Arjen M. Dondorp, M.D., François Nosten, M.D., Poravuth Yi, M.D., Debashish Das, M.D., Aung Phae Phyo, M.D., Joel Tarning, Ph.D., Khin Maung Lwin, M.D., Frederic Ariey, M.D., Warunee Hanpithakpong, Ph.D., Sue J. Lee, Ph.D., Pascal Ringwald, M.D., Kamolrat Silamut, Ph.D., Mallika Imwong, Ph.D., Kesinee Chotivanich, Ph.D., Pharath Lim, M.D., Trent Herdman, Ph.D., Sen Sam An, Shunmay Yeung, Ph.D., Pratap Singhasivanon, M.D., Nicholas P.J. Day, D.M., Niklas Lindegardh, Ph.D., Duong Socheat, M.D., and Nicholas J. White, F.R.S.
ABSTRACT
Background Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai–Cambodian border, historically a site of emerging antimalarial-drug resistance.
Methods In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.
Results We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). p="0.31)." style="font-weight: bold;">
Discussion
Our study shows that P. falciparum parasites from patients in Pailin, western Cambodia, had significantly reduced in vivo susceptibility to artesunate, as compared with parasites from northwestern Thailand — or indeed, apparently, anywhere else in the world. Artesunate resistance was characterized by a markedly prolonged time to parasite clearance, with relatively little heterogeneity among patients. These reduced parasitologic responses could not be explained by pharmacokinetic or other host factors.
The principal pharmacodynamic advantage of using artemisinins rather than other antimalarial drugs is that they accelerate parasite clearance1 by clearing young, circulating, ring-stage parasites and preventing the further maturation and sequestration of these parasites.19,20 This effect accounts for the rapidity of the therapeutic response, its lifesaving benefit in patients with severe malaria, and the notable gametocytocidal activity of the drugs. A few cases of reduced efficacy of artemisinin-based combination therapy have been reported previously. Most of these cases can be explained by the counterfeit nature of the drugs tested.21 In 2002–2003, decreased in vitro sensitivity of P. falciparum to artemether was reported in French Guiana (but not in Cambodia) and was associated with the S769N mutation in the PfSERCA gene.22,23 There were no clinical correlates. In our study, there was no consistent pattern of PfSERCA mutations, despite clear evidence of in vivo artesunate resistance.
Monitoring in western Cambodia has shown a decline in the efficacy of artemisinin-based combination therapy in recent years, but the relative contributions of resistance to artemisinin, the partner drug, and other factors have been unclear.7,8,9,10,24 In a recent Cambodian study, increased numbers of copies of the PfMDR1 gene, a well-established cause of mefloquine resistance,18 was associated with high failure rates with artesunate–mefloquine therapy.7,25 In the current study, despite artesunate resistance, the efficacy of artesunate–mefloquine use was excellent in Pailin (63-day cure rate, 95%), presumably because 95% of parasite isolates had a single PfMDR1 copy. PfMDR1 amplification also causes a small decrease in artemisinin susceptibility,18 but neither this nor any other molecular markers of antimalarial-drug resistance that we evaluated could explain the resistance to artesunate in Pailin.
There was an unexpected discrepancy between the slow clinical and parasitologic responses in Pailin and the relatively normal in vitro susceptibility. The discrepancy can be explained by the reduced susceptibility of the young, ring-form parasites as compared with the more mature trophozoites and schizonts. Currently available in vitro susceptibility tests assess drug exposure over the entire parasite cycle; therefore, the results would be relatively unaffected if only part of the cycle were affected by the mechanism underlying the resistance. Previous studies have not indicated significant differences in parasitologic responses within the dose range that we evaluated (2 to 4 mg per kilogram per day).26 A concentration–effect relationship was evident in Wang Pha but not in Pailin, suggesting that a small shift to the right along the dose–response curve may also have occurred at the Thai–Burmese border.27
Chloroquine and sulfadoxine–pyrimethamine resistance in P. falciparum emerged in the late 1950s and 1960s on the Thai–Cambodian border and spread across Asia and then Africa, contributing to millions of deaths from malaria.28,29 Artemisinins have been available as monotherapies in western Cambodia for more than 30 years, in a variety of forms and doses, whereas in most countries (other than China, where they were discovered), they have been a relatively recent introduction.1 Despite the early implementation of an active malaria-control program by the Ministry of Health of Cambodia, including the introduction of artemisinin-based combination therapies in 2001, a recent survey showed that 78% of artemisinin use in western Cambodia consisted of monotherapy provided through the private sector.30 The extended period of often-suboptimal use, and the genetic background of parasites from this region,31 might have contributed to the emergence and subsequent spread of these new artemisinin-resistant parasites in western Cambodia. In contrast, artemisinin derivatives have been used almost exclusively in combination with mefloquine on the Thai–Burmese border, where parasitologic responses to artemisinins remain good, even after 15 years of intensive use.27 Measures for containment are now urgently needed to limit the spread of these parasites from western Cambodia and to prevent a major threat to current plans for eliminating malaria.
Supported by grants from the Wellcome Trust of Great Britain (Major Overseas Programme–Thailand Unit Core Grant), the Li Ka Shing Foundation (B9RMXT0-2), the Global Malaria Program, and the WHO (Bill and Melinda Gates Foundation grant 48821 and Western Pacific Regional Office grant WP/07/66224 CAM).
No potential conflict of interest relevant to this article was reported.
We thank the patients for their participation; all staff members of the Pailin Referral Hospital and the SMRU clinic for their dedicated care for the patients and assistance in the study; Tim Anderson for help with the in vitro sensitivity testing; the Village Malaria Workers in Pailin for their collaboration; and Vasee Moorthy, Golam Kibria, Mark Fukuda, and George Watt for help in executing and organizing the trial in Pailin.
Management of Type 2 Diabetes
Sumber : nejm org
Case Vignette
A 55-year-old woman with type 2 diabetes, obesity, and hypertension has been under your care for the past 2 years. She has no history of microalbuminuria, retinopathy, or neuropathy. She has never had a cardiovascular event and reports no cardiac symptoms.
In the past, she has successfully lost weight (from 5 to 12 kg) on various diets but each time has regained all of the weight she lost. She tries to walk 30 minutes each day. She monitors her fasting glucose levels three times weekly using a personal glucometer, and her morning fasting glucose levels have ranged between 110 and 140 mg per deciliter (6.1 and 7.8 mmol liter). She has been receiving metformin (1000 mg twice a day) and glipizide (10 mg twice daily).
She has hypertension that is treated with hydrochlorothiazide (25 mg daily) and lisinopril (20 mg daily). She takes aspirin (81 mg daily) and simvastatin (20 mg daily). She notes that she consistently takes her medications.
She has a family history of cardiovascular disease with early stroke. On physical examination, her body-mass index (the weight in kilograms divided by the square of the height in meters) is 31. Her blood pressure is 128/78 mm Hg. Her general assessment, including cardiorespiratory, abdominal, and neurologic examinations, is normal.
Her glycated hemoglobin level is 8.1%, and her creatinine 0.9 mg per deciliter (80 mmol per liter). She has no microalbuminuria, and liver-function studies are normal. She seeks advice about the management of her diabetes.
Treatment Options
I.Add Pioglitazone
Ronald B. Goldberg, M.D.
The case vignette illustrates a key therapeutic decision most physicians face when managing type 2 diabetes: namely, how to advance treatment in patients whose glycated hemoglobin levels remain above the target value despite dual oral antihyperglycemic therapy, such as with metformin and glipizide, as in this patient. Medications such as pioglitazone can delay the almost inevitable necessity of initiating the use of insulin in such patients. Furthermore, patients receiving a thiazolidinedione who later need insulin may have a better response to it than those not receiving a thiazolidinedione. However, there are no comparative data to determine what the optimal treatment should be when a patient does not have a response to dual oral therapy. I believe the addition of pioglitazone is a rational next step.
