 0.2/100 female years with the combined 110-Draznin-Chap110.indd 646 3/31/2011 5:33:18 PM GESTATIONAL DIABETES 647 OCP. In a population in which pregnancy carries signi \201 cant risks, other forms of cont raception are now more often advocated. Intrauterine contraceptive devices (lUD) There is concern that diabetes might make a pelvic infection associated with an IUD more severe and render both copper-containing and inert I UDs less effective, but not all studies have con \201 rmed these worries. Nevertheless, if an IUD is used in a woman with diabetes, a progestagen- releasing variety or a small copper device with regular use of spermicides are the current favorite options. Hormone replacement therapy (HRT) As with the OCP, diabetes itself is not a contraindicatio n to the use of HRT. The estrogens in HRT differ from those in the OCP and may actu- ally r educe insulin resistance and also protect against coronary disease, although they may not a ctually reduce cardiovascular events in those with established coronary artery disease. Further reading Dornhorst A, Chan SP (1998). The elusive diagnosis of gestational diabetes. Diabet Med 15:7 \200\22310. Garner P (1995). Type 1 DM and pregnancy. Lancet 346:157 \200 \223161. Iikova H (1995). Screening for gestational diabetes. Diabet Rev Int 3(3):1 \200\2232. NICE (2008). Interpartum care. Clinical guideline CG63. Diabetes in pregnancy. http://www.n ice. org.uk /guidance NICE (2008). NICE guidelines. Diabetes in pregnancy. http://www.nice.org.uk/guidance 110-Draznin-Chap110.indd 647 3/31/2011 5:33:18 PM CHAPTER 111 Intercurrent events or disease 648 Intercurrent events or disease Surgery Preoperative assessment Careful preoperative assessment is essential because of an i risk o f death and complications such as \202 uid overload from coronary heart disease and diabe tic nephropathy. Any preoperative assessment in a patient with known diabetes should theref ore include the following: \200 An adequate history of diabetic complications \200 A fu ll examination looking for evidence of peripheral vascular disease, peripheral neuropathy, and lying or standing BPs in case of autonomic neuropathy Assessment of current and overall diabetic control using blood glucose measurements in all patients and glycated hemoglobin General investigations should include serum urea + electrolytes/ creatinine, FBC, urine dip testing for protein, and an ECG (in anyone >45 years old). Any further investigation will be based on problems found in the history or examination, su ch as foot ulceration and potential osteomyelitis, which may give a source for infection su ch as an MRSA. Attempts should be made to improve diabetic control, either on the ward or in a diabetic cl inic, for any patient undergoing an elective proce- dure whose control is inadequate. An Hb A1c <7.2% is considered good control, but an acceptable levels for most procedures would be <9%. Even with a good HbA1c level, the preoperative glucose level (and if >200 mg/dL, the urine ketones) should always be measured, as the peri- operative treatment is based on this and s ome stabilization before admin- istration of an anesthetic may be required, particularly in an emergency situation. Perioperative management Ideally, patients with diabetes are best operated on in the mornin g at the start of the list. Patients normally on diet alone should have their capillary blood glucose levels checked ho urly. IV dextrose, should be avoided in these patients. Often no other modi \201 cation to their treatment is needed. Patients taking oral agents should stop metformin for at least 48 hours preoperatively and miss their other agents on the morning of the proce- dure. Capillary blood glucose levels a re again monitored regularly (every 1 \200\2232 hours) and insulin IV infusion may be start ed if necessary. 