Monitoring of Immunomodulators in Inflammatory Bowel Disease

In This ArticleSummary and IntroductionMethodsMercaptopurine and AzathioprineCiclosporinMethotrexateConclusionFiguresTablesReferences

Methods

A Medline search was conducted from 1966 to 2004, for randomized-controlled trials of AZA, MP, ciclosporin and methotrexate for the treatment of IBD. A Medline search was also completed for studies assessing monitoring efficacy and toxicity of these medications in the setting of IBD. Additional references were obtained and reviewed from a search in BIOSIS Previews, a database, which includes published abstracts, and if pertinent literature was known to the authors or identified during searches. All searches were limited to the English language.Previous PageSection 2 of 6Next Page: Mercaptopurine and Azathioprine
Aliment Pharmacol Ther.  2005; 21 (4): 307-319.  ©2005 Blackwell Publishing


This is a part of article Monitoring of Immunomodulators in Inflammatory Bowel Disease Taken from "Danazol Danocrine" Information Blog

Antiresorptive Treatment of Postmenopausal Osteoporosis: Review

Comparison of Antiresorptive Therapies in Head-to-Head Trials and the EVista and Alendronate Comparison Trial

Several head-to-head comparisons of the effects of antiresorptive therapies on surrogate markers of bone efficacy have been performed to date. These studies essentially confirm results from placebo-controlled trials in terms of magnitude of effects on surrogate markers. Similar increases in lumbar spine BMD and decreases in bone turnover were observed for alendronate (10 mg/day) and conjugated equine estrogen (CEE) (0.625 mg/day) in postmenopausal women with low BMD.[37] However, CEE was associated with greater gains in BMD than alendronate when it was compared with lower doses of alendronate (5 or 2.5 mg/day) in healthy young postmenopausal women.[38] Alendronate produced greater increases in BMD and greater decreases in bone turnover than did intranasal calcitonin in two separate head-to-head studies.[39,40] Greater increases in BMD and decreases in bone turnover have been also observed with CEE (0.625 mg/day) plus medroxyprogesterone[41,42] or alendronate (10 mg/day),[43] as compared with raloxifene (60 mg/day).

Given the difficulties in comparing results across clinical trials with fracture as an endpoint, as well as interpreting the results of head-to-head trials with surrogate markers of bone efficacy as an endpoint, a head-to-head comparison of antiresorptive agents with the endpoint of total fracture would assist the physician in making informed therapeutic decisions. The measurement of total fracture risk reduction is a more clinically relevant endpoint than either vertebral or nonvertebral fractures alone, because radiographic and clinical vertebral fractures and nonvertebral fractures are associated with increased morbidity and mortality[5,6,44,45] and a majority of the patients are treated with antiresorptive agents with the goal of preventing any fracture, not a specific fracture type. Given the importance of preventing the first vertebral fracture,[5-9] patients with osteoporosis by BMD definitions who have not yet sustained a vertebral fracture are particularly well suited for study in such a trial. Therefore, a fracture endpoint trial, the Evista Alendronate Comparison (EVA) trial, is currently underway to compare directly the osteoporotic fracture risk reduction efficacy of raloxifene and alendronate in postmenopausal women with osteoporosis as defined by BMD. In addition to a direct comparison of the bone efficacy of these drugs, this trial will also allow comparison of extraskeletal effects and the safety of the two therapies. Because of the lack of anti-fracture efficacy data of the alendronate 70 mg weekly formulation, the alendronate 10 mg/day dosage was selected for comparison to raloxifene.

The EVA trial is a multi-center, double-blind, double-dummy, randomized clinical trial with two active treatment arms. After giving informed consent, approximately 3000 patients will be randomly assigned to one of two treatment groups: raloxifene HCl 60 mg/day or alendronate Na 10 mg/day. We calculate that with 1500 patients per arm there will be more than 90% power to establish the equivalence of raloxifene to alendronate with an equivalence margin of 30% at 5 years of treatment. All patients will also receive approximately 500 mg elemental calcium and 400 IU of vitamin D daily as supplements to their usual daily intake. The study will consist of two phases: a screening phase and a treatment phase lasting 5 years.

The study endpoints are shown in Table 2. The primary endpoint of this study is to compare the effects of treatment with raloxifene with those of alendronate in postmenopausal women with osteoporosis on the number of patients who experience at least one new osteoporotic fracture (vertebral or nonvertebral). Secondary objectives of this study include a comparison of the effects of the two treatments on the number of woman with any osteoporotic fracture at a particular site (such as vertebral, hip, wrist, etc.), on the incidence of newly diagnosed breast cancer, integrated measures of health utility scores, height loss, percentage change in lumbar spine or femoral neck BMD.

Bone mineral density measurements will be performed using dual-energy X-ray absorptiometry (DXA) in the spine and hip at baseline and again at 2 years. Lateral thoracic and lumbar spine radiographs will be obtained at baseline and at 3 and 5 years. Vertebral osteoporotic fractures will be determined from lateral spine radiographs using semiquantitative analysis.[46] Nonvertebral fractures will be collected and confirmed via radiograph or written report. Mammograms will be performed at baseline and annually. Adverse events and height measurements will be made at baseline and annually.

Eligible participants are ambulatory postmenopausal women, 50-80 years of age, with osteoporosis defined by femoral neck BMD T-score between -4.0 and -2.5 using the NHANES reference database[47] and no prior vertebral fracture. This age range was chosen because this is when most osteoporotic fractures are likely to occur. Patients over 80 years were not included because of issues related to life expectancy in a 5-year trial. Among the important exclusion criteria are a history of estrogen-dependent neoplasia, a history of venous thromboembolism, long-term treatment with glucocorticoids, diseases that affect calcium or skeletal metabolism, and recent treatment with bone active drugs. Investigators may also exclude any patients in whom a disease of any kind could compromise the safety or evaluation of this study.