Several short-term trials have examined the effects of thiazolidinedione treatment as an "add-on" therapy in patients with elevated glycated hemoglobin values who are already taking maximum doses of metformin and a sulfonylurea. Collectively, these studies demonstrate that the addition of a thiazolidinedione can lower the glycated hemoglobin level by as much as 2 percentage points. Three such studies compared the addition of a thiazolidinedione or insulin to the metformin–sulfonylurea treatment regimen of subjects with baseline glycated hemoglobin values of more than 9.0%.1,2,3 These studies showed that a thiazolidinedione had an efficacy similar to that of insulin in lowering glycated hemoglobin levels. Together, the studies suggest that, as compared with treatment with insulin, treatment with pioglitazone is associated with a lower incidence of hypoglycemia, a similar amount of weight gain, and an increase in the high-density lipoprotein (HDL) cholesterol level. The expenses associated with the triple oral therapies that include a thiazolidinedione are greater than those of either insulin (70% NPH insulin and 30% regular insulin) or insulin glargine added to metformin–sulfonylurea.2,3
Pioglitazone is likely to have few side effects and can be taken once daily. The weight gain that typically accompanies its use (3–4 kg, on average) can be mitigated by intensifying medical nutrition therapy at the time of initiation. Since recent evidence suggests that the use of thiazolidinediones may reduce bone density, a bone-density scan may be appropriate, particularly for women who are already postmenopausal.
It is possible that the need for initiating insulin therapy is delayed by the addition of pioglitazone in patients whose diabetes is inadequately controlled with the use of metformin and sulfonylurea. One study, A Diabetes Outcome Progression Trial (ADOPT), showed that rosiglitazone, when used as initial monotherapy in patients with a recent diagnosis of type 2 diabetes, maintained glycemic targets for longer than did treatment with sulfonylurea or metformin and suggested that this might be due to a beneficial effect on beta-cell function. Though the addition of pioglitazone to a regimen of metformin and a sulfonylurea could be expected to have a durable effect on the maintenance of improved glycemic control, especially if administered soon after the glycated hemoglobin level begins to rise, longer-term studies are needed to evaluate the effectiveness of this approach.
In support of this strategy, the ratio of proinsulin to insulin, considered a marker of beta-cell function, improved when pioglitazone was added to metformin and sulfonylurea as treatment.4 Pioglitazone also mobilizes fat from the liver, an effect that is thought to be accompanied by sensitization of the liver to insulin. Fatty liver is common in patients with diabetes and is linked in selected patients to the development of steatohepatitis, which pioglitazone has been shown to ameliorate.
Finally, despite the findings in meta-analyses that rosiglitazone may increase the risk of ischemic events, a similar effect has not been demonstrated for pioglitazone.5 In fact, there is evidence that treatment with pioglitazone increases the HDL cholesterol level by 10 to 15%, lowers the systolic blood pressure by 4 to 5 mm Hg, and reduces the thickness of the carotid wall, as compared with a sulfonylurea. In addition, a marginally beneficial effect on ischemic events was found when pioglitazone was added to existing treatment in patients with type 2 diabetes in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), a randomized, double-blind, controlled clinical trial of a strategy that was considered cost-effective. In combination, these results support the possibility that pioglitazone may have cardioprotective effects; it would be my choice for this patient.
Dr. Goldberg reports receiving speaker's honoraria from both Takeda and GlaxoSmithKline and consulting fees and grant support from Takeda. No other potential conflict of interest relevant to this article was reported.
From the Division of Endocrinology, Diabetes, and Metabolism, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami.
II. Add Neutral Protamine Hagedorn (NPH) Insulin before Bedtime
Rury Holman, F.R.C.P.
The case vignette of a patient with type 2 diabetes who has suboptimal glycemic control despite receiving maximum-dose oral therapy with metformin and a sulfonylurea is all too familiar. It reflects the progressive nature of the condition, in which declining beta-cell function results in elevations in glycemia year after year6 unless antidiabetes medications are added or the doses of these medications are increased. In this obese patient who has no clinical evidence of complications from diabetes and whose cardiovascular risk factors are currently well managed, the immediate concern is the need to reduce the glycated hemoglobin level to below that recommended in the International Diabetes Federation 2005 guidelines (6.5%) to minimize the risk of future complications. Ideally, glycemic control should be handled in a proactive manner, according to the joint consensus algorithm for the management of hyperglycemia from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD),7 which suggests that a glycated hemoglobin value of 7% or more should serve as "a call to action to initiate or change therapy, with the goal of achieving a glycated hemoglobin level as close to the nondiabetic range as possible."
Adding a third oral agent is not recommended, given that the patient already has a glycated hemoglobin value of 8.1% and that this approach is relatively more expensive and potentially not as effective in reducing glycemia as adding insulin would be.7 Adding a basal insulin to existing oral therapy has been shown to be more effective in reducing glycated hemoglobin levels than adding a thiazolidinedione — especially at higher initial glycated hemoglobin values — with less weight gain, no edema, salutary lipid changes, and a lower cost.3 Indeed, the increased risk of edema, congestive heart failure, and fractures in women now recognized to be associated with thiazolidinediones and the uncertainty about their effects on the risk of cardiovascular disease have led to an updated recommendation by the ADA–EASD that greater caution should be exercised in their use. Adding exenatide in this patient would be unlikely to achieve the target glycated hemoglobin levels (<6.5% style="font-weight: bold;">III.Add Exenatide Twice Daily
Daniel J. Drucker, M.D.
The management options for the treatment of type 2 diabetes have become more complex since the introduction of several new classes of drugs and emerging data about the safety and efficacy of older drugs. It remains difficult to predict the response to specific therapies targeting different antidiabetes mechanisms, and all three options posed in the case vignette are reasonable and efficacious. There are no available head-to-head trials that have directly compared the efficacies of pioglitazone, NPH insulin, and exenatide in patients in whom glycemic control has not been achieved with the use of metformin and a sulfonylurea; thus, it seems reasonable to make clinical decisions on the basis of available data. The addition of pioglitazone will improve insulin sensitivity and glucose control but probably will be associated with fluid retention and weight gain and an increased risk of osteoporosis.10 Insulin therapy, while effective, may also be associated with weight gain and a need for more frequent glucose monitoring to minimize the risk of hypoglycemia.
Two new classes of antidiabetes agents based on the potentiation of incretin action have been approved for the treatment of type 2 diabetes: the glucagon-like peptide 1 (GLP-1) receptor agonists, exemplified by exenatide, and the dipeptidyl peptidase IV inhibitors that include sitagliptin and vildagliptin11; other drugs are currently in clinical trials. Exenatide (as well as GLP-1) lowers blood glucose levels by stimulating insulin secretion and inhibiting glucagon secretion. These drugs also appear to inhibit gastric emptying and enhance satiety, leading to weight loss in a substantial number of patients.
A recent meta-analysis of clinical trials involving incretin therapies concluded that the efficacy of these agents was generally similar to that of other antidiabetes therapies. Of direct relevance to the treatment of this patient, exenatide produces more potent control of postprandial glycemia than NPH insulin or pioglitazone, probably because exenatide suppresses gastric emptying. This finding may be important, in view of data linking the control of postprandial glycemia to cardiovascular risk in patients with diabetes. The opportunity to improve postprandial glucose control, while achieving weight loss, is appealing.
Although considerable preclinical data suggest that GLP-1–receptor agonists improve beta-cell function and are cardioprotective, such discussions may not be directly relevant for the care of this patient. The actions of GLP-1–receptor agonists on the stimulation of insulin and inhibition of glucagon secretion are glucose-dependent; hence, there is a very low risk of hypoglycemia in the absence of concomitant sulfonylurea therapy. The remarkable ability of GLP-1–receptor agonists to improve the glucose sensitivity of beta cells and potentiate insulin secretion rapidly suggests that discontinuation of the glipizide (or alternatively, the initial reduction of the dose by 50%), coincident with initiation of exenatide therapy, would be prudent.