111-Draznin-Chap111.indd 648 3/31/2011 5:33:40 PM SKIN, CONNECTIVE TISSUE, OR JOINT DISEASE 649 In patients taking insulin who are undergoing a morning operation, from 0 to one-half of th e morning insulin dose might be given and IV insu- lin infusion may be started. The aim is to keep the blood glucose in the 120 \200\223180 mg/dL range. Every hospital in the United States has developed insulin infusion proto- cols used in the intensive care unit (ICU) in pre-, peri- and postoperative patients as well as in patients on enteral and parenteral nutrition. Skin, connective tissue, or joint disease Skin Diabetes results in an i occurrence of infec tions such as vaginal candida, Candida balanitis , and Staphylococcus aureus folliculitis. Ulceration in the feet due to neuropathy and peripheral vascular disease should also be con sidered. Other skin features to look for include the following. Conditions speci \201 c to diabetes \200 Pretibial diabetic dermopathy \200\224shin spot s \200 Diabetic bullae \200\224bullosis diabeticorum, very rare tense blistering on feet and lower legs classically Diabetic thick skin \200\224cleroderma of diabetes seen in 2.5% with type 2 diabetes Periungual telangectasia \200\224venous capillary dilatation at the nail fold seen in up to 50% of people with diabetes The most common skin lesion in diabetes is shin spots, or diabetic der- mopathy. These occu r more commonly in males than in females and affect up to 50% of people with diabetes. Thei r etiology is uncertain. They present initially as red papules and progress to give well-circum- scribed atrophic ar eas that are brownish in color. Usually seen on the shins, they can also be found on the fo rearms and thighs. There is no effective treatment of these; they usually resolve spontane- ously over 1 \200\2232 years. Conditions seen more commonly in those with diabetes \200 Necrobiosis lipoidica \200 Vi tiligo (seen in 2% with type 1 diabetes) \200 Granuloma annulare (although this associati on is not proven conclusively) Necrobiosis lipoidica is seen in 0.3 \200\2231% of people with diabetes, and 40 \200\22360% of those with necrobiosis also have diabetes. It is more common in females than in males. Classically seen on the shins, it has an atrophic center with telangectasia around the edge of an oval or irregular lesion, although early lesions can be dull red plaques or papules. Treatment with topical or injectable steroids may help improve these lesions; skin grafting and cosmetic camou \202 age have also been used. 111-Draznin-Chap111.indd 649 3/31/2011 5:33:41 PM CHAPTER 111 Intercurrent events or disease 650 Conditions associated with the other biochemical features seen in diabetes \200 Acanthosi s nigricans \200\224with insulin resistance \200 Eruptive xanthomata \200\224with hypertr iglyceridemia When looking at the skin do not forget to check injection sites for lipo- hyp ertrophy or lipoatrophy as these are often much more amenable to treatment or correction. I n the past, an insulin allergy rash was also com- monly seen, but more recently a transient local reaction, thought to be an IgE-mediated reaction, is more often seen. Connective tissue and joint disease Diabetes is associated with an i incidence of pseudogou t and osteoarthri- tis, but the classical condition to consider is the \200\234stiff hand syndrome, \200\235 or diabetic cheiroarthropathy . In this disorder, the skin thickens and tightens, which, in association with sclerosis of t he tendon sheaths, results in limited joint mobility in the hands and, less commonly, the f eet. This reduced joint mobility leads to an inability to place the palms of the hand \202 at together and make the \200\234prayer sign. \200\235 No speci \201 c treatment for this currently exists. 111-Draznin-Chap111.indd 650 3/31/2011 5:33:41 PM DIABETIC KETOACIDOSIS 651 Emergencies in diabetes Diabetic ketoacidosis Diabetic ketoacidosis has a mortality of 2 \200\2235%. Many deaths oc cur from delays in presentation and initiation of treatment. It has a mortality rate of up to 50% in the elderly. Diagnosis This is usually based on a collection of biochemical abnormalities: \200 Hyperg lycemia >200 mg/dL \200 Acidosis arterial pH <7.3, serum bicarbonate <15 mmol/L, base exc ess < \200\22310 Ketonuria. Some dip testing methods only check for acetoacetate and acetone but not B-hydro xybutyrate. Captopril can also give a false- positive test for urinary acetone. Ketones may interfere with some creatinine assays and give falsely high readings. There is an uncommon condition of