This is the first comparative study of two drugs known to be effective against osteoporotic fracture, raloxifene and alendronate, with fracture as a primary endpoint. By studying both drugs in one large, well-defined population of postmenopausal women with osteoporosis, we can expect to overcome many of the problems inherent in comparing their overall safety and efficacy from separate studies. Data obtained from this study will thus permit more informed judgment by practitioners and provider groups concerning the relative clinical utility of these two drugs.

Reprint Address

Address for correspondence: Dr Edward Gwynne Lufkin, Lilly Research Laboratories, Lilly Corporate Center , DC 4109, Eli Lilly and Company, Indianapolis, IN 46285, USA. Tel.: +1-317-277-3187; Fax: +1-317-277-3743; email: elufkin@lilly.comPrevious PageSection 4 of 4Curr Med Res Opin 20(3):351-357, 2004. © 2004 Librapharm Limited
This is a part of article Antiresorptive Treatment of Postmenopausal Osteoporosis: Review Taken from "Danazol Danocrine" Information Blog

Male Breast Enlargement in Patients With HIV/AIDS

Male Breast Enlargement in Patients With HIV/AIDS

from The AIDS Reader ®

Treatment

Initiation of early treatment (Table 3) is important. If gynecomastia is present for more than 1 year, glandular tissue will be replaced by fibrosis, rendering medical therapy unsuccessful. A rapid and complete resolution of gynecomastia can be expected if treatment of the underlying cause is started early. When medical treatment is unlikely to be successful, surgery remains an option.

The identification and removal of the causative agent is the main-stay of treatment for medication-associated gynecomastia. Antiretroviral therapy-associated gynecomastia may resolve when all or a part of the antiretroviral combination is switched.[4,6,7] For instance, switching current treatment with ritonavir to nelfinavir and switching ritonavir and lamivudine to didanosine and efavirenz led to complete resolution of true gynecomastia in 2 patients.[7] In addition, Donovan and colleagues[4] reported 4 cases of gynecomastia associated with saquinavir therapy. In 3 of these cases, switching saquinavir to nevirapine led to a complete resolution of the gynecomastia. However, switching the PI component of HAART may not always be successful. In one study, switching zidovudine, lamivudine, and nelfinavir to stavudine, didanosine, and nevirapine did not result in a resolution of the gynecomastia.[6] Clearly, in the cases where gynecomastia is associated with PI-containing HAART, it is prudent to switch the PI for a nonnucleoside reverse transcriptase inhibitor (NNRTI). When the gynecomastia is associated with an NNRTI-containing regimen, switching to abacavir may be an option.

Both androgens (particularly, danazol) and antiestrogens (namely, tamoxifen) have been used in the management of idiopathic gynecomastia. In a recent analysis, Ting and associates[18] compared the efficacy of these 2 agents. Tamoxifen, 20 mg once daily, resulted in complete resolution of breast masses in 78% of patients; danazol, 400 mg once daily, in 40%, although the relapse rate was higher for tamoxifen.

However, tamoxifen has many metabolites, and some of these have estrogen agonist activity. This probably explains its side effects, especially its prothrombotic nature, and may explain its lack of ability to maintain resolution of gynecomastia. Newer and purer antiestrogens with little or no agonist activity are currently being developed.

Aromatization of androgens to estrogen in peripheral tissue, as mentioned earlier, has been noted to play a role in the development of gynecomastia. Delta1-Testolactone was one of the earliest aromatase inhibitors to be developed and used. Given at a dosage of 450 mg once daily for 2 to 6 months to pubertal patients, Delta1-testolactone was associated with breast glandular tissue softening and a decrease in breast diameter.[19]

The triazoles anastrozole and letrozole and the steroid exemestane are newer potent aromatase inhibitors. These can substantially inhibit in situ aromatase by more than 95% without significant effects on other endocrine pathways and are known to have a relatively good side-effect profile.[20] The role of these newer agents has yet to be evaluated in the management of idiopathic gynecomastia, and they may prove to be of great benefit in HIV-associated gynecomastia.

Prophylactic breast bud irradiation has long been used in the management of patients with metastatic carcinoma of the prostate before the commencement of diethylstilbestrol therapy. Its place in the treatment of gynecomastia in HIV disease is not known, and the potential for carcinogenesis in breast tissue that was previously benign should not be disregarded.

Surgery is the last line of therapy in benign gynecomastia. Circumareolar breast reduction is the surgical method of choice. The indications for surgical intervention are:

Psychological upset.

Cosmetic disfigurement.

Progression despite medical intervention.

Suspected underlying malignancy.

Clearly, excluding medical and often reversible causes is important in the treatment of gynecomastia. However, once true gynecomastia has been ascribed to HAART, switching antiretroviral therapy appears to be the most promising treatment strategy. One must bear in mind, however, that many cases do resolve spontaneously; so, it is important not to be too hasty with regimen change, because this has implications for resistance and future treatment options. Furthermore, some patients may be on salvage regimens with few therapeutic alternatives; in these cases, antiestrogens or aromatase inhibitors may be an option.

This is a part of article Male Breast Enlargement in Patients With HIV/AIDS Taken from "Danazol Danocrine" Information Blog

Diagnosis and Management of Mesenteric Ischaemia

Experimental Treatment in Non-Occlusive Mesenteric Ischaemia

Bailey et al. have demonstrated that mesenteric vasoconstriction is mediated in large part by the renin-angiotensin axis. Bailey and colleagues showed in pigs subjected to prolonged pericardial tamponade, that blockade of this pathway either by intravenously infused angiotensin converting enzyme inhibitor (ACEi) or by bilateral nephrectomy protected the small bowel from ischaemia. Further, phenoxybenzamine, an α -adrenergic inhibitor was not protective against the development of ischaemic changes; this finding contradicts the theory that the sympathetic nervous system primarily regulates mesenteric vasoconstriction.[53] These findings may be difficult to extrapolate to hypovolemic-induced ischaemia given the different pathophysiology of tamponade-induced cardiogenic shock. A subsequent experimental study supported this study's findings: intra-arterial captopril given at the beginning of shock reduced the extent of tamponade-induced mesenteric ischaemia in piglets.[54] The narrow window of time in which the ACEi must be administered to be effective, however, limits its clinical application, although the prophylactic use of ACEi in high-risk patients is an intriguing idea. The risk of systemic hypotension with an ACEi also needs to be considered in the clinical setting. Glucagon, histamine and perhexiline also have been shown to restore blood flow and oxygen consumption via vasodilation in dogs with digoxin-induced mesenteric vasoconstriction.[55]