The addition of exenatide to ongoing metformin and sulfonylurea therapy was associated with an absolute reduction of 0.8 to 1.0% in the glycated hemoglobin level, with 0.9 to 1.6 kg of weight loss, after 30 weeks of therapy in subjects with type 2 diabetes.12 There have been several head-to-head comparisons of regimens of insulin administration, as compared with twice-daily exenatide, in patients who did not have adequate glycemic control when they were taking metformin and a sulfonylurea.13,14 The use of exenatide and the use of insulin resulted in similar degrees of reduction in glycated hemoglobin and similar numbers of hypoglycemic events, but the resultant body weight was significantly higher at the end of the study in patients receiving insulin, often as much as 4 kg higher than in subjects taking exenatide.
What are the potential limitations associated with exenatide therapy? Gastrointestinal side effects, principally nausea, generally abate several weeks after the initiation of exenatide therapy. Nausea and gastrointestinal upset may limit tolerability in 10 to 20% of patients, and pancreatitis has recently been described in subjects treated with exenatide, although the actual prevalence is low and the pathophysiological characteristics remain uncertain. Exenatide therapy is expensive, and its long-term durability and safety have not been defined. Since incretin drugs are new, they are comparatively more expensive than older agents, and we do not yet have outcome studies to determine the long-term effects of exenatide on beta-cell function or cardiovascular events. On the other hand, the use of exenatide reduces glycemia through multiple mechanisms of action, is simple to use, and provides superior control of postprandial glucose. Critically, unlike with existing diabetes therapies, many subjects will experience satiety and weight loss. These features make exenatide an appealing option for the treatment of patients in whom existing antidiabetic agents fail to achieve glycemic control.
Dr. Drucker reports receiving advisory or consulting fees from Amylin Pharmaceuticals, Arisaph Pharmaceuticals, Chugai, Conjuchem, Eli Lilly, Emisphere Technologies, GlaxoSmithKline, Glenmark Pharmaceuticals, Isis Pharmaceuticals, Merck Research Laboratories, Novartis Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Phenomix, Takeda, and Transition Pharmaceuticals; and grant support from Eli Lilly, Merck, and Novo Nordisk. No other potential conflict of interest relevant to this article was reported.
From Banting and Best Diabetes Centre, University of Toronto, Mount Sinai Hospital, Toronto.
Case Vignette
A 55-year-old woman with type 2 diabetes, obesity, and hypertension has been under your care for the past 2 years. She has no history of microalbuminuria, retinopathy, or neuropathy. She has never had a cardiovascular event and reports no cardiac symptoms.
In the past, she has successfully lost weight (from 5 to 12 kg) on various diets but each time has regained all of the weight she lost. She tries to walk 30 minutes each day. She monitors her fasting glucose levels three times weekly using a personal glucometer, and her morning fasting glucose levels have ranged between 110 and 140 mg per deciliter (6.1 and 7.8 mmol liter). She has been receiving metformin (1000 mg twice a day) and glipizide (10 mg twice daily).
She has hypertension that is treated with hydrochlorothiazide (25 mg daily) and lisinopril (20 mg daily). She takes aspirin (81 mg daily) and simvastatin (20 mg daily). She notes that she consistently takes her medications.
She has a family history of cardiovascular disease with early stroke. On physical examination, her body-mass index (the weight in kilograms divided by the square of the height in meters) is 31. Her blood pressure is 128/78 mm Hg. Her general assessment, including cardiorespiratory, abdominal, and neurologic examinations, is normal.
Her glycated hemoglobin level is 8.1%, and her creatinine 0.9 mg per deciliter (80 mmol per liter). She has no microalbuminuria, and liver-function studies are normal. She seeks advice about the management of her diabetes.
Treatment Options
I.Add Pioglitazone
Ronald B. Goldberg, M.D.
The case vignette illustrates a key therapeutic decision most physicians face when managing type 2 diabetes: namely, how to advance treatment in patients whose glycated hemoglobin levels remain above the target value despite dual oral antihyperglycemic therapy, such as with metformin and glipizide, as in this patient. Medications such as pioglitazone can delay the almost inevitable necessity of initiating the use of insulin in such patients. Furthermore, patients receiving a thiazolidinedione who later need insulin may have a better response to it than those not receiving a thiazolidinedione. However, there are no comparative data to determine what the optimal treatment should be when a patient does not have a response to dual oral therapy. I believe the addition of pioglitazone is a rational next step.
Several short-term trials have examined the effects of thiazolidinedione treatment as an "add-on" therapy in patients with elevated glycated hemoglobin values who are already taking maximum doses of metformin and a sulfonylurea. Collectively, these studies demonstrate that the addition of a thiazolidinedione can lower the glycated hemoglobin level by as much as 2 percentage points. Three such studies compared the addition of a thiazolidinedione or insulin to the metformin–sulfonylurea treatment regimen of subjects with baseline glycated hemoglobin values of more than 9.0%.1,2,3 These studies showed that a thiazolidinedione had an efficacy similar to that of insulin in lowering glycated hemoglobin levels. Together, the studies suggest that, as compared with treatment with insulin, treatment with pioglitazone is associated with a lower incidence of hypoglycemia, a similar amount of weight gain, and an increase in the high-density lipoprotein (HDL) cholesterol level. The expenses associated with the triple oral therapies that include a thiazolidinedione are greater than those of either insulin (70% NPH insulin and 30% regular insulin) or insulin glargine added to metformin–sulfonylurea.2,3
Pioglitazone is likely to have few side effects and can be taken once daily. The weight gain that typically accompanies its use (3–4 kg, on average) can be mitigated by intensifying medical nutrition therapy at the time of initiation. Since recent evidence suggests that the use of thiazolidinediones may reduce bone density, a bone-density scan may be appropriate, particularly for women who are already postmenopausal.
It is possible that the need for initiating insulin therapy is delayed by the addition of pioglitazone in patients whose diabetes is inadequately controlled with the use of metformin and sulfonylurea. One study, A Diabetes Outcome Progression Trial (ADOPT), showed that rosiglitazone, when used as initial monotherapy in patients with a recent diagnosis of type 2 diabetes, maintained glycemic targets for longer than did treatment with sulfonylurea or metformin and suggested that this might be due to a beneficial effect on beta-cell function. Though the addition of pioglitazone to a regimen of metformin and a sulfonylurea could be expected to have a durable effect on the maintenance of improved glycemic control, especially if administered soon after the glycated hemoglobin level begins to rise, longer-term studies are needed to evaluate the effectiveness of this approach.
In support of this strategy, the ratio of proinsulin to insulin, considered a marker of beta-cell function, improved when pioglitazone was added to metformin and sulfonylurea as treatment.4 Pioglitazone also mobilizes fat from the liver, an effect that is thought to be accompanied by sensitization of the liver to insulin. Fatty liver is common in patients with diabetes and is linked in selected patients to the development of steatohepatitis, which pioglitazone has been shown to ameliorate.
Finally, despite the findings in meta-analyses that rosiglitazone may increase the risk of ischemic events, a similar effect has not been demonstrated for pioglitazone.5 In fact, there is evidence that treatment with pioglitazone increases the HDL cholesterol level by 10 to 15%, lowers the systolic blood pressure by 4 to 5 mm Hg, and reduces the thickness of the carotid wall, as compared with a sulfonylurea. In addition, a marginally beneficial effect on ischemic events was found when pioglitazone was added to existing treatment in patients with type 2 diabetes in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), a randomized, double-blind, controlled clinical trial of a strategy that was considered cost-effective. In combination, these results support the possibility that pioglitazone may have cardioprotective effects; it would be my choice for this patient.
Dr. Goldberg reports receiving speaker's honoraria from both Takeda and GlaxoSmithKline and consulting fees and grant support from Takeda. No other potential conflict of interest relevant to this article was reported.
From the Division of Endocrinology, Diabetes, and Metabolism, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami.
II. Add Neutral Protamine Hagedorn (NPH) Insulin before Bedtime
Rury Holman, F.R.C.P.