euglycemic ketoacidosis (in 1 \200\2233% of cases at most ) when ketones are produced early on in patients with a reduced carbohydrate intake. Blood glucose is <300 mg/dL, acidosis is marked, and dehydration is not usually severe. Clinical features are listed in Box 112.1. Box 112.1 Clinical features of diabetic ketoacidosis Polyuria, polydypsia, and weight loss are often seen. Muscle cramps, abdominal pain, and sh ortness of breath (air hunger or Kussmaul \200\231s breathing, with deep, regular, rapid br eaths, suggesting acidosis) can also occur. Subsequent nausea and vomiting can worsen both the dehydra- tion and electrolyte losses that often precede the onset of coma (occur- ring in about 10% of cases). Consider other causes of coma and a raised blood glucose level, such as head injury, alcohol, and drug overdose. On examination, the breath can smell of ketones (like nail-varnish remover). Postural hypot ension (exacerbated by peripheral vasodilata- tion due to acidosis) and hypothermia are als o frequently seen. Infection and trauma can precipitate this problem and should be carefull y looked for, especially in the unconscious patient. Hypovolemia at presentation is usually at least 5 L, along with elec- trolyte losses of 300 \200\223700 mmol of sodium, 200 \200\223700 mmol of potassium, and 350 \200\223500 mmol of chloride. The daily intake of both sodium and potassium is 60 mmol, so the severity of thi s condition is apparent 112-Draznin-Chap112.indd 651 3/31/2011 5:36:18 PM CHAPTER 112 Emergencies in diabetes 652 Initial treatment is to start oral carbohydrate intake and monitor the need for IV insulin/ \202 uids as in full-blown hyperglycemic ketoacidosis. Epidemiology Diabetic ketoacidosis is common in patients with type 1 diabetes. The incidenc e is 5 \200\2238/1000 diabetic patients per year, usually patients with type 1 diabetes. Up to 25% of cases are patients with newly diagnosed or pre- senting diabetes, some of whom s ubsequently obtain adequate control with oral agents or diet alone. In up to 50% of cases an infection is the precipitant, and in 10 \200\22330% of cases it is their \201 rst presentation with diabetes. Pathogenesis Diabetic ketoacidosis occurs as a result of insulin de \201 ciency and coun- terregulatory hormone excess. Insulin de \201 ciency results in excess mobi lization of fr ee fatty acids from adipose tissue. This provides the substrate for ketone production from the liver. Ketones (B-hydroxy-butyrate, ace- toacetate, and acetone) are excreted by the ki dneys and buffered in the blood initially, but once this system fails, acidosis develops. Hyperglycemia also occurs, as the liver produces glucose from lactate and alanine generated by muscle proteinolysis. The reduced peripheral glucose utilization associated with insuli n de \201 ciency exacerbates this. Hyperglycemia and ketonuria cause an osmotic diuresis and hypovo- lemia with both intracell ular and extracellular dehydration. Glomerular \201 ltration is reduced and blood glucose levels thus rise even further, as do the levels of counterregulatory hormones such as gluc agon. The metabolic acidosis due to ketone accumulation leads to widespread cell death that, combined with hypovolemia, is fatal if untreated. Management Having \201 rst assessed the need for immediate resuscitation and started a 0. 9% saline IV infusion, take a history and examine the patient to look for obvious precipita nts, such as surgery, trauma, sites of infection, or myo- cardial infarction (Box 112.2). W hile initial investigations will be modi \201 ed by the history and examination and sugges ted site of infection, they should include at least the following: \200 Blood for urea/el ectrolytes (note ketone/creatinine assay interaction) \200 CBC (a leukocytosis can occur without infection) \200 Arterial blood gasses ( P a CO 2 will be low due to hyperventilat ion with a metabolic acidosis; check pH and bicarbonate) Cultures of blood and urine \200 Chest X-rays and ECG \200 In the older patient (>40 ye ars), also include an ECG and cardiac enzymes, even if asymptomatic. Replacement of \202 uids, electrolytes, and insulin is the mainstay of treat- ment, along with treatment of any precipitant, such as infection. To moni- tor this treatment, central venous access and urinary catheterization are often necessary and an NG tube may be useful , especially in the uncon- scious patient. 