Iloprost, a synthetic derivative of prostacyclin, has been shown to be beneficial in patients with peripheral vascular disease; it is a potent inhibitor of platelet aggregation and may also promote fibrinolysis by decreasing an inhibitor of plasminogen activation. Additionally, in low doses, it has been shown to increase SMA blood flow and oxygen delivery in septic shock. Kang et al. recently conducted an experimental study to examine the effect of intravenous iloprost in NOMI secondary to cardiac tamponade: compared with a control group given normal saline, the iloprost group was found to have increased SMA blood flow, decreased intestinal mucosal hypercarbia and increased pHI; interestingly, mucosal oxygen consumption did not change significantly during its use. Unfortunately, the intestine was not studied at the conclusion of the experiment, thus making the significance of these findings less clear.[56]

Ovine corticotropin releasing factor, sauvagine and urotensin I are three chemically related peptides that have been shown to be selective mesenteric vasodilators in a canine model. Each intravenously administered peptide improved mesenteric blood flow and decreased mesenteric vascular resistance in animals subjected to mesenteric hemodynamic changes induced by intravenous digoxin.[57] In a follow-up canine study, intravenous urotensin I was found to be as effective as intra-arterial papaverine in correcting mesenteric blood flow and oxygen kinetics. Systemic side effects were not observed with intravenous urotensin I, but as expected, hypotension was marked when papaverine was given intravenously at sufficient doses to restore mesenteric blood flow to baseline values.[58] While these studies are certainly intriguing, these peptides have yet to be examined for a possible clinical role in the treatment of NOMI in humans.

Finally, gastric inhibitory peptide (GIP) is a member of the secretin-glucagon-vasoactive intestinal polypeptide family of gastrointestinal hormones and has been shown to increase SMA blood flow selectively in a canine model.[59] GIP has yet to be studied in NOMI.Mesenteric Venous Thrombosis

MVT may have an acute, subacute or chronic presentation. Patients with MVT are typically younger than those with other types of mesenteric ischaemia. MVT is associated with a myriad of hypercoaguable states (including protein C, protein S or antithrombin III deficiency, factor V Leiden mutation, anticardiolipin antibodies, malignancy, estrogens and pregnancy, and peripheral deep vein thrombosis), portal hypertension, intra-abdominal inflammation and sepsis, post-operative states, and trauma. MVT secondary to cirrhosis or neoplasm tends to start at the site of obstruction and propagate peripherally, while the opposite sequence is observed in hypercoaguable states. If collateral blood flow does not permit venous drainage around the obstructed vessel, the bowel will become congested and oedematous. Coincidental arterial vasoconstriction may occur and cause bowel infarction. Standard CT is the current diagnostic test of choice for MVT, unlike its use in patients with arterial occlusive or non-occlusive mesenteric ischaemia.[1]

Treatment of MVT generally involves surgery, anticoagulation or both. Surgical intervention includes resection of necrotic bowel and/or thrombectomy; thrombolytics have been used successfully in case reports. Papaverine and second-look operations are advocated as appropriate, using similar guidelines as for arterial causes of AMI.[1] Traditionally it has been taught that peritoneal signs warrant immediate surgical intervention, but Brunaud et al. in a retrospective review of patients with acute MVT found that peritoneal signs do not always indicate transmural necrosis, and may be seen with only mucosal necrosis, a situation which may be reversible with anticoagulation alone. Based on his comparison of patients who were treated surgically with those who were treated medically, he suggested that non-operative management of acute MVT may be a reasonable option provided the initial CT diagnosis is unequivocal and if bowel infarction has not led to transmural necrosis and bowel perforation.[60]

Current recommendations for continued anticoagulation are based on whether an underlying hypercoaguable state is discovered, in which case lifelong coumadin is advocated.[39] If no underlying thrombotic state is found, then anticoagulation is generally recommended for 3-6 months. Chronic MVT is primarily found in the setting of portal hypertension and is generally asymptomatic or presents with gastrointestinal bleeding from varices; treatment is aimed at control of haemorrhage.[1]Focal Segmental Ischaemia

FSI is generally not a life-threatening condition as only short segments of bowel are involved and adequate collateral blood flow generally limits transmural necrosis. The aetiology of FSI is varied and includes atheromatous emboli, strangulated hernias, immune complex disorders and vasculitis, blunt abdominal trauma, segmental thrombosis, radiation therapy and oral contraceptives.[1] Partial necrosis may manifest as acute enteritis, chronic enteritis (often difficult to distinguish from Crohn's disease) or a stricture. Definitive treatment of FSI is resection of the involved bowel.[1]Chronic Mesenteric Ischaemia

CMI, also known as intestinal angina or claudication, almost always is caused by severe mesenteric atherosclerotic disease; over 90% of patients have occlusion of at least two of the major splanchnic vessels, and over 50% have occlusion of all three.[1] Abdominal pain results from ischaemia in the small intestine as blood is 'stolen' from this organ to meet the heightened need for gastric blood flow as food enters the stomach. Classically, patients complain of abdominal pain that begins approximately 30 min after eating and gradually remits over the next 1-3 h; fear of eating (sitophobia) often leads to food avoidance and consequent weight loss. Diagnosis is made by clinical history, angiographic findings of at least two-vessel occlusion and the absence of any other cause for symptoms.