The case vignette of a patient with type 2 diabetes who has suboptimal glycemic control despite receiving maximum-dose oral therapy with metformin and a sulfonylurea is all too familiar. It reflects the progressive nature of the condition, in which declining beta-cell function results in elevations in glycemia year after year6 unless antidiabetes medications are added or the doses of these medications are increased. In this obese patient who has no clinical evidence of complications from diabetes and whose cardiovascular risk factors are currently well managed, the immediate concern is the need to reduce the glycated hemoglobin level to below that recommended in the International Diabetes Federation 2005 guidelines (6.5%) to minimize the risk of future complications. Ideally, glycemic control should be handled in a proactive manner, according to the joint consensus algorithm for the management of hyperglycemia from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD),7 which suggests that a glycated hemoglobin value of 7% or more should serve as "a call to action to initiate or change therapy, with the goal of achieving a glycated hemoglobin level as close to the nondiabetic range as possible."
Adding a third oral agent is not recommended, given that the patient already has a glycated hemoglobin value of 8.1% and that this approach is relatively more expensive and potentially not as effective in reducing glycemia as adding insulin would be.7 Adding a basal insulin to existing oral therapy has been shown to be more effective in reducing glycated hemoglobin levels than adding a thiazolidinedione — especially at higher initial glycated hemoglobin values — with less weight gain, no edema, salutary lipid changes, and a lower cost.3 Indeed, the increased risk of edema, congestive heart failure, and fractures in women now recognized to be associated with thiazolidinediones and the uncertainty about their effects on the risk of cardiovascular disease have led to an updated recommendation by the ADA–EASD that greater caution should be exercised in their use. Adding exenatide in this patient would be unlikely to achieve the target glycated hemoglobin levels (<6.5% style="font-weight: bold;">III.Add Exenatide Twice Daily
Daniel J. Drucker, M.D.
The management options for the treatment of type 2 diabetes have become more complex since the introduction of several new classes of drugs and emerging data about the safety and efficacy of older drugs. It remains difficult to predict the response to specific therapies targeting different antidiabetes mechanisms, and all three options posed in the case vignette are reasonable and efficacious. There are no available head-to-head trials that have directly compared the efficacies of pioglitazone, NPH insulin, and exenatide in patients in whom glycemic control has not been achieved with the use of metformin and a sulfonylurea; thus, it seems reasonable to make clinical decisions on the basis of available data. The addition of pioglitazone will improve insulin sensitivity and glucose control but probably will be associated with fluid retention and weight gain and an increased risk of osteoporosis.10 Insulin therapy, while effective, may also be associated with weight gain and a need for more frequent glucose monitoring to minimize the risk of hypoglycemia.
Two new classes of antidiabetes agents based on the potentiation of incretin action have been approved for the treatment of type 2 diabetes: the glucagon-like peptide 1 (GLP-1) receptor agonists, exemplified by exenatide, and the dipeptidyl peptidase IV inhibitors that include sitagliptin and vildagliptin11; other drugs are currently in clinical trials. Exenatide (as well as GLP-1) lowers blood glucose levels by stimulating insulin secretion and inhibiting glucagon secretion. These drugs also appear to inhibit gastric emptying and enhance satiety, leading to weight loss in a substantial number of patients.
A recent meta-analysis of clinical trials involving incretin therapies concluded that the efficacy of these agents was generally similar to that of other antidiabetes therapies. Of direct relevance to the treatment of this patient, exenatide produces more potent control of postprandial glycemia than NPH insulin or pioglitazone, probably because exenatide suppresses gastric emptying. This finding may be important, in view of data linking the control of postprandial glycemia to cardiovascular risk in patients with diabetes. The opportunity to improve postprandial glucose control, while achieving weight loss, is appealing.
Although considerable preclinical data suggest that GLP-1–receptor agonists improve beta-cell function and are cardioprotective, such discussions may not be directly relevant for the care of this patient. The actions of GLP-1–receptor agonists on the stimulation of insulin and inhibition of glucagon secretion are glucose-dependent; hence, there is a very low risk of hypoglycemia in the absence of concomitant sulfonylurea therapy. The remarkable ability of GLP-1–receptor agonists to improve the glucose sensitivity of beta cells and potentiate insulin secretion rapidly suggests that discontinuation of the glipizide (or alternatively, the initial reduction of the dose by 50%), coincident with initiation of exenatide therapy, would be prudent.
The addition of exenatide to ongoing metformin and sulfonylurea therapy was associated with an absolute reduction of 0.8 to 1.0% in the glycated hemoglobin level, with 0.9 to 1.6 kg of weight loss, after 30 weeks of therapy in subjects with type 2 diabetes.12 There have been several head-to-head comparisons of regimens of insulin administration, as compared with twice-daily exenatide, in patients who did not have adequate glycemic control when they were taking metformin and a sulfonylurea.13,14 The use of exenatide and the use of insulin resulted in similar degrees of reduction in glycated hemoglobin and similar numbers of hypoglycemic events, but the resultant body weight was significantly higher at the end of the study in patients receiving insulin, often as much as 4 kg higher than in subjects taking exenatide.
What are the potential limitations associated with exenatide therapy? Gastrointestinal side effects, principally nausea, generally abate several weeks after the initiation of exenatide therapy. Nausea and gastrointestinal upset may limit tolerability in 10 to 20% of patients, and pancreatitis has recently been described in subjects treated with exenatide, although the actual prevalence is low and the pathophysiological characteristics remain uncertain. Exenatide therapy is expensive, and its long-term durability and safety have not been defined. Since incretin drugs are new, they are comparatively more expensive than older agents, and we do not yet have outcome studies to determine the long-term effects of exenatide on beta-cell function or cardiovascular events. On the other hand, the use of exenatide reduces glycemia through multiple mechanisms of action, is simple to use, and provides superior control of postprandial glucose. Critically, unlike with existing diabetes therapies, many subjects will experience satiety and weight loss. These features make exenatide an appealing option for the treatment of patients in whom existing antidiabetic agents fail to achieve glycemic control.
Dr. Drucker reports receiving advisory or consulting fees from Amylin Pharmaceuticals, Arisaph Pharmaceuticals, Chugai, Conjuchem, Eli Lilly, Emisphere Technologies, GlaxoSmithKline, Glenmark Pharmaceuticals, Isis Pharmaceuticals, Merck Research Laboratories, Novartis Pharmaceuticals, Novo Nordisk, NPS Pharmaceuticals, Phenomix, Takeda, and Transition Pharmaceuticals; and grant support from Eli Lilly, Merck, and Novo Nordisk. No other potential conflict of interest relevant to this article was reported.
From Banting and Best Diabetes Centre, University of Toronto, Mount Sinai Hospital, Toronto.
STUDI DESKRIPTIF GAMBARAN HASIL SPIROMETRI PADA PASIEN-PASIEN PENYAKIT PARU OBSTRUKTIF PARU KRONIK DI RSUP DR. WAHIDIN SUDIROHUSODO MAKASSAR
BAB I
PENDAHULUAN
A. LATAR BELAKANG
Penyakit Paru Obstruktif Kronik ini merupakan penyakit pernafasan yang prevalensi, tingkat morbiditas dan mortalitasnya meningkat dari tahun ke tahun. Saat ini PPOK menempati urutan keempat dalam hal penyebab kematian di seluruh dunia dan WHO memperkirakan pada tahun 2020 PPOK akan menempati peringkat ketiga penyakit dalam menyebabkan kematian. Angka laju kematiannya juga meningkat dalam 20 tahun terakhir ini di Aamerika Serikat. Pada wanita tahun 1980, 20,1 : 100.000, dan pada tahun 2000, 56,7 : 100.000. sedangkan pada laki-laki, tahun 1980, sebanyak 73,0 : 100.000 dan pada tahun 2000, sebanyak 82,6 : 100.000. 1, 2, 3
National Health Institue mengatakan bahwa dahulu Penyakit Paru Obstruktif Kronik kurang populer dibandingkan sekarang. Namun, sekarang PPOK sangatlah sering terjadi. Rata-rata 12 juta orang dewasa di Amerika Serikat didiagnosa PPOK, dan 120.000 diantaranya meninggal tiap tahunnya. Di lain pihak juga masih terdapat 12 juta orang lagi di Amerika Serikat yang belum terdiagnosa. Disamping itu, sekarang tingkat kematian PPOK meningkat.1
Di Indonesia, PPOK (Penyakit Paru Obstruktif Kronik) merupakan masalah kesehatan umum dan menyerang sekitar 10% penduduk usia 40 tahun ke atas. Jumlah kasus PPOK ini memiliki kecenderungan untuk meningkat.4
Disamping itu untuk menegakkan diagnosa PPOK, dibutuhkan spirometri untuk mengukur fungsi faal paru-paru. Sehingga diagnosis PPOK dapat ditegakkan secara pasti. Namun, ukuran standar pada spirometri berubah-ubah dan berbeda-beda pada tiap institut atau guideline.5
Pada PPOK, terjadi hambatan aliran udara pada saat ekspirasi sehingga mempengaruhi hasil spirometri seperti FEV1 (Forced Expiratory Volume in one second), FVC (Forced Vital Capacity), dan total volume paru-paru. Namun, perubahan hasil spirometri pada PPOK ini berbeda-beda sesuai umur, jenis kelamin, suku, riwayat merokok, pekerjaan , riwayat penyakit pernafasaan lainnya, dan adanya riwayat penyakit jantung.2
Untuk itulah dilakukan penelitian tentang gambaran pasien-pasien PPOK berdasarkan hasil spirometri di RSUP DR. Wahidin Sudirohusodo Makassar. Karena penulis merasa bahwa PPOK ini sangat penting dan ingin memperoleh gambaran penyakit pada pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar.