112-Draznin-Chap112.indd 652 3/31/2011 5:36:19 PM DIABETIC KETOACIDOSIS 653 Box 112.2 Precipitants of diabetic ketoacidosis \200 Infection \200 Noncompliance with treatment \200 Inappropriate alterations in insulin (i.e., errors by patient or doctor) 30 \200\22340% 25% 13% Newly diagnosed diabetes \200 Myocardial infarction 10 \200\22320% 1% In elderly people, those with a cardiac history, or those with autonomic neuropathy, central venous access is imperative. Monitoring Once treatment has commenced, monitor \202 uid balance carefully and avoid \202 uid overload. Check capillary blood glucose hourly, serum potas- sium, sodium, and glu cose every 2 hours, and arterial blood gasses every 2 \200\2234 hours depending on response . Reduce the frequency of tests once the patient is stabilized, but check electrolytes at lea st daily for the \201 rst 72 hours. Continuous ECG monitor- ing will aid in detection of hypo- and hyperkalemia in the acute phase. Magnesium and phosphate levels should also be checked, as these can occasionally require replacement therapy. Additional therapies IV bicarbonate is only rarely indicated, as it can cause hypokalemia a nd paradoxically worsen intracellular acidosis. If used, give only when the pH is <6.9 usin g 250 mL of 1.26% bicarbonate given over 30 \200\22360 minutes ini- tially. Monitor arteria l blood gasses to assess response, aiming for pH no greater than 7.1. This should probably only be used in an intensive care setting. Do not use 8.4% bicarbonate , as its high sodium load can too rapidly alter electro- lyte levels and precipitate pulmon ary edema as well as cause local tissue necrosis if it extravasates. In severe hypotension unresponsive to colloids and crystalloids, ino- tropes may be require d, but agents such as dopamine , dobutamine , and adrenaline will all exacerbate insulin re sistance, necessitating a more aggressive sliding-scale regime. Heparin in SC prophylactic doses can be given in the unconscious or immobile patent. Cover with IV broad-spectrum antibiotics should be used if no obvious precipitant is found and appropriate antibiotics used if a site of infection is found. Cerebral edema typically presents 8 \200\22324 hours after starting IV \202 uids with a d eclining conscious level and can have a mortality rate as high as 90%. If this occurs, dexa methasone (12 \200\22316 mg/day) and mannitol (1 \200\2232 g/kg body weight) may be given. 112-Draznin-Chap112.indd 653 3/31/2011 5:36:19 PM CHAPTER 112 Emergencies in diabetes 654 Subsequent treatment Once the blood glucose is stable in the 180 \200\223270 mg/dL range, t he ketoaci- dosis has settled, and the patient is eating and drinking normally, consider sw itching to a SC insulin regimen, but overlap the IV and the \201 rst SC dose by 2 hours. Stabilize the patient on this therapy before discharge from the hospital. Once the IV potassium supplements have been stopped, give oral sup- plements for at least 48 hours with regular serum monitoring. Patient education on determining the cause and avoiding a further occurrence, or on earlier presentation if it does occur, should also ideally be given before discharge. Initial treatment of ketoacidosis IV 0.9% saline \200 2 L in 2 hours, then 1 L over 2 hours, 2 L in next 8 hours, and 4 L/ day thereafter until blood glucose is <200 mg/dL. Then convert to dextrose saline or 5% dex trose. If the patient is profoundly shocked (e.g., systolic BP <80 mmHg with severe dehydration or sepsis) or oliguric, this dosage may need to be given more rapidly and colloids may also b e needed. If the patient is elderly or there are signs of heart failure or cerebral edema, it may need to be given more slowly. Potassium Once the serum potassium is known, potassium is added to the 0.9% saline. The dos e of potassium is adjusted on the basis of hourly serum potassium measurements until the pa tient is stable, and measured every 2 \200\2234 hours over the next 12 \200\22324 hours. Ad d the following: \200 40 mmol/L if K + <3.0 mmol/L \200 30 mmol/L if K + 3.0 \200\2234. 