The mainstay of treatment for CMI is surgical bypass, although percutaneous angioplasty and stenting procedures have also been studied. Therapeutic outcomes may be difficult to assess as success has been defined in different ways, including graft patency, relief of symptoms and long-term survival. As reviewed in one recent article, means of 85% for long-term pain relief, 86% for graft patency and 7% for mortality rate were found for surgical revascularization.[61] Presently, only retrospective reviews of percutaneous angioplasty and stenting are available and are hampered not only by their inherent suboptimal study design but also by lack of homogeneity in terms of patient population, procedural technique, post-procedural assessment and length of follow-up. Additionally, it may be difficult to compare surgery with percutaneous procedures as usually more vessels are bypassed in surgery than are treated percutaneously; further, generally only stenosed and not occluded vessels are treated percutaneously. Although initial success rates for percutaneous angioplasty and stenting are reported to range between 63 and 100%,[1,62] long-term efficacy is generally less than that for surgery; one recent study reported recurrent symptoms in 34% of patients at 3 years.[61] More recently, a study looking at patients treated with only angioplasty plus stenting found success rates equivalent to those of surgery (83% symptomatic relief at 15 months, 92% stent patency at 6 months and a 10% complication rate).[62] More data are likely needed before definitive conclusions can be reached.Experimental Treatment of Reperfusion Injury

As mentioned previously, reperfusion injury may be more detrimental than primary ischaemic injury, especially when ischaemia is short-lived. Reperfusion injury is likely multifactorial, but oxygen radicals and polymorphonuclear cells (PMNs) are thought to be integral. Xanthine oxidase-derived oxygen radicals stimulate leukotriene B4 (LTB4) and platelet activating factor (PAF) production, which in turn promote neutrophil adherence and migration; these leukocytes mediate microvascular injury by the release of proteases and physical disruption of the endothelial barrier.[7] Because the two main effectors of reperfusion injury are reactive oxygen metabolites and PMNs, it follows that they are also the major foci of experimental studies aimed at reducing reperfusion injury.  Printer- Friendly Email This

Aliment Pharmacol Ther.  2005;21(3):201-215.  ©2005 Blackwell Publishing
This is a part of article Diagnosis and Management of Mesenteric Ischaemia Taken from "Metronidazole Flagyl 500Mg" Information Blog

Swab test ‘may have saved twins’

A Lincolnshire woman who lost her newborn twins to a bacterial infection is hoping to raise awareness of the condition which killed them.

Jane Gothorpe's children, Euan and Kirsten, died from Group B Streptococcus, an infection related to meningitis, within days of being born.

The infection, carried in the mother's gut, is passed on during labour.

But a swab test not routinely given on the NHS can detect it. Campaigners want this to be made available to everyone.

Mrs Goathorpe from Dunholm near Lincoln had been trying for a family with her husband John for more than four years.

The twins were born in February.

She said that although the babies appeared perfectly healthy after their normal birth in February, their conditions soon worsened.

"About six o'clock the following evening John and the midwife were changing Kirsten's nappy and the midwife just thought she didn't look very well, so they called a paediatrician.

"It became apparent very quickly that she wasn't going to survive and Euan also started to deteriorate."

But the condition can be detected by a simple swab test costing around £32.

Mrs Gothorpe added: "You wonder why it's not available for everybody - and can you put a price on a treatment that might prevent what me and my husband have been through?"

Campaigners say women should be offered swab tests during pregnancy to see if they have the bacteria, and be given intravenous antibiotics in labour as an option.

But critics of the proposal fear antibiotics may do more harm than good and that there is a risk of allergic reaction.

This is a part of article Swab test ‘may have saved twins’ Taken from "Metronidazole Flagyl 500Mg" Information Blog

Emerging Therapies in the Treatment of C difficile-Associated Disease

Rifaximin

Rifaximin is a semisynthetic analog of the rifamycin antimicrobial rifampin. The addition of a benzimidazole ring makes rifaximin essentially nonabsorbed (bioavailability <0.4%); hence, its usefulness for treatment of intraabdominal infections. The Food and Drug Administration (FDA) approved this agent for the treatment of travelers' diarrhea caused by noninvasive strains of Escherichia coli in patients who are 12 years of age or older. Rifaximin has been used in Italy since 1987 for the treatment of various infections. It has also been useful in hepatic encephalopathy, as well as in pre- and postsurgical prophylaxis.[14,15] This drug exerts its activity by inhibiting the initiation of RNA synthesis by binding to the ß subunit of the RNA polymerase.[14]

In vitro, the minimum inhibitory concentration (MIC) values of C. difficile are among the lowest of any enteric pathogen for rifaximin. Gerard et al.[14] identified one study in which 34 of 56 clinical isolates of C. difficile were inhibited by rifaximin at a concentration of 0.78 µg/mL, with the remainder inhibited at concentrations greater than 25 µg/mL. Although the interpretation of these MIC results is difficult in the absence of known gastrointestinal concentrations, it is likely that the drug concentration achieved at the site of action would largely exceed the reported MIC values. Fecal levels after oral administration of the agent have been shown to range from 4000 to 8000 µg/g of stool.[15] In addition, the microorganism shows a particularly low incidence of spontaneously resistant mutants (<1 × 10-9), which could prove useful in treating the emergent strain.

In an open-label study, Boero et al.[16] compared rifaximin 200 mg 3 times daily for 10 days with oral vancomycin 500 mg twice daily for 10 days (N = 20). Time to toxin disappearance ± SD was significantly shorter with vancomycin, at 4.8 ± 1.48 days, versus rifaximin, at 8.1 ± 1.79 days (p < 0.005). Time to stool normalization was similar with vancomycin, at 3.8 ± 1.48 days, versus rifaximin, at 4.9 ± 2.38 days (p = NS). Overall, rifaximin was found to be effective in 9 of 10 patients, while vancomycin was successful in all 10 patients who received it.