B. RUMUSAN MASALAH
Berdasarkan latar belakang masalah di atas, maka kami mengambil rumusan masalah dalam penelitian ini sebagai berikut : Bagaimana gambaran hasil spirometri pada pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar berdasarkan umur, jenis kelamin, suku, pasien dengan riwayat merokok, pekerjaan , riwayat penyakit pernafasaan lainnya, dan adanya riwayat penyakit jantung.
C. TUJUAN PENELITIAN
1. Tujuan Umum
Penelitian ini bertujuan untuk melihat gambaran hasil spirometri secara umum pada pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar.
2. Tujuan Khusus
2.1. Mengetahui gambaran umur dengan hasil spirometri pada pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar.
2.2. Mengetahui gambaran jenis kelamin dengan hasil spirometri pada pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar.
2.3. Mengetahui gambaran suku dengan hasil spirometri pada pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar.
2.4. Mengetahui gambaran riwayat merokok dengan hasil spirometri pada pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar.
2.5. Mengetahui gambaran pekerjaan dengan hasil spirometri pada pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar.
2.6. Mengetahui gambaran riwayat penyakit pernafasan penyerta dengan hasil spirometri pada pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar.
2.7. Mengetahui gambaran riwayat penyakit jantung dengan hasil spirometri pada pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar.
D. MANFAAT PENELITIAN
1. Hasil dari penelitian ini sebagai salah satu sumber informasi bagi Fakultas Kedokteran Unhas.
2. Data yang diperoleh diharapkan dapat menjadi bahan masukan bagi pihak-pihak yang memerlukan informasi berkaitan dengan data-data yang kami kumpulkan.
3. Hasil penelitian ini diharapkan dapat memperkaya khasanah ilmu pengetahuan dan menjadi salah satu bahan bacaan bagi peneliti berikutnya.
4. Penelitian ini merupakan aplikasi dari tridarma perguruan tinggi dan merupakan pengalaman berharga dan wadah latihan pengembangan diri dan ilmu yang telah diperoleh dan dapat diaplikasikan langsung pada masyarakat.
BAB II
TINJAUAN PUSTAKA
A. TINJAUAN TENTANG PENYAKIT PARU OBSTRUKTIF KRONIK (PPOK)
Penyakit Paru Obstruktif Kronik merupakan penyakit saluran pernafasan akibat terhambatnya aliran udara yang bersifat progresive yang disebabkan oleh inflamasi pada saluran pernafasan dan parenkim paru. Penyakit Paru Obstruktif Kronik merupakan penyakit yang dapat dicegah dan diobati yang ditandai dengan terbatasnya atau terdapat hambatan aliran udara yang bisa reversibel sebagian maupun irreversibel. Aliran udara yang terhambat ini berlangsung secara progresif dan berhubungan dengan proses inflamasi yang terjadi pada paru-paru terhadap response dari partikel debu atau gas, biasanya disebabkan oleh asap rokok. Penyakit ini juga dapat bersifat sistemik namun biasanya hanya mengenai paru.2, 6
Pada pasien PPOK terdapat dua keadaan yang dapat terjadi yaitu bronkitis kronik dan emfisema. Bronkitis kronik merupakan batuk produktif selama tiga bulan dalam dua tahun berturut-turut. Sedangkan emfisema merupakan keadaan patologis yang ditandai pelebaran saluran pernafasan bagian distal sampai ke bronkiolus terminal, disertai destruksi dinding tanpa disertai fibrosis yang nyata.2
Asma berbeda dengan PPOK, namun keduanya mempunyai prevalensi yang tinggi pada masyarakat. Keduanya terdapat hambatan aliran udara secara signifikan dan mempunyai respon yang kuat terhadap bronkodilator. Namun, asma memiliki kadar IgE yang tinggi dalam darah.2, 7
Keadaan-keadaan lain seperti bronkiektasis dan TBC tidak termasuk dalam PPOK, namun sebaiknya di masukkan ke dalam diagnosis banding.2
Untuk menegakkan diagnosis pada PPOK sebaiknya di lihat gejala dari batuknya, produksi dari sputumnya, sesak nafas, atau adakah riwayat terpapar dengan faktor resiko.6
Diagnosis dari PPOK itu sendiri ditentukan oleh anamnesis, pemeriksaan fisis, dan pemeriksaan spirometri.Spirometri sebaiknya dilakukan pada semua pasien yang dicurigai PPOK. Pada PPOK nilai FEV1 semakin hari semakin berkurang nilainya yang dimulai pada umur diatas 30 tahun, sebanyak 30-60 ml per tahun. Biasanya gejala muncul pada nilai FEV1 di bawah 50 % dari nilai normal, namun tidak selamanya seperti itu karena banyak hal yang mempengaruhi.6
b. Epidemiologi
Sebuah lembaga survey nasional di USA yaitu National Health and Nutrition Examination Survey (NHANES), mengatakan bahwa di USA pada umur 25-75 tahun, prevalensi PPOK yang derajat ringan (FEV1/FVC <70% class="small">1/FVC <70% class="small">1 ≤80% predicted) was 6.6%. Tingkta mortalitas dan morbiditasnya juga meningkat dari tahun ke tahun.2
Menurut studi NHANES III, PPOK diestimasikan mengenai 14,2 % laki-laki kulit putih yang merokok, 6,9 % bekas perokok, dan 3,3 % yang tidak pernah merokok. Pada wanita kulit putih, 13,6 % perokok, 6,8 % bekas perokok, dan 3,1 % tidak pernah merokok.2
Menurut American Thoracic Society (ATS), faktor risiko terjadinya PPOK adalah:
- Faktor host : faktor genetik, jenis kelamin, dan anatomi saluran napas
- Faktor exposure : merokok, status sosioekonomi, hipereaktivitas saluran napas, pekerjaan, polusi lingkungan, kejadian saat perinatal, infeksi bronkopulmoner rekuren, dll. 2, 8
c. Patologi, Patogenesis, dan Patofisiologi
Faktor resiko utama terjadinya PPOK adalah akibat paparan asap rokok. Karena terjadi paparan yang terus-menerus, maka akan mengakibatkan terjadinya inflamasi, ketidak seimbangan proteinase dan antiproteinase serta meningkatnya stres oksidatif.2,6,7
Inflamasi yang terjadi akan meningkatkan neutrofil, makrofag, T-limfosit khususnya CD8+, juga akan meningkatkan sitokin dan mediator inflamasi seperti leukotriene 4, interleukin-8 and tumour necrosis factor-α.2
