When ongoing glucose control remains difficult cheap propranolol amex cardiovascular 10, having the patient demonstrate all aspects of insulin injection technique should be part of the evaluation buy propranolol 40mg visa capillaries exchange vessels. This is true even if the patient had mastered the technical aspects of insulin self-administration buy propranolol online pills cardiovascular disease men and women. Elderly patients may need additional reinforcement of diabetes instruction despite years of diabetes experience. Insulin pen injection devices for management of patients with type 2 diabetes: considerations based on an endocrinologist’s practical experience in the United States. Assessment of patient-reported outcomes of insulin pen devices versus conventional vial and syringe. Survey on transition from inpatient to outpatient for patients on insulin: what really goes on at home? His insulin requirements pointed to a significant component of insulin resistance and therapies directed at improving insulin resistance and possibly preserving β-cell function were added. Pioglitazone and metformin were added to his regimen and his mealtime insulin was able to be discontinued. Basal insulin was stopped 7 months after diagnosis, and he has remained on the pioglitazone, metformin, and exenatide with excellent glycemic control for the past 7 years. The effects of lifestyle interventions greatly improved his “acquired” insulin resistance. Addition of pharmacological agents known to improve insulin sensitivity was successful in helping achieve an A1C in the prediabetic range for a long duration. It is tempting to ascribe some preservation of β-cell function to his pharmacologic regimen. His human insulin antibodies were undetectable 5 years after his initial presentation. On initial presentation, our patient did require insulin, as do many patients with type 2 diabetes, but he was able to discontinue insulin therapy after weight loss and dietary changes. Seven years after discontinuation of insulin, his C-peptide level remains stable and he does not require insulin. The factors that contribute to this extremely long “honeymoon” include his ability to adhere to a carbohydrate restricted diet and active exercise program. Antibodies to glutamic acid decarboxylase as predictors of insulin-dependent diabetes mellitus before clinical onset of disease. Diabetes was diagnosed 12 years ago and she had been taking insulin for 1 year after failing oral medication. Furthermore, both doses of regular insulin were increased because the before-lunch and before-bedtime snack values were high. Second, if both doses were changed, it would be more difficult to determine which dose change was responsible for the subsequent fasting glucose levels. The morning dose of regular insulin was increased because the before-lunch glucose values were high. The before-supper dose of regular insulin was not changed because the change in glucose values between supper and bedtime was close to zero. In addition, there was a concern that if the before-supper glucose levels were lowered to target, then an increased dose of regular insulin might cause hypoglycemia. Because the before-supper glucose levels were still too high, the before- lunch dose of regular insulin was increased. Visit 8 Because the before-supper glucose levels were nearly at target but the before-bedtime values were high, the before-supper dose of regular insulin was increased. Because the insulin doses were relatively stable, the patient was next seen in 6 weeks. Visit 9 Because the before-bedtime snack glucose values were still slightly above target, the before-supper dose of regular insulin was again increased with no other changes made. The approach of our diabetes program with insulin-requiring patients taking two or more injections per day is to see them every 3 weeks when out of control and substantial dose adjustments may be necessary. We routinely ask patients to test preprandially because the most important determinant of postprandial glucose levels are the preprandial ones. That is, the increment over the preprandial level is 1–3 similar regardless of the preprandial value. Therefore, postprandial hyperglycemia is best treated by lowering preprandial glycemia. Although we (like most providers) prefer that patients taking more than one injection of insulin test four times a day, realistically most will not test that often. In my 50 years of caring for people with diabetes, I would estimate seeing ~20 cases. For those of us who follow challenging patients, it is important to recognize them. If not, adjusting their insulin doses can be very frustrating, and they are at increased risk of overnight hypoglycemia as well as daytime hyperglycemia. The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes. Evaluation of a simple policy for pre- and post-prandial blood glucose self-monitoring in people with type 2 diabetes not on insulin. Peripheral neuropathy was presenThat diagnosis, with pain sufficient to interrupt sleep becoming severe within 3 months. Over the following 2 years, metformin and glipizide were ineffective at maintaining glycemic control and not well tolerated because of gastrointestinal adverse effects. In July 2010, insulin was commenced (insulin glargine once daily with insulin lispro before meals). Access to medical services was limited for the patient, who had no medical insurance. Diagnosis of type 2 diabetes is often significantly delayed and presentation can be years after hyperglycemia has already developed. The initial presentation can be with hyperglycemic emergencies, including hyperglycemic hyperosmolar state or ketoacidosis. The presence of neuropathy at diagnosis supports the likelihood of a prolonged period of unrecognized hyperglycemia. Difficult access to health care providers because of financial constraints often contributes to delayed diagnosis and limits treatment options for patients based on affordability. Metformin and sulphonylureas are cheap and usually effective agents for improving glycemic control. Metformin is recommended as a first-line therapy for chronic management of type 2 1 diabetes by the American Diabetes Association, although gastrointestinal side effects may be dose limiting. Newer hypoglycemic therapies are typically more expensive and unaffordable for some patients. Insulin is an effective strategy for those unable to achieve glycemic control with alternative agents.