We have identified several cases in our practice in which rifaximin wassuccessfully used for CDAD when other agents failed or were contraindicated,but more supportive evidence is needed. Overall, rifaximin appears to be avalid alternative for the treatment and management of CDAD, although further,larger studies are needed to clearly define its role.  Printer- Friendly Email This

Ann Pharmacother.  2006;40(12):2164-2169.  ©2006 Harvey Whitney Books Company
This is a part of article Emerging Therapies in the Treatment of C difficile-Associated Disease Taken from "Metronidazole Flagyl 500Mg" Information Blog

Stress-Dose Corticosteroid Therapy for Sepsis

Stress-Dose Corticosteroid Therapy for Sepsis

from Pharmacotherapy

Clinical Studies

Historical Perspective

The association of inflammation with sepsis has long been established. Corticosteroids were first administered to treat sepsis as early as 1940.[89] Until a decade ago, common practice was to administer short courses (< 24 hrs) of extremely high doses (supraphysiologic) of corticosteroids in an effort to halt the systemic inflammatory response syndrome. Results of two meta-analyses that included several randomized, double-blind studies conducted from 1966-1993 showed no survival benefit when supraphysiologic doses of corticosteroids were administered for short-term treatment of sepsis or ARDS.[90, 91] Moreover, higher infection rates were associated with corticosteroids. The authors of these two meta-analyses recommended that high-dose corticosteroids be abandoned for the treatment of sepsis and ARDS.[90, 91] Of interest, several of these studies found that despite no long-term survival benefit, therapy with corticosteroids was associated with early shock reversal or blood pressure elevation.[92-95] With the recognition of adrenal insufficiency as a physiologic component of sepsis and ALI-ARDS, the focus of recent research has involved adrenocortical replacement dosage regimens administered for several days to weeks, with doses corresponding to the stress level of the disease state (physiologic or stress dose).Sepsis

The administration of stress-dose regimens of exogenous corticosteroids should reduce the systemic inflammatory process associated with the host defense response to sepsis. Results of a randomized, placebo-controlled study that enrolled 24 patients with hyperdynamic septic shock who were vasopressor dependent demonstrated that serum concentrations of the proinflammatory cytokines IL-6 and IL-8 were significantly reduced within 24 hours of starting stress-dose hydrocortisone.[96] Survivors had the greatest reductions of either cytokine. Compared with placebo, IL-6 concentrations were significantly lower after 5 days of hydrocortisone, but IL-8 concentrations were not statistically significantly different. In this study, hydrocortisone was administered as a 100-mg bolus, followed by 0.18 mg/kg/hour for at least 6 days, and gradually discontinued in daily 24-mg increments once the infection was treated successfully. The investigators did not define successful treatment. The inciting microbes and the specific antimicrobials that were administered were not reported, but most infections were polymicrobial (54%) from abdominal sources (46%), nosocomial pneumonia (29%), or community acquired pneumonia (25%). A cohort study by the same authors showed that serum concentrations of the late inflammatory mediators phospholipase A2 and neutrophil elastase were reduced within 48 hours of starting stress-dose hydrocortisone.[97] Hydrocortisone was administered as a 100-mg bolus followed by 10 mg/hour, and tapered by the attending physician after shock reversal. The investigators did not define shock reversal. Of note, the serum concentration of the antiinflammatory cytokine IL-10 was not altered by stress-dose hydrocortisone. Elevated heart rate and body temperature, two manifestations of systemic inflammatory response syndrome, and serum cortisol concentration returned to normal during hydrocortisone administration but trended upward after hydrocortisone was discontinued. This observational study was designed so that the results from one center that administered hydrocortisone were compared with those from several control centers that did not administer hydrocortisone. Consequently, only 12 (21%) of 57 patients with severe sepsis or septic shock received hydrocortisone. The study protocol did not influence therapy, and the investigators did not specify other treatment differences between centers or possible population differences, so consistency of therapy among centers is questionable. No information was provided regarding infection site, inciting microbe, or antimicrobial therapy. These two studies provide evidence that stress-dose administration of hydrocortisone reduces the systemic inflammatory response associated with severe sepsis and septic shock. However, the data are limited by poor study design and small patient populations that were not well described.

Patients with adrenal insufficiency display a rightward shift in the dose-response curve to norepinephrine.[98] Moreover, vasopressor response to norepinephrine is correlated positively with the degree of corticotropin-induced cortisol production.[98, 99] Through upregulation of adrenergic receptors, stress-dose corticosteroids should enhance vasopressor activity. Phenylephrine responsiveness was restored 1 hour after the intravenous administration of a single dose of hydrocortisone 50 mg in 12 patients with septic shock who had impaired adrenocortical function.[100] A similar response was obtained in 12 age-matched control subjects. Numerous case series have shown rapid shock reversal and/or discontinuation of vasopressor therapy after starting stress-dose hydrocortisone in patients with refractory vasopressor-dependent septic shock (Table 1).[63, 69, 101-108] Of note, three of these reports found no difference in adrenocortical function between patients who responded to hydrocortisone and those who did not.[105-107] One report showed that despite similar overall hemodynamic response rates for shock reversal, patients with relative adrenal insufficiency were able to discontinue vasopressor therapy significantly faster after hydrocortisone was begun than were patients with normal adrenocortical function (median of 3 days vs 5 days, respectively, p<0.01).[108] However, mortality rates were similar (45% vs 44%, respectively). Although limited, these reports provide initial evidence that the administration of stress-dose corticosteroids may sensitize patients with septic shock to the hemodynamic effects of vasopressor therapy. Whether the presence of adrenal insufficiency enhances response is questionable, as overall hemodynamic response rates and mortality rates were similar regardless of adrenal function.

Several placebo-controlled studies evaluating stress-dose corticosteroids are described in this article according to mortality results. Results of one case-control study[97] and three randomized, double-blind studies[96, 109, 110] found that hydrocortisone therapy did not alter mortality in patients with severe sepsis or vasopressor dependency (Table 2). The case-control study[97] already was described in this review. Although mortality rates were not statistically significantly different, only 3 (25%) of the 12 patients treated with hydrocortisone died while in the hospital compared with 25 (56%) of the 45 control patients. Of note, all 12 patients who received hydrocortisone were in shock at baseline compared with only 27 (60%) of the 45 control patients. Therefore, patients receiving corticosteroids were sicker than the control group, but mortality rate was half that of the control group. One of the randomized, double-blind studies[109] was published in 1963, so the applicability of the methodology and results to modern day medicine are questionable. In this study, 329 patients with life-threatening infection were randomly assigned to placebo or hydrocortisone 300 mg, followed by a daily taper of 50 mg for a total of 6 days of treatment. Limited patient demographic data were provided, but 25.8% of subjects had meningitis, 22.4% had pneumonia, and 12.8% had bacteremia. Antibiotic and vasopressor therapies were not altered by the study protocol. Overall mortality rates were 34.7% in the hydrocortisone group and 22.6% in the placebo group.