Hal ini menyebabkan peningkatan produksi proteinase dan penurunan aktivitas dari antiproteinase. Karena terjadi proses inflamasi, maka sel-sel neutrofil akan keluar dan menghasilkan zat proteinase seperti elastase, cathepsin G dan proteinase-3, dan makrofag yang menghasilkan cathepsins B, L, dan S, dan matrix metalloproteinase. Sedangkan pada PPOK terjadi penurunan aktivitas antiproteinase seperti α1-antitrypsin, penghambat sekresi leukoproteinase and penghambat matrix metaloproteinase. Neutrofil elastase tidak hanya berperan dalam rusaknya parenkim paru tetapi juga juga sangat poten dalam menginduksi produksi mukus dan hiperplasia kelenjar mukus.2
PPOK juga disebabkan oleh adanya stres oksidatif. Pada udara yang dikeluarkan serta urin penderita PPOK yang merokok, ternyata mengandung hydrogen peroxide, nitric oxide dan lipid peroxidation products (isoprostane F2α-III). Zat-zat oksidatif ini bisa mengoksidasi molekul-molekul biologi yang bisa menyebabkan kematian sel.2
Karena terjadi proses inflamasi, ketidakseimbangan proteinase dan antiproteinase, serta munculnya stres oksidative, maka hal-hal tersebut dapat menyebabkan perubahan patologis dari saluran nafas baik saluran nafas atas maupun saluran nafas bawah.2
Pada saluran nafas bagian atas (saluran nafas yang mengandung jaringan kartilago dan diameternya > 2 mm), terjadi hipertrofi kelenjar-kelenjar pada bronkus dan terjadi metaplasia dari sel goblet. Hal ini menyebabkan peningkatan produksi mukus atau bronkitis kronik..Terjadi infiltrasi sel-sel radang pada kelenjar-kelenjar di bronkus. Pada epitel-epitel dinding saluran nafas atas, terjadi metaplasia sel-sel skuamosa, silianya juga berkurang dan mengalami disfungsi. 2
Pada saluran nafas bagian bawah (saluran nafas yang mengandung tidak jaringan kartilago dan diameternya <>2
Pada parenkim paru, bronkus terminal dan alveolus, terjadi emfisema, yaitu pembesaran dari ruangan alveolar, dan rusaknya dinding dari alveolar.2, 7
Perubahan patologis yang terjadi akan mengakibatkan fungsi fisiologis menjadi terganggu. Akibatnya terjadi hipersekresi mukus, disefungsi dari sel-sel silia saluran nafas, terhambatnya aliran udara dan hiperinflasi, pertukaran gas terganggu, hipertensi pulmonal, dan efek sistemik.2, 7
Pada PPOK, hambatan aliran udara yang terjadi adalah terhambatnya aliran ekspirasi. Hambatan aliran udara ini bisa di deteksi dengan spirometri.2, 6
d. Gejala Klinik
Batuk terjadi secara intermitten pada pagi hari, dan terjadi secara progresive sepanjang hari, dan jarang pada malam hari. Sputum biasanya keluar pada pagi hari. Sputumnya biasanya bersifat mukoid dan jumlahnya sedikit. Warnanya juga harus diperhatikan. Sesak juga bisa dirasakan ketika melakukan aktifitas seperti menaiki tangga, namun juga bisa muncul pada saat istirahat.2
Gambaran klinis sistemik PPOK dapat berupa penurunan berat badan, disfungsi otot-otot skelet dan kelainan sistemik yang bersifat potensial. Penurunan berat badan akibat adanya ketidaksesuaian intake kalori, oleh karena pada pasien PPOK terjadi peningkatan metabolisme basal. Peningkatan metabolisme basal ini akibat adanya inflamasi sistemik, hipoksia jaringan dan pemakaian obat-obatan pada pasien PPOK (misalnya beta-2 agonis). 2
Adanya disfungsi otot skelet dapat menyebabkan penurunan kualitas hidup penderita karena akan membatasi kapasitas latihan dari pasien PPOK. Disfungsi ini terjadi akibat perubahan gaya hidup pasien PPOK (aktivitas fisik yang menurun karena pasien mudah sesak), kelainan nutrisi, hipoksia jaringan, apoptosis otot skelet, stres oksidatif, rokok, kepekaan individu, perubahan hormon, perubahan elektrolit, kelainan regulasi nitrit oksida, dan obat-obatan. 2
Riwayat penyakit terdahulu juga harus ditanyakan seperti riwayat asma dan alergi. Riwayat keluarga yang menderita PPOK atau penyakit paru yang lain serta riwayat dirawat di rumah sakit juga penting untuk ditanyakan. Hal yang paling penting juga untuk di tanyakan adalah riwayat merokok atau terpapar asap rokok.2
Pada pemeriksaan fisis, dapat di temui barrel chest dan sela-sela iga melebar pada inspeksi. Pada palpasi dan perkusi bisa didapatkan hipersonor dan hepar mudah diraba. Pada auskultasi juga bisa didapatkan ronchi dan wheezing.2
e. Diagnosis
Diagnosis PPOK sebaiknya dipertimbangkan dari gejala klinik yang muncul, seperti gejala batuknya, produksi sputum, sesak serta pajanan faktor resiko.6
Diagnosis PPOK membutuhkan spitrometri. Angka spirometri FEV1/FVC <0.7 style="">reversibel dan kemungkinan irreversibel.9
Table 1. Klasifikasi umum dari spirometri
| Derajat Keparahan | Setelah di beri Bronchodilator FEV1/FVC | FEV1 % prediksi |
| Resiko tinggi Pasien yang:
| >0.7 | ≥80 |
| PPOK ringan | ≤0.7 | ≥80 |
| PPOK sedang | ≤0.7 | 50-80 |
| PPOK berat | ≤0.7 | 30-50 |
| PPOK yang sangat berat | ≤0.7 | <30 |
| FEV1: forced expiratory volume in one second; FVC: forced vital capacity.2,8,9 | ||
f. Diagnosis Banding
PPOK didiagnosis banding dengan asma, TBC, bronkiektasis, dan gagal jantung kongestif. Untuk meningkirkannya di perlukan anamnesis, pemeriksaan fisis, dan pemeriksaan penunjang seperti foto thorax sinar X dan spirometri, serta pemeriksaan penunjang yang lain.2
g. Pengobatan
Prinsip Pengobatan pada pasien PPOK adalah menghilangkan gejala dan meningkatkan kualitas hidup, memperbaiki kualitas paru-paru dan mencegah eksaserbasi ulang. Pasien dianjurkan untuk menghidari merokok, juga dilakukan terapi farmakologis dan nonfarmakologis. Pasien harus diperhatikan nutrisi atau status gizinya. 2
Pemberian bronkodilator (beta-2 agonis atau anti-kolinergik) merupakan terapi utama pada kasus PPOK. Global initiative for chronic obstructive lung disease (GOLD) telah merekomendasikan pemberian bronkodilator sebagai obat utama dalam penatalaksanaan PPOK, disamping obat golongan lain seperti inhalasi glukokortikoid, antioksidan dan lainnya. 2, 7
Bronkodilatator dapat diberikan secara insidentil, ataupun diberikan secara reguler dan lebih disukai ialah dalam bentuk inhalasi.