0 mmol/L \200 20 mmol/L if K + 4.1 \200\2235.0 mmol/L \200 10 mmol/L if K + 5.1 \200 \2236.0 mmol/L \200 None if K + >6.0 mmol/L Insulin (via continuous IV infusion) Every hospital in the United States has developed IV i nsulin infusion proto- cols. Following these protocols is mandatory and the safest way of a dmin- istering insulin IV. 112-Draznin-Chap112.indd 654 3/31/2011 5:36:19 PM HYPEROSMOLAR, NONKETOTIC HYPERGLYCEMIA 655 Hyperosmolar, nonketotic hyperglycemia This is a more sinister complication than ketoacidos is with a mortality rate as high as 50%. It is found in 11 \200\22330% of adult hyperglycem ic emergencies. It affects an older population than that with ketoacidosis (middle-aged or elderly), 2/3 of cases are in patients with previously undiagnosed diabetes, and its insidi ous onset can be mistaken for many other conditions, includ- ing stroke. See Box 112.3 for clinical features. Diagnosis This is again a biochemical diagnosis: \200 Hyperglycemia (usually 30 \200\2237 0 mmol/L) \200 Serum osmolality is high (>350 mmol/kg) \200 No acidosis arterial pH 7.3 5 \200\2237.45, serum bicarbonate >18 mmol/L, but lactic acidosis with infection or a myoca rdial infarction may alter this. No ketonuria + on urine dip testing can occur with starvation and vomiting. Serum osmolality (in mosmol/kg) can be calculated if not available from the laboratory usin g the following equation: Osmolality = 2(sodium + potassium) + glucose + urea Epidemiology This condition occurs in an older age group of insulin-producing type 2 patien ts, a large proportion of whom will not previously be known to have diabetes. Ingestion of high-sugar-containing drinks, intercurrent infection, and myocardial infarctio n are all commonly seen as precipitants of this condi- tion. Drugs such as glucocorticoids, cimetidine, phenytoin, thiazide, and loop diuretics are all implicated in the pathogenesis of this problem. Pathogenesis This condition results from a combination of insulin de \201 ciency and coun- terregulatory hormone excess. The insulin present stops ketone produc- tion but in insuf \201 cient quantities to prevent worsening hyperglycemia. Box 112.3 Clinical features of hyperosmolar, nonketotic hyperglycemia There is normally an insidious onset with several days of ill health and profound dehydrati on at presentation (equivalent to a 9 \200\22310 L de \201 cit). Confusion is not uncommon , nor is coma (especially once serum osmo- lality >440). Occasionally, \201 ts occur. Gastroparesis and associated vomiting with gastric erosions and sub- sequent hematemesis ca n occur. These patients are also hypercoagula- ble, and venous thromboses and cerebrovascul ar events are important to exclude. 112-Draznin-Chap112.indd 655 3/31/2011 5:36:19 PM CHAPTER 112 Emergencies in diabetes 656 Management Initial investigation and treatment are the same as for ketoacidosis, with \202 uid, electrolyte, and insulin replacement, although there are a few impor- tant except ions as these are older patients: \200 The \202 uid regimen should be less rapid and vi gorous. Central venous access for monitoring is more often required, e.g., 1 L of 0.9% sali ne over the \201 rst hour, 1 L q2h for the next 2 hours, then 1 L q4 \200\2236h. \200 I f hypernatremic (serum sodium >155 mmol/L) consider 0.45% saline, rather than 0.9%, although this may increase the risk of cerebral edema if serum sodium or osmolality is altered too rapidly, which has a mortality as high as 70%. Prophylactic SC heparin should be considered, although recent evidence suggests more formal anticoagulation carries a high risk of upper gastrointestinal bleeding. A gentler insulin regimen is needed, with 3 \200\2236 units/hour of soluble insulin IV, aim ing to reduce the blood glucose by a maximum of 5 mmol/h to avoid precipitating cerebral ed ema. A more aggressive use of IV antibiotics is encouraged. Subsequent treatment Continue IV \202 uids and insulin for at least 24 hours after initia l stabiliza- tion and then convert to maintenance therapy such as SC insulin or oral hypogl ycemic agents. Patient education on how to avoid further episodes is also