Another previously described study[96] found that despite no differences in mortality rates between the hydrocortisone and placebo groups, median daily scores of sepsis-related organ failure assessment decreased significantly after 3 days of hydrocortisone (14 on day 0 to 11 on day 3, p<0.05) but remained constant in the placebo group.[96] Mean baseline acute physiology and chronic health evaluation (APACHE) II scores were 25 ± 1 for the hydrocortisone group and 27 ± 1 for the control group. Therefore, organ function improved only in the group of patients who received hydrocortisone, despite similar baseline levels of illness severity. The investigators did not report duration of ICU stays; therefore, whether accelerated reversal of organ dysfunction resulted in shorter ICU stays is not known.

A third randomized, double-blind study[110] of 40 patients with hyperdynamic septic shock showed no mortality difference and similar overall hemodynamic response rates despite faster vasopressor therapy discontinuation in the group receiving hydrocortisone compared with that in the placebo group (median 2 vs 7 days, respectively, p=0.005). Respiratory function tended to improve quicker with hydrocortisone administration (p=0.09), resulting in substantially fewer days of mechanical ventilation (median 18 vs 38 days, p=0.19) and shorter ICU stays (median 27 vs 44 days, p=0.27). Hydrocortisone was administered as a 100-mg bolus, followed by 0.18 mg/kg/hour for as long as vasopressor therapy was required, then 0.08 mg/kg/hour for 6 days, and gradually discontinued in daily 24-mg increments. Patient demographics were similar, with mean APACHE II scores of 26 ± 1 and 27 ± 1 for the hydrocortisone group and placebo group, respectively. Hemodynamic parameters were similar at the time of enrollment, with the mean duration of shock before recruitment being 20.7 ± 3.67 and 26.5 ± 4.39 hours for the hydrocortisone group and placebo group, respectively. Thirty patients (75%) had ARDS at the time of enrollment. The most frequent infections were abdominal in origin (40%), nosocomial pneumonia (32.5%), and community acquired pneumonia (17.5%), and the most common microbes were gram positive (52.5%), polymicrobial (27.5%), and gram negative (15%). This study was conducted at a single center in Germany. Many of their routine ICU practices are not standard in North America, including selective decontamination of the gastrointestinal tract, antithrombin and immunoglobulin therapies for severe sepsis, and dopexamine or dobutamine therapy to enhance cardiac output. Of interest, a retrospective analysis of this study found hydrocortisone therapy, compared with standard therapy, reduced the frequency of posttraumatic stress disorder in patients surviving sepsis (18.5% vs 59.3%, respectively; p=0.01).[115]

A fourth randomized, double-blind study[111] of patients with septic shock who required vasopressor therapy for more than 72 hours did not report mortality data. However, similar to the previous study, the results of this study found that hydrocortisone therapy was associated with accelerated discontinuation of vasopressor therapy.[111] Sixteen (70%) of 23 patients receiving hydrocortisone were vasopressor independent on day 3 of therapy compared with only 7 (33%) of 21 patients receiving placebo (p=0.001). The mean duration of vasopressor therapy was 72 hours in the hydrocortisone group compared with 122 hours in the placebo group (p<0.005). Since this study has been reported only as an abstract, it is difficult to ascertain the clinical relevance of these results.

In all cases, the studies that reported no mortality benefit with stress-dose hydrocortisone found accelerated resolution of shock or vasopressor discontinuation. Patients were not stratified according to adrenal function in the above-mentioned studies.

Three randomized, double-blind, placebo-controlled studies found that mortality was significantly reduced with stress-dose corticosteroid therapy (Table 2).[112-114] The applicability of the results of one of these studies is questionable as dexamethasone therapy was investigated for severe typhoid infection, an extremely rare disease.[112] In this study, 38 patients with typhoid-induced mental status changes were randomly assigned to placebo or dexamethasone 3 mg/kg followed by 1 mg/kg every 6 hours for eight doses. Limited patient demographic data were provided, but 6 (30%) of 20 dexamethasone-treated patients had shock before enrollment compared with 5 (28%) of 18 patients receiving placebo. All patients had the organism isolated from bone marrow, and 80% had bacteremia. Chloramphenicol was provided to all patients. Overall mortality rates were 10% in the dexamethasone group and 56% in the placebo group (p=0.003). Adrenal function was not assessed in this study but was assessed in the two remaining studies.[113, 114]

The largest randomized study of stress-dose corticosteroid therapy is published only as an abstract.[113] In this study, 299 patients with septic shock were enrolled, including 229 (76.6%) with adrenal insufficiency based on an increase of serum cortisol of less than 9 µg/dl after corticotropin 0.25 mg. All patients required vasopressor therapy for less than 8 hours before enrollment. Hydrocortisone was administered as 50 mg every 5 hours for 7 days. Concurrently, fludrocortisone 50 µg/day was administered enterally to prevent hydrocortisone-induced hyperkalemia. The relative risk reduction in mortality with hydrocortisone therapy compared with placebo was 0.67 (95% confidence interval [CI] 0.474-0.946) in patients with adrenal insufficiency. The relative risk reduction was similar in patients without adrenal insufficiency but was not statistically significant (0.696, 95% CI 0.349-1.387). Whether the statistical insignificance is due to too few patients to show a difference or to a lack of clinical benefit in patients with normal adrenal function is indeterminate.