Pemakaian antioksidan yang direkomendasikan oleh Internasional dan nasional guideline adalah N-acetylcysteine (NAC). NAC selain sebagai agen mukolitik, juga berperan sebagai antioksidan dan anti-inflamasi, serta imunomodulator. NAC sebagai agen mukolitik bekerja dengan cara menghancurkan/memecah jembatan disulfida dari makromolekul mukoprotein yang terdapat dalam sekresi bronkial, sehingga mukus menjadi lebih encer, serta bekerja dengan cara memperbaiki kerja silia saluran napas. 2
Dengan adanya kerja silia yang membaik ini, maka akan sedikit mukus yang melekat pada epitel dan menyebabkan penetrasi antibiotika ke dalam jaringan akan meningkat, dan hal ini akan mengurangi kolonisasi bakteri. Efek ini dikenal sebagai anti adherens bacteria dari NAC. 2
NAC sebagai antioksidan akan menjadi prekursor glutation (antioksidan) karena NAC mudah untuk berpenetrasi kedalam sel dan diasetilasi menjadi sistein. Sistein ini berperan terhadap sintesis glutation. Selain berperan secara tidak langsung sebagai antioksidan, peranan NAC secara langsung sebagai antioksidan adalah membawa gugus tiol (gugus SH) bebas yang dapat berinteraksi dengan gugus elektrofilik ROS. 2, 7
Peranan NAC sebagai anti-inflamasi yaitu menghambat pelepasan sitokin pro-inflamasi, dan sebagai imunomodulator dengan cara meningkatkan fungsi sel-sel imunitas seperti limfosit dan makrofag terhadap radikal bebas dan bakteri atau benda asing. 2
Uji klinis NAC pada PPOK yang melibatkan 1392 pasien membuktikan bahwa pemberian NAC dapat mengurangi viskositas ekspektorasi, memudahkan ekspektorasi, dan mengurangi derajat keparahan batuk. 2
Terapi lain yang saat ini sedang diteliti peranannya dalam PPOK adalah anti-TNF alpha (telah ditunjukan efektif pada penyakit inflamasi kronis seperti artritis reumatoid).2
B. TINJAUAN TENTANG SPIROMETRI
Metode sederhana untuk mempelajari veentilasi paru adalah dengan mencatat volume udara yang masuk dan keluar paru-paru, suatu proses yang disebut spirometri.10, 11
Gambar 1. Diagram yang memperlihatkan peristiwa pernafasan selama bernafas normal, inspirasi maksimal, dan ekspirasi maksimal.11
1. Volume Paru
a. Volume alun nafas (tidal) / Tidal Volume (TV) adalah volume udara yang diinspirasi atau dikespirasi setiap kali orang bernafas normal, besarnya kira-kira 500 ml pada rata-rata orang dewasa muda.
b. Volume cadangan inspirasi / Inspiratory Reserve Volume (IRV) adalah volume udara yang dapat diinspirasi setelah dan di atas diatas volume alun nafas normal, dan biasanya mencapai 3000 ml.
c. Volume cadangan ekspirasi / Ekspiratory Reserve Volume (ERV) adalah jumlah udara ekstra yang dapat diekspirasi oleh ekspirasi kuat pada akhir ekspirasi alun nafas normal, jumlah normalnya adalah sekitar 1100 ml.11
d. Volume residu / Residual Volume (RV) yaitu volume udara yang masih tetap berada dalam paru setelah ekspirasi paling kuat. Volume ini besarnya kira-kira 1200 ml. Namun, volume residu tidak dapat diukur secara langsung oeleh spirometer.
e. Forced Ekspiratory Volume (FEV1)
FEV1 adalah volume ekspirasi yang kuat dalam 1 detik.10
2. Kapasitas Paru
Untuk menguraikan peristiwa-peristiwa dalam siklus paru, kadang-kadang perlu menyatukan dua atau lebih volume diatas. Kombinasi seperti itu disebut kapasitas paru.
a. Kapasitas inspirasi / Inspiratory Capasity (IC) sama dengan volume alun nafas ditambah volume cadangan inspirasi. Ini adalah jumlah udaranya kira-kira 3500 ml, yang dapat dihirup seseorang, dimulai pada tingkat ekspirasi normal dan pengembangan paru sampai jumlah maksimum.
b. Kapasitas residu fungsional / Fungsional Residual Capacity (FRC) sama dengan volume cadangan ekspirasi ditambah volume residu. Ini adalah jumlah udara yang tersisa dalam paru pada akhir ekspirasi normal kira-kira 2300 ml.
c. Kapasitas vital / Vital Capacity (VC) sama dengan volume cadangan inspirasi ditambah volume alun nafas dan volume cadangan ekspirasi. Ini adalah jumlah udara maksimum yang dapat dikeluarkan seseorang dari paru, setelah terlebih dahulu mengisi paru secara maksimum dan mengeluarkan sebanyak-banyaknya kira-kira 4600 ml.
d. Kapasitas paru total / Total Lung Volume (TLV) adalah volume maksimum di mana paru dapat dikembangkan sebesar mungkin dengan inspirasi paksa kira-kira 5800 ml. Jumlah ini sama dengan kapasitas vital ditambah volume residu. Kapasitas paru total juga tidak dapat secara langsung diukur oleh spirometer.10, 11
e. Forced Vital Capacity (FVC)
Volume ekspirasi yang kuat dan secepat mungkin setelah inspirasi maksimal. 10
Nilai spirometri yang biasa diukur pada pasien PPOK adalah rasio FEV1/FVC. Biasanya pada pasien PPOK nilainya adalah ≤0.7.9
Beberapa faktor yang mempengaruhi hasil tes spirometri pada orang normal diantaranya umur, jenis kelamin, ras, riwayat merokok, pekerjaan, penyakit intrapulmonal, penyakit jantung, dan bahkan berdasarkan penelitian yang dilakukan Rahmawati dan Asriyani Azikin ternyata IMT juga mempengaruhi hasil spirometri. 10
1. Umur
Hubungan umur dengan spirometri bervariasi, Knudson menggambarkan 3 fase pada fungsi spirometri :
a. Fase pertumbuhan pada anak <>
b. Fase matur. Dimulai sejak pertumbuhan spure sampai umur 20 tahun pada wanita dan 25 tahun pada laki-laki. Fungsi spirometri berkorelasi secara positif sesuai umur dan tinggi badan.
c. Fase penurunan. Fungsi spirometri menurun bberdasarkan umur > 20 tahun pada wanita dan > 25 tahun pada laki-laki. FVC meningkat pada umur 24 tahun, stabil pada umur 35 tahun menurun setelah umur 35 tahun.10, 11
2. Ras atau Suku
Koevesien volume paru dan aliran udara pada ras kulit hitam lebih tinggi dibandingkan dengan ras kulit putih. Ras Indiana, Pakistan, Oriental berada diantara kedua ras tersebut. Beberapa penelitian menentukan nilai FEV1/FVC pada ras kulit hitam lebih tinggi dengan ras kulit putih.10
3. Jenis Kelamin
Volume dan kapasitas seluruh paru pada wanita kira-kira 20 sampai 25 persen lebih kecil daripada pria. Peningkatan morbiditas juga lebih sering pada laki-laki yang terkena PPOK dibandingkan dengan perempuan.11
4. Pekerjaan
Pada pekerjaan yang membutuhkan aktivitas lebih banyak maka cenderung kekuatan pernafasannya menjadi meningkat, sehingga kapasitas vital paru pada orang itu meningkat Sebaliknya orang yang memiliki pekerjaan atau exercise yang sedikit maka cenderung kekuatan pernafasannya menjadi menurun, sehingga kapasitas parunya pun kecil.11
5. Merokok
Beberapa penelitian menyimpulkan bahwa pada orang yang merokok, FEV1/FVC nya cenderung menurun. Karena rokok bisa merusak paru-paru maka fungsi paru-paru pun menjadi terganggu.8
6. Penyakit pernafasan.
Seluruh penyakit pernafasan otomatis akan mempengaruhi atau menurunkan fungsi paru. Sehingga nilai spirometrinya pun juga akan menurun. Aliran udara akan terhambat dan kemampuan paru-paru untuk mengembangkempis pun akan menurun sehingga fungsi faal paru juga akan menurun.10
7. Penyakit Jantung
Jantung sangat erat hubungannya dengan paru-paru, karena kedua organ ini tidak bisa dipisahkan. Keduanya saling mendukung fungsi masing-masing. Jantung menyuplai darah ke paru-paru untuk di tukarkan oksigen di paru-paru, sehingga suplai oksigen jantung jug bisa tercukupi. Sehingga kalau ada gangguan di jantung, maka juga akan terjadi gangguan fungsi paru-paru, seperti terjadi bendungan paru. Maka hal ini, akan mempengaruhi fungsi faal paru. 2, 10
BAB III
KERANGKA KONSEP
A. DASAR PEMIKIRAN VARIABEL PENELITIAN
Spirometri merupakan analisis perubahan volume paru. Hasil tes spirometri dapat digunakan untuk mendiagnosis PPOK (Penyakit Paru Obstruktif Kronik), selain itu digunakan untuk keperluan penelitian. Beberapa faktor mempengaruhi hasil tes spirometri pada PPOK yaitu umur, jenis kelamin, suku, kebiasaan merokok, pekerjaan, riwayat penyakit saluran pernafasan yang menyertai, dan riwayat penyakit jantung. Namun, hubungan secara kuantitas dari hasil spirometri belum dapat dijelaskan. Oleh karena itu, akan digambarkan bagaimana hubungan antara umur, jenis kelamin, suku, kebiasaan merokok, pekerjaan, riwayat penyakit saluran pernafasan yang menyertai, dan riwayat penyakit jantung dengan hasil uji spirometri.