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An example is of cases K C falling into various diagnostic groups on the basis of their clinical Note that sij is the ratio of the number of variables on which the ith features buy generic propranolol 40mg on-line arteries near the stomach. A name is subsequently assigned to these groups depend- and the jth units match to the total number of variables discount propranolol 40mg online 5 cardiovascular disorders. Similar measures are available for be conceived so that one or more units belong simultaneously to polytomous variables [1] buy propranolol 40mg free shipping coronary heart disease high blood pressure. This reference also discusses strategies for two or more clusters, this section is restricted to exclusive clusters. Cluster analysis is a nonparametric procedure and does not require In the case of quantitative variables, the usual Pearsonian corre- values to follow a Gaussian or any other pattern. If yi1, yi2,…, dure is primarily used for multivariate observations and not so yiK are K quantitative (multivariate) measurements on the ith subject much for univariate observations. Note that this is being used here for Measures of Similarity assessing similarity between subjects, whereas the general use is to Division of subjects into a few but unknown number of affnity or measure strength of correlation between variables. A more accept- natural groups requires that proximity between subjects is objec- able method in this case is to compute a measure of dissimilarity tively assessed. This, between the ith and the jth subjects, can those with low proximity are assigned to some other group. Thus, be measured by the subjects resembling one another are put together in one group. As many groups are formed as needed for internal homogeneity and ij k ik jk external isolation of the groups (Figure C. Otherwise, the variables Similarity between two subjects can be measured in a large with larger numerical values will mostly determine clustering. The methods are different for qualitative than for This distance can also be calculated for a setup with one variable quantitative variables. On the basis of such measurement of similarity or dissimilarity, the subjects are classifed into various groups using one of the sev- eral possible algorithms. With hierarchical algorithm, two units (or subjects) that are most similar (or least distant) are grouped together in the frst step to form one group of two units. Now the distance of this entity from other units is compared with the other distances between various pairs of units. This hierarchical agglomerative process goes on in stages, reducing the number of entities by one each time. The process is continued until all units are clustered together as one big entity. This process is graphically depicted by a dendrogram of the type shown in Figure C. Note that in this method, subsequent clusters completely contain previously formed clusters. It may not be immediately clear how to compute the distance between two entities containing, say, n1 and n2 units, respectively. These values should be high com- - Guyana 64 pared with the adjacent stages of the clustering process. Another cri- - Guatemala 68 terion could be the distance between the two units or entities that are - Honduras 68 being merged in different stages. If this shows a sudden jump, it is - Dominican Republic 68 indicative of a very dissimilar unit joining the new entity. Thus, the - Suriname 69 - Colombia 73 stage where the entities are optimal in terms of internal homogeneity - Venezuela 73 and external isolation can be identifed. You can use a hierarchical divisive - Trinidad and Tobago 70 algorithm in which the beginning is from one big entity - Bahamas 70 containing all the units, and divisions are made in sub- - Nicaragua 70 - Haiti 52 sequent stages. However, this is rarely favored because 4 agglomeration is considered a natural clustering process. One is to consider all units in an • Cluster analysis methods have the annoying feature of entity centered on their average. Another method is to compute the “discovering” clusters when, in fact, none exists. A care- distance of each unit of one entity with each of the other entity and ful examination of the computer output for cluster analy- take the average. Depending on how this distance is com- number of clusters, should tell you whether or not natural puted, names such as centroid, average linkage, single linkage, clusters really exist. Different methods can give differ- • Since there is no target variable, the clusters so discovered ent