advisable. Hypoglycemia This complication of the treatment of diabetes should be excluded in any uncon scious or relevant patient. If prolonged it can result in death. Most insulin-treated patie nts can expect to experience hypoglycemic episodes at some time, with up to 1/7 having a mo re severe episode each year and 3% suffering recurrent episodes. The 25% of people on long- term insulin who lose their hypoglycemic awareness are of particular concern. Nocturnal hypoglycemic episodes with a hyperglycemic response the next morning (due to i co unterregulatory hormones \200\224the Somogyi phenomenon), which tend to occur in younger in sulin-treated patients, should be assessed for and may only present with morning headaches or a drunken feeling. Diagnosis This is a biochemical diagnosis from a blood glucose <50 mg/dL, but is often \201 rst picked up by the patient, their family, or their doctor from the clinical features listed in Box 112.4. Saving serum before treatment for blood glucose, insulin, and C-peptide levels will con \201 rm the diagnosis and may help determine the cause. 112-Draznin-Chap112.indd 656 3/31/2011 5:36:19 PM HYPOGLYCEMIA 657 Box 112.4 Clinical features The features of hypoglycemia can be divided into two main groups: auto- nomic symptoms and neuroglycopenic symptoms, as shown in Box 112.5. The autonomic symptoms usually occur \201 rst (when the blood glucose is <65 mg/dL), but some drugs, such as the nonselective B- blockers, and alcohol may mask these with neuroglycopenia (at blood glucose <46 mg/dL), cau sing confusion with no warning. Some patients lose these predominantly autonomic warning sy mptoms and are therefore at higher risk of injury. Box 112.5 Signs and symptoms of hypoglycemia Autonomic \200 Sweating \200 Pallor \200 Anxiety \200 Nausea \200 Tremor \200 S hivering \200 Palpitations \200 Tachycardia Neuroglycopenia \200 Confusion \200 Tiredness \200 Lack of concentration \200 Heada che \200 Dizziness \200 Altered speech \200 Incoordination \200 Drowsiness \200 A ggression \200 Coma Pathogenesis Hypoglycemia results from an imbalance between glucose supply, glucose utiliza tion, and insulin levels that results in more insulin than is needed at that time. A reduced glucose supply occurs when a meal or snack is missed, or as a late effect of alco hol. It can also be due to delayed gastric emptying with autonomic neuropathy or be associa ted with celiac disease, Addison \200\231s dis- ease, or an acute illness, such as gastroen teritis. Increased utilization occurs with exercise and high insulin levels mostly with sulfonylurea or exogenous insulin therapy. The net result of this imbalance is hypoglycemia. Human insulins have a slightly faster onset of action and a shorter dura- tion of action th an their animal predecessors, and a lot of patients report alterations in hypoglycemic awar eness when they switch from one form to the other. Even so, no de \201 nite evidence of sp eci \201 c hypoglycemic altera- tions due to human insulin itself has been reported. Sulfonylurea therapy can cause hypoglycemia due to B-cell stimulation. This is most commonl y seen from glibenclamide , especially in the elderly and those with reduced renal excretin g ability, but can occur in anyone who takes this therapy and fasts. 112-Draznin-Chap112.indd 657 3/31/2011 5:36:19 PM CHAPTER 112 Emergencies in diabetes 658 The biguanide metformin and the A-glucosidase inhibitor acarbose are unlikely to precipitate hypoglycemia. Management In the conscious patient, oral carbohydrate (20 \200\22330 g) is often suf \201 cient to resolve the problem. This can be given as 5 \200\2236 glucose tablets or as a gla ss of milk or orange juice. Having raised the sugar rapidly, the patient should then eat so mething to maintain a normal blood glucose. In the confused patient, a buccal gel (e.g., GlucoGel , a 30% glucose gel) is an alterna tive, although this should not be used in the unconscious patient as there is a risk of asp iration. In the unconscious patient, once a blood sample has been taken for glucose estimation, trea t with 25 \200\22350 mL of 50% glucose IV or 1 mg of IM or deep SC glucagon. Glucagon mobil izes glycogen from the