B. SKEMA POLA PIKIR VARIABEL PENELITIAN
| UMUR |
| JENIS KELAMIN |
| SUKU |
| KEBIASAAN MEROKOK |
| PEKERJAAN |
| RIWAYAT PENYAKIT PERNAFASAN LAINNYA |
| RIWAYAT PENYAKIT JANTUNG |
PASIEN PPOK (PENYAKIT PARU OBSTRUKTIF KRONIK) HASIL UJI SPIROMETRI - TV - FEV1/FVC rasio - ERV - VC
C. KLASIFIKASI VARIABEL, DEFENISI OPERASIONAL DAN KRITERIA OBYEKTIF
1. Variabel Penelitian
a. Variabel Dependen
Variabel dependen pada penelitian ini hasil uji spirometri seperti TV (Tidal Volume), FEV1/FVC rasio, ERV (Ekspiratory Reserve Volume) dan VC (Vital Capacity) .
b. Variabel Independen
Variabel Independen pada penelitian ini adalah umur, jenis kelamin, suku, kebiasaan merokok, pekerjaan, riwayat pernafasan lainnya dan riwayat penyakit jantung.
2. Defenisi Operasional dan Kriteria Objektif
2.1. Hasil uji spirometri yaitu hasil yang tertulis pada grafik setelah melakukan uji spirometri, dengan skala 1 kotak = 250 cc udara, meliputi :
2.1.1. Tidal Volume (TV), yaitu volume udara yang diinspirasi atau diekspirasi setiap kali orang bernafas normal, besarnya kira-kira 500 ml pada rata-rata orang dewasa muda.
Kriteria objektif :
a. <350>
b. 350-500 cc
c. > 500 cc
2.1.2. Rasio FEV1/FVC
Kriteria objektif :
a. <>
b.0,5-0,7
c. 0,7-0,9
d. > 0,9
2.1.3. ERV (Ekspiratory Reserve Volume) adalah jumlah udara ekstra yang dapat diekspirasi oleh ekspirasi kuat pada akhir ekspirasi alun nafas normal, jumlah normalnya adalah sekitar 1100 ml.
Kriteria objektif :
a. <900>
b. 900-1100 ml
c. > 1100 ml
2.1.4. Vital Capacity (VC) yaitu sama dengan volume cadangan inspirasi ditambah volume alun nafas dan volume cadangan ekspirasi. Ini adalah jumlah udara maksimum yang dapat dikeluarkan seseorang dari paru, setelah terlebih dahulu mengisi paru secara maksimum dan mengeluarkan sebanyak-banyaknya kira-kira 4600 ml.
Kriteria objektif :
a. <4000>
b. 4000-4600 ml
c. >4600 ml
2.2. Karakter pasien PPOK mulai dari umur, jenis kelamin, suku, kebiasaan merokok, pekerjaan, riwayat pernafasan lainnya dan riwayat penyakit jantung.
2.2.1. Umur yang di maksud disini adalah usia orang tersebut pertama kali didiagnosa PPOK.
Kriteria objektif :
a. 0-9 tahun.
b. 10-19 tahun.
c. 20-29 tahun.
d. 30-39 tahun.
e. 40-49 tahun.
f. 50-59 tahun.
g. 60-69 tahun.
h. > 70 tahun.
2.2.2. Jenis Kelamin.
Kriteria objektif :
a. Laki-laki.
b. Perempuan.
2.2.3. Suku
Kriteria objektif :
a. Bugis
b. Makassar.
c. Jawa.
d. Toraja.
e. Mandar.
f. Tionghoa.
g. dll.
2.2.4. Kebiasaan merokok
Kriteria objektif :
a. Merokok (Orang yang merokok dalam 1 bulan terakhir dalam jumlah berapa
pun).
b. Tidak Merokok.
2.2.5. Pekerjaan
Kriteria objektif :
a. Petani.
b. Tukang becak.
c. Guru
d. TNI.
e. Polisi Lalu Lintas
f. Wiraswasta.
g. Dokter
h. Belum bekerja
2.2.6. Riwayat penyakit pernafasan lainnya
Kriteria objektif :
a. Asma.
b. TBC.
c. Kanker paru-paru.
d. Bronkiektasis.
2.2.7. Riwayat penyakit jantung
Kriteria objektif
a. Gagal Jantung Kongestif.
b. Sindrom koroner akut.
c. Korpulmonale.
BAB IV
METODE PENELITIAN
A. JENIS PENELITIAN
Jenis penelitian yang digunakan adalah studi observasional dengan pendekatan survey deskriptif, untuk mengetahui gambaran hasil spirometri pada pasien-pasien PPOK (Penyakit Paru Obstruktif Kronik) di RSUP DR. Wahidin Sudirohusodo Makassar.
B. LOKASI DAN WAKTU PENELITIAN
Lokasi penelitian adalah di RSUP DR. Wahidin Sudirohusodo Makassar. Waktu penelitian mulai tanggal 31 Agustus sampai 12 September 2009.
C. POPULASI DAN SAMPEL
Populasi :
Semua pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar periode 1 Januari - 30 Juni 2009.
Sampel :
Sampel yang diambil adalah total sampling, yaitu semua pasien-pasien PPOK di RSUP DR. Wahidin Sudirohusodo Makassar periode 1 Januari - 30 Juni 2009.
D. JENIS DAN CARA PENGUMPULAN DATA
Data yang dikumpulkan adalah data sekunder berupa pengumpulan data dari rekam medik RSUP DR. Wahidin Sudirohusodo Makassar.
DAFTAR PUSTAKA
1. National Institue of Health, Chronic Obstructive Pulmonary Disease, USA. 2007.
2. Celli B.R., dkk, Standards for the Diagnosis and Treatment of Patients with Chronic Obstructive Pulmonary Disease, American Thoracic Society dan European Respiratory Society. New York. 2004.
3. Global Alliance against Chronic Respiratory Disease, Global Surveillance, Prevention and Control of Chronic Respiratory Diseases: A Comprehensive Approach, WHO, 2009.
4. Soetodjo, F.A., Penyakit Paru Obstruktif Kronik, 2007.
5. Nathel, L, dkk,. COPD Diagnosis Related to Different Guidelines and Spirometry Techniques. BioMed Central. 2007.
6. Sutherland, E.R., dan Cherniack, R, M., Measuremen pada Management of Chronic Obstructive Pulmonary Disease. New Englad Journal of Medicine, Massachusetts Medical Society. 2004.
7. Price , S.A, dan Wilson, L.M., Patofisiologi Konsep-Konsep Proses-Proses Penyaki, Edisi ke-4, ECG, 1995.
8. Qozih, H.A., dkk., Spirometric Screening of Chronic Obstructive Pulmonary Disease in Smokers Presenting to Tertiary Care Centre. Pakistan. Journal of Medicine 2009;10:40-44.
9. Pawels R, Sonia Buist A, Calverley P, Jenkins C, Hurd S. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD). Workshop summary. Am J Respi Crit Care Med 2001; 163: 1256–1276.
10. Rahmawati dan Asriyani Azikin, Hubungan Indeks Massa Tubuh Dengan Hasil Uji Spirometri Pada Mahasiswa Kedokteran Unhas Angkatan 2002. 2004
11. Guyton & Hall, Fisiologi Manusia dan Mekanisme Penyakit. Edisi ke-7. Jakarta : EGC.
Hal. 604-605. I997.
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