results. No specifc guideline can • Different clustering methods can give different clusters. This method uses the by several different methods and then look for consensus farthest distance between units belonging to different entities as the among them. The consensus may be diffcult to identify in a multivariate Cluster analysis can also be done on just one variable. Indrayan and Kumar [4] have given a procedure to shows the dendrogram obtained for Pan American countries when identify consensus clusters in the case of multivariate data. The method followed for this clustering is the average link- Details of the procedures just described and of several age. The distance on the horizontal axis is rescaled in proportion other cluster procedures are available in a book by Everitt to the actual distances between entities. These are given in • The clustering mentioned above is different from the clus- Table C. For this, papers by Mantel [6] and Fraser [7] makes them distinct, and qualify them to be called natural clusters. Monte Carlo comparison of six The most diffcult decision in the hierarchical clustering process is hierarchical clustering methods on random data. An examination of procedures for determin- cluster sampling for feld surveys, the clusters are mostly villages, ing the number of clusters in a data set. Re: Clustering of disease in population units: An exact test instead of individual units. Clustering of disease in population units: An exact test When the size of the clusters is not large, i. This tends to increase the total number of subjects in the sample without a corresponding increase clustering effect, see design effect in the cost. When subjects in close proximity are included in the and the rate of homogeneity sample, the travel time and cost are saved. If a population comprises a total of N clusters, then n clusters out of N are randomly selected. If the ith cluster has Mi subjects, then a total of ΣMi elements of these cluster randomization, see block, cluster, n clusters are investigated. This sampling gives extremely good results when the units within the clusters are heterogeneous with respect to the outcome of interest. The method is used also in settings with a large number clusters, see also cluster analysis of units, but then they are divided into small clusters. The term is used generally for a ters are delimited by bold lines and 3 have been selected out of 10 collection of those units who have something in common. For example, it is easy to distinctive statistical feature of clusters is their internal homogeneity draw a list of hospitals than a list of patients of a particular disease.

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Prolonged membrane depolarization Myopathies (eg propranolol 40 mg discount capillaries exercise, Duchenne’s dystrophy) and contraction of extraocular muscles follow- ing administration of succinylcholine transiently raise intraocular pressure and theoretically could compromise an injured eye generic propranolol 80 mg with mastercard coronary heart 7 acupuncture. However buy 40mg propranolol fast delivery heart disease 30s, there is no Following denervation injuries (spinal cord evidence that succinylcholine leads to worsened injuries, larger burns), the immature isoform of outcome in patients with “open” eye injuries. Masseter Muscle Rigidity release is not reliably prevented by pretreatment with Succinylcholine transiently increases muscle tone a nondepolarizer. Some difculty may ini- seems to peak in 7–10 days following the injury, but tially be encountered in opening the mouth because the exact time of onset and the duration of the risk of incomplete relaxation of the jaw. The risk of hyperkalemia from succinyl- increase in tone preventing laryngoscopy is abnor- choline is minimal in the frst 2 days afer spinal cord mal and can be a premonitory sign of malignant or burn injury. Malignant Hyperthermia Patients who have received succinylcholine have Succinylcholine is a potent triggering agent in an increased incidence of postoperative myal- patients susceptible to malignant hyperthermia, gia. The efcacy of nondepolarizing pretreatment a hypermetabolic disorder of skeletal muscle (see is controversial. The relation- pathogenesis is completely diferent and there is no ship between fasciculations and postoperative myal- need to avoid use of succinylcholine in patients with gias is also inconsistent. Generalized Contractions serum creatine kinase can be detected following Patients aficted with myotonia may develop myoc- administration of succinylcholine. Prolonged Paralysis Nondepolarizing