In another study, 41 patients with septic shock who required more than 48 hours of vasopressor therapy were randomly assigned to placebo or hydrocortisone 100 mg every 8 hours for 5 days and tapered by 50% increments every 3 days over 6 days.[114] Only 12 (29%) of the 41 patients with shock had adrenal insufficiency, defined as an increase of serum cortisol concentration of less than 6 µg/dl after corticotropin 0.25 mg. However, only 4 (19%) of 21 patients receiving hydrocortisone had adrenal insufficiency compared with 8 (42%) of 19 patients receiving placebo (p=0.093). Demographic data were similar between the groups, with 63% of patients being enrolled in the surgical ICU and 32% of patients experiencing at least two organ failures. The most frequent infections were abdominal (39%) and pulmonary (37%) in origin, and the most common microbes were gram negative (44%), gram positive (17%), and polymicrobial (12%). Mean elapsed time from the onset of shock to administration of the first dose was 6 ± 5 days and 5 ± 3 days for the hydrocortisone group and placebo group, respectively. Hemodynamic response rates and mortality rates within groups were similar between patients with and those without adrenocortical dysfunction but consistently favored hydrocortisone therapy. Seven-day shock reversal, defined as a stable systolic blood pressure greater than 90 mm Hg for at least 24 hours without volume expansion or vasopressor therapy, was achieved in 15 (68%) hydrocortisone-treated patients compared with 4 (21%) control patients (p=0.007). In the hydrocortisone group, hemodynamic response rates were 75% and 67% for patients with and those without adrenal insufficiency, respectively. However, rates of shock reversal for the two placebo subgroups were 25% and 18%, respectively (p<0.05 vs subgroups receiving hydrocortisone). Mortality rates at day 28 were 32% in the hydrocortisone group compared with 63% in the placebo group (p=0.045). In summary, stress-dose therapy with hydrocortisone in patients with septic shock who require vasopressor treatment is associated with accelerated hemodynamic stability and reduced mortality. When to begin stress-dose corticosteroids and whether patients with and those without adrenal insufficiency respond differently require further investigation.

In general, patients were excluded from studies if they were younger than 18 years; were immunocompromised; received corticosteroids before developing ALI-ARDS; or had active pancreatitis, terminal illness, hemorrhagic shock, recent gastrointestinal hemorrhage, or extensive burns. None of the case series reported adverse events, but a few adverse events were attributable to corticosteroid therapy in the comparative studies. The combined rates of occurrence of gastrointestinal hemorrhage, reported in four studies, were 5.3% (12 of 227) for corticosteroid therapy and 2.3% (5 of 216) for placebo.[109, 110, 112, 114] The combined rates of occurrence of secondary infections, reported in four studies, were 15.1% (35 of 232) for corticosteroid therapy and 13.9% (30 of 216) for placebo.[109, 110, 112, 114] One study reported no laboratory aberrations,[114] whereas another reported statistically significant hypernatremia during the first 7 days of hydrocortisone therapy.[110] Serum sodium concentrations exceeded 155 mEq/L in 6 (30%) of 20 patients receiving hydrocortisone therapy compared with only 1 (5%) of 20 patients receiving placebo. Sodium concentrations returned to normal values after hydrocortisone was discontinued, as per protocol. The same study found serum alanine aminotransferase concentrations were statistically significantly elevated from baseline after 14 days of hydrocortisone therapy. Serum glucose and urea nitrogen concentrations tended to be higher with hydrocortisone therapy. What clinical significance the biochemical aberrations have is indeterminate, but one must question how blinding was maintained.ALI or ARDS

Similar to sepsis, the administration of stress-dose regimens of exogenous corticosteroids should reduce the systemic inflammatory process associated with ALI-ARDS. The administration of methylprednisolone 200 mg followed by 2-3 mg/kg/day for a mean of 15 ± 9 days after the onset of ARDS significantly reduced the serum concentrations of the proinflammatory cytokines IL-1 and IL-6 by days 5 and 7 of therapy, respectively.[116] Similar to sepsis, survivors had the greatest reduction. Alveolar concentrations of IL-1, IL-6, and TNF- were significantly reduced by day 14 of methylprednisolone therapy. The median APACHE II score was 23, and all nine patients in this cohort study had sepsis-induced ALI-ARDS. Serum and alveolar concentrations of collagen markers were reduced during 7 days of stress-dose methylprednisolone.[117] Similar to sepsis, serum and alveolar concentrations of the antiinflammatory cytokine IL-4 were not altered by stress-dose methylprednisolone.

The combined mortality rate in five case series of patients with ARDS treated with stress-dose methylprednisolone is 20.6% (14 of 68 patients), considerably lower than the 34-60% reported for standard therapy for ARDS (Table 3).[118-122] Similarly, two of three case-control analyses showed substantial, although statistically insignificant, reductions in mortality with corticosteroid treatment (Table 4).[123-125] The first was a retrospective analysis of 31 cases of ALI-ARDS, 29 with ARDS, in a medical or surgical ICU.[123] Sixteen of these patients received methylprednisolone 120 mg/day until improvement of unresolving ALI. The investigators did not define improvement, but methylprednisolone was started after a mean of 9.7 ± 0.7 days in the ICU. Demographic data and other therapeutic interventions were similar. Mean admission APACHE II scores were 14.4 ± 1.6 and 14.8 ± 1.6 for the methylprednisolone group and control group, respectively. The cause of ALI-ARDS was pneumonia for all patients, with pneumococcus representing 58% of the microbes. Oxygenation, represented by the PaO2:FiO2 ratio, improved significantly after 3 days of methylprednisolone but did not change in the control group (60 ± 12.9 vs -6.0 ± 7.6, respectively, p=0.004). However, duration of mechanical ventilation (20.5 ± 2.3 vs 20.1 ± 2.7 days, respectively), length of ICU stay (20.9 ± 2.2 vs 20.8 ± 2.8 days, respectively), and 30-day mortality rates (19% vs 20%, respectively) did not differ between groups. The second case-control analysis was also retrospective in design and involved 31 patients with infection-induced ARDS (17 due to sepsis and 14 due to pneumonia).[124] The median duration of ARDS was 15 days. Thirteen patients received methylprednisolone 100-250 mg/day for 1-3 days, which was tapered over 5-44 days. Demographic data were similar, with median APACHE II scores of 17 and 19 for the methylprednisolone group and control group, respectively. Oxygenation did not change significantly after 48 hours of methylprednisolone but decreased in the control group (median change of 5 vs -26, respectively, p=0.039). After 7 days, oxygenation improved by 23% in the methylprednisolone group but decreased by 11.1% in the control group. Lung injury score did not change after 7 days of methylprednisolone therapy but increased 11.1% in the control group. Of greatest interest is that only 5 (38%) methylprednisolone-treated patients died in the ICU compared with 12 (67%) control patients (p=0.117).