liver and will not work if given repeatedly or in starved patients w ith no glycogen stores. In this situation or if prolonged treatment is needed, IV glucose i s better (50% initially then 10%). The worry with 50% glucose is tissue necrosis if extravasation occurs. Subsequent management Having corrected the acute event, determine why it happened and, if p os- sible, alter treatment or lifestyle to prevent recurrance. Extreme exercise may require an alteration in insulin doses for 24 hours, and alcohol causes not only initial hyperglyc emia but also a degree of hypoglycemia 3 \200\2236 hours after ingestion, and may alter ins ulin requirements the next morning. Education on how to avoid precipitating hypoglycemic episodes in these situations is advisa ble. Recurrent hypoglycemic events may also her- ald deterioration in renal or liver functi on; these conditions should be excluded. Patients on long-acting sulfonylureas who experience hypoglycemia will need careful monitor ing, as the drug may last longer than the glucose or glycogen given to correct it and repea ted hypoglycemic episodes may occur. A continuous IV glucose infusion is therefore often ne eded in this situation, particularly in overdose with these agents. Further reading Amiel SA, Tamborlane WV, Sherwin RS (1987). Defective glucose counterregula tion after strict glycemic control of insulin-dependent DM. N Engl J Med 316:1376 \200\2231 384. Cranston ICP, Amiel SA (1995). Hypoglycaemia. In Leslie RDG, Robbins DC (Eds). Diabetes: Cl inical Science and Practice. Cambridge, UK: Cambridge University Press, pp. 375 \200\223391 . Hepburn D, Deary IJ, Frier BM, et al. (1991). Symptoms of acute insulin induced hypoglycaem ia in humans with and without IDDM. Diabetes Care 14:949 \200\223957. Krentz AJ, Nattrass M (1997). Acute metabolic complications of DM: diabetic ketoacidosis, h yper- osmolar non-ketotic syndrome and lactic acidosis. In Pickup J, Williams G (Eds.), Tex tbook of Diabetes , 2nd ed. Oxford, UK: Blackwell Science, pp. 1 \200\22323. Lebovitz HE (1995). Diabetic ketoacidosis. Lancet 345:767 \200\223772. Pickup JC, Williams G (Eds.) (2003). Hypoglycaemia in diabetes. In Textbook of Diabetes , 3 rd ed. Oxford, UK: Wiley-Blackwell. 112-Draznin-Chap112.indd 658 3/31/2011 5:36:19 PM Part 12 Lipids and hyperlipidemia Barrie Weinstein and Dina Green 113 Lipids and coronary heart disease 114 Primary hyperlipidemias 115 Secondary hyperlipide mias 116 Management of dyslipidemia 660 669 674 677 113-Draznin-Chap113.indd 659 4/1/2011 6:44:37 PM CHAPTER 113 Lipids and coronary heart disease 660 Lipids and coronary heart disease Physiology The two main circulating lipids, triglycerides and cholesterol, are bound with p hospholipid and lipoproteins to make them more water soluble for transportation throughout the body. The apoproteins on the surface of these soluble masses help the body to recognize each of the different transportation complexes. Chylomicrons These contain 85% triglycerides and 4% cholesterol. Made in the mucosa of the small intestine, they are broken down in the liver and peripheral tis- sues by lipoprotein lipase. Initially they contain apoprotein B-48 (apo B-48) but also acquire apo E and apo C- II from circulating HDL. Following metabolism by lipoprotein lipase in capillary endothelial cells, which is activat ed by apo C-II, chylomicron remnants are then removed by speci \201 c apo B and apo E rece ptors in the liver. Very low \200\223density lipoproteins (VLDLs) VLDLs contain 50% triglyceride, 15% cholester ol, and 18% phospholipid. They are the main carrier of triglycerides in circulation. Made w ith triglyc- erides synthesized in the liver, they also contain apo B-100 and apo E. VLDLs are broken down by lipoprotein lipase in peripheral tissue to give IDLs, or other remnants that are removed by the liver. Intermediate-density lipoproteins (IDLs) These VLDL remnants contain mostly cholesterol and phospholipid and are either removed by the liver or metabolized to form LDLs. Low-density lipoproteins (LDLs) LDLs contain 45% cholesterol, 10% triglycerides, and 20% ph ospholipid. LDL has apo B-100 in its surface and transports most of the cholesterol in circ ulation.