As discussed above, patients with reduced levels of normal pseudocholinesterase may have a longer Muscle Relaxants than normal duration of action, whereas patients with atypical pseudocholinesterase will experience Unique Pharmacological markedly prolonged paralysis. Intracranial Pressure is a wide selection of nondepolarizing muscle Succinylcholine may lead to an activation of the relaxants (Tables 11–6 and 11–7). Based on their electroencephalogram and slight increases in cere- chemical structure, they can be classifed as benzyl- bral blood fow and intracranial pressure in some isoquinolinium, steroidal, or other compounds. Muscle fasciculations stimulate muscle ofen said that choice of a particular drug depends stretch receptors, which subsequently increase on its unique characteristics, which are ofen related cerebral activity. The increase in intracranial pres- to its structure; however, for most patients, the dif- sure can be attenuated by maintaining good airway ferences among the intermediate-acting neuro- control and instituting hyperventilation. In general, be prevented by pretreating with a nondepolarizing steroidal compounds can be vagolytic, but this prop- muscle relaxant and administering intravenous lido- erty is most notable with pancuronium and clini- caine (1. The efects of intubation on intracranial pressure far Benzylisoquinolines tend to release histamine. Histamine Release None of the currently available nondepolarizing Slight histamine release may be observed following muscle relaxants equals succinylcholine’s rapid succinylcholine in some patients. Chemical Primary Histamine Vagal Relaxant Structure1 Metabolism Excretion Onset2 Duration 3 Release 4 Blockade5 Atracurium B +++ Insignificant ++ ++ + 0 Cisatracurium B +++ Insignificant ++ ++ Pancuronium S + Renal ++ +++ 0 ++ Vecuronium S + Biliary ++ ++ Rocuronium S Insignificant Biliary +++ ++ 0 + Gantacurium C +++ Insignificant +++ + + 0 1 B, benzylisoquinolone; S, steroidal; C, chlorofumarate. For neuromuscular block- intubating dose 5 min before induction will occupy ers, one ofen specifes the dose that produces 95% enough receptors so that paralysis will quickly follow twitch depression in 50% of individuals. The conse- ing dose produces distressing dyspnea, diplopia, or quence of a long duration of action is the ensuing dysphagia; in such instances, the patient should be difculty in completely reversing the blockade and reassured, and induction of anesthesia should pro- a subsequent increased incidence of postoperative ceed without delay. As a general rule, the measureable deterioration in respiratory function more potent the nondepolarizing muscle relax- (eg, decreased forced vital capacity) and may lead to ant, the slower its speed of onset; the “explana- oxygen desaturation in patients with marginal pul- tory dogma” is that greater potency necessitates monary reserve. Tese negative side efects are more a smaller dose, with fewer total drug molecules, common in older, sicker patients. Potentiation by Other Nondepolarizers To prevent fasciculations and myalgias, 10% to Some combinations of nondepolarizers produce a 15% of a nondepolarizer intubating dose can be greater than additive (synergistic) neuromuscular administered 5 min before succinylcholine. The lack of synergism (ie, the drugs are administered only shortly before succinylcholine, only additive) by closely related compounds (eg, myalgias, but not fasciculations, will be inhibited. In clinical doses, the nondepolarizers difer in their relative efects on nicotinic and muscarinic choliner- C. Some older agents (tubocurarine and, Following intubation, muscle paralysis may need to to a lesser extent, metocurine) blocked autonomic be maintained to facilitate surgery, (eg, abdominal ganglia, reducing the ability of the sympathetic ner- operations), to permit a reduced depth of anesthe- vous system to increase heart contractility and rate sia, or to control ventilation. Tere is great variabil- in response to hypotension and other intraoperative ity among patients in response to muscle relaxants. In contrast, pancuronium (and gallamine) Monitoring neuromuscular function with a nerve block vagal muscarinic receptors in the sinoatrial stimulator helps to prevent over- and underdos- node, resulting in tachycardia. All newer nondepo- ing and to reduce the likelihood of serious residual larizing relaxants, including atracurium, cisatracu- muscle paralysis in the recovery room. Maintenance rium, vecuronium, and rocuronium, are devoid of doses, whether by intermittent boluses or con- signifcant autonomic efects in their