The third case-control analysis retrospectively evaluated 18 patients with life-threatening varicella pneumonia from 1980-1996.[125] Six patients received hydrocortisone 200 mg every 6 hours for 48 hours, the majority during more recent years of the evaluation. Demographic data were similar between groups, except the baseline PaO2:FiO2 ratio was significantly lower in the hydrocortisone group (median 86.5 vs 129.5, p=0.045). Follow-up oxygenation parameters were not reported, so the effect of hydrocortisone on oxygenation is indeterminate. The group receiving hydrocortisone had a significantly shorter ICU stay (median 5.5 vs 12 days, p=0.008) and hospital stay (median 10 vs 20 days, p<0.006). Mortality rates were not significantly different, but no patient receiving hydrocortisone died compared with four patients (33%) in the control group. Unfortunately, it is difficult to attribute clinical differences between groups to corticosteroid therapy because patient data collection occurred over 16 years, with most patients who received hydrocortisone being evaluated recently. Therefore, differences between groups may be due to changes in other therapies or diagnostic approaches that occurred over the time period.

After enrollment of 24 patients, the only randomized, double-blind study was terminated by an external safety review board because methylprednisolone therapy for ARDS was associated with significantly lower ICU and hospital mortality rates compared with placebo.[126] Intravenous methylprednisolone was started on day 7 of ARDS as a 2-mg/kg bolus, then 0.5 mg/kg/day every 6 hours for 2 weeks or extubation, then tapered over 3 weeks. Demographic data were similar between groups, with mean APACHE III scores of 58 ± 14 and 55 ± 16 for the methylprednisolone group and placebo group, receptively. Twelve patients (50%) had undergone surgery within 2 days of enrollment, and 17 (71%) had sepsis-induced ARDS with 13 (54%) experiencing shock. The ICU mortality rates were 0% and 62% for the methylprednisolone group and placebo group, receptively (p=0.002). Two (12%) of 16 methylprednisolone-treated patients died during their hospital stay compared with 5 (62%) of 8 patients receiving placebo (p=0.03). Neither death in the methylprednisolone group was from unresolving ARDS, whereas all five deaths in the placebo group were attributed to ARDS. Oxygenation improved 34.8%, and lung injury score decreased 33.3% by day 5 of methylprednisolone therapy compared with no change in either parameter for the placebo group. As a result, the median duration of ventilation was 11.5 days with methylprednisolone therapy compared with 23 days in the placebo group (p=0.001). Of note, serum concentrations of the proinflammatory cytokines IL-1, IL-6, and TNF- were significantly reduced after 3 days of methylprednisolone therapy and 5 days of placebo.[78] Although adrenocortical function was not assessed, serum corticotropin and cortisol concentrations were reduced significantly after 3 days of methylprednisolone therapy but did not change with placebo, suggesting that exogenous administration of methylprednisolone resets the HPA axis.

These results are encouraging; however, there are several concerns with this study. Owing to early study termination, only 24 (24%) of 99 patients were enrolled. Of the eight patients receiving placebo, four eventually received corticosteroids because the protocol provided a blind crossover to the other treatment arm if a patient did not improve after 10 days. The methodology included weekly bronchoscopies for surveillance of new pulmonary infections, a procedure that likely would not be conducted at most institutions. When patient characteristics are compared at onset of ARDS to study entry (day 7 of ARDS), the group that received methylprednisolone appeared to be improving to a greater extent than the placebo group, even before treatment was started. For example, the PaO2:FiO2 ratio increased 46.4% in the methylprednisolone group versus only 14.6% in the placebo group during the 7 days before starting the respective treatment arms.

Definitive recommendations cannot be made regarding corticosteroid therapy for ALI-ARDS. In most of the studies, the patients had infection-induced ALI-ARDS. A course of stress-dose methylprednisolone should be considered only in cases of refractory sepsis-induced ARDS when impending mortality is likely. A multicenter study is under way, with enrollment of 125 of 180 subjects, and should provide definitive information.[127]

In general, patients were excluded from ALI-ARDS studies if they were younger than 18 years; were immunocompromised; had received corticosteroids before developing ALI-ARDS; or had a terminal illness, recent gastrointestinal hemorrhage, fungal infection, uncontrolled diabetes mellitus, or extensive burns. Three of the five case series reported adverse events.[120-122] The combined rates of occurrence of gastrointestinal hemorrhage and secondary infections were 10% (4 of 42) and 28% (12 of 42), respectively. Two of the three case-control studies reported adverse events.[123, 124] No cases of gastrointestinal hemorrhage were reported in 29 patients receiving methylprednisolone and 33 patients receiving placebo. The combined rates of occurrence of secondary infections were 31% (9 of 29) in the corticosteroid group and 15% (5 of 33) in the placebo group. Similarly, the infection rate/day of mechanical ventilation was nearly double for methylprednisolone therapy compared with placebo in the randomized, double blind study (relative risk 1.8, 95% CI 0.86-3.76).[126] Six (38%) of 16 patients treated with methylprednisolone developed new ventilator-associated pneumonia compared with only 1 (12%) of 8 patients receiving placebo. Unfortunately, early termination of the study may have prevented sufficient enrollment to detect a statistically significant difference. The occurrence of hyperglycemia was similar between groups.

This is a part of article Stress-Dose Corticosteroid Therapy for Sepsis Taken from "Generic Chloromycetin (Chloramphenicol) Information" Information Blog