recommended tinuous infusion (Table 11–7), should be guided dosage ranges. Histamine Release some instances, clinical signs may precede twitch Histamine release from mast cells can result in recovery because of difering sensitivities to mus- bronchospasm, skin fushing, and hypotension from cle relaxants between muscle groups or technical peripheral vasodilation. Some return curium are capable of triggering histamine release, of neuromuscular transmission should be evident particularly at higher doses. Slow injection rates and prior to administering each maintenance dose, if H1 and H2 antihistamine pretreatment ameliorate the patient needs to resume spontaneous ventila- these side efects. Hepatic Clearance at or just above the rate that allows some return of Only pancuronium and vecuronium are metab- neuromuscular transmission so that drug efects olized to any signifcant degree by the liver. Clinically, liver failure Volatile agents decrease nondepolarizer dosage prolongs pancuronium and rocuronium block- requirements by at least 15%. The actual degree of ade, with less efect on vecuronium, and no efect this postsynaptic augmentation depends on both the on pipecuronium. Renal Excretion except with cisatracurium Doxacurium, pancuronium, vecuronium, and Obese Dosage 20% more than lean body weight; 9 pipecuronium are partially excreted by the onset unchanged kidneys, and their action is prolonged in patients Prolonged duration, except with cisatracurium with renal failure. The elimination of atracurium, Hepatic Increased volume of distribution cisatracurium, mivacurium, and rocuronium is disease Pancuronium and vecuronium – prolonged independent of kidney function. Temperature Cisatracurium – safest alternative Hypothermia prolongs blockade by decreasing Critically Myopathy, polyneuropathy, nicotinic metabolism (eg, mivacurium, atracurium, and cisa- ill acetylcholine receptor up-regulation tracurium) and delaying excretion (eg, pancuronium and vecuronium). Age Respiratory acidosis potentiates the blockade of Neonates have an increased sensitivity to nondepo- most nondepolarizing relaxants and antagonizes larizing relaxants because of their immature neu- its reversal. Tis sensitivity muscular recovery in a hypoventilating postop- does not necessarily decrease dosage requirements, erative patient. Conficting fndings regarding the as the neonate’s greater extracellular space provides neuromuscular efects of other acid–base changes a larger volume of distribution. Drug Interactions or structural diferences between drugs (eg, mono- As noted earlier, many drugs augment nondepo- quaternary versus bisquaternary; steroidal versus larizing blockade (see Table 11–4). Hypermagnese- The presence of neurological or muscular disease mia, as may be seen in preeclamptic patients being can have profound efects on an individual’s response managed with magnesium sulfate (or afer intra- to muscle relaxants (Table 11–9). Cirrhotic 10 venous magnesium administered in the operating liver disease and chronic renal failure ofen room), potentiates a nondepolarizing blockade by result in an increased volume of distribution and a competing with calcium at the motor end-plate. Disease Response to Depolarizers Response to Nondepolarizers Amyotrophic lateral sclerosis Contracture Hypersensitivity Autoimmune disorders Hypersensitivity Hypersensitivity Systemic lupus erythematosus Polymyositis Dermatomyositis Burn injury Hyperkalemia Resistance Cerebral palsy Slight hypersensitivity Resistance Familial periodic paralysis (hyperkalemic) Myotonia and hyperkalemia Hypersensitivity? Guillain–Barré syndrome Hyperkalemia Hypersensitivity Hemiplegia Hyperkalemia Resistance on affected side Muscular denervation (peripheral nerve injury) Hyperkalemia and contracture Normal response or resistance Muscular dystrophy (Duchenne type) Hyperkalemia and malignant hyperthermia Hypersensitivity Myasthenia gravis Resistance Hypersensitivity Myasthenic syndrome Hypersensitivity Hypersensitivity Myotonia Generalized muscular contractions Normal or hypersensitivity Dystrophica Congenital Paramyotonia Severe chronic infection Hyperkalemia Resistance Tetanus Botulism water-soluble drugs, such as muscle relaxants. On persistent diaphragmatic contractions can be dis- the other hand, drugs dependent on hepatic or renal concerting in the face of complete adductor pollicis excretion may demonstrate prolonged clearance paralysis. Tus, depending on the drug chosen, a to blockade, as is ofen confrmed during laryngos- greater initial (loading) dose—but smaller mainte- copy.

By F. Sinikar. Philadelphia University.