Corticosteroids

Residents Series – Inflammatory Shock Syndromes

November 14, 2015 Cardiology, Critical Care, Infectious Diseases No comments , , , , , , , , , , ,

Grim-ReaperDefinitions and Impactions

SIRS/Systemic inflammatory response syndrome is a condition that is characterized by signs of systemic inflammation (e.g., fever, leukocytosis). The diagnosis of SIRS requires at least 2 of the following:

1.Temperature >38 C or <36 C

2.Heart rate >90 beats/min

3.Respiratory rate >20 breaths/min, or arterial PCO2 <32 mm Hg

4.WBC count >12,000/mm3 or <4000/mm3, or >10% immature neutrophils (band forms)

Sepsis is a kind of SIRS caused by an infection.

Severe sepsis is a sepsis condition accompanied by dysfunction in one or more vital organs, or an elevated blood lactate level (>4 mM/L).

Septic shock is a severe sepsis accompanied by hypotension that is refractory to volume infusion.

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Inflammatory injury involving more than one vital organ is called multiorgan dysfunction syndrome (MODS), and the subsequent failure of more than one organ system is called multiorgan failure (MOF).

The organs most often damaged by systemic inflammation are the lungs, kidneys, cardiovascular system, and central nervous system. The most common manifestation of inflammatory organ injury is the acute respiratory distress syndrome (ARDS), which has been reported in 40% of patients with severe sepsis, and is one of the leading causes of acute respiratory failure in critical ill patients.

The number of organs that are damaged by inflammatory injury has important prognostic implications. There is a direct relationship between the mortality rate and the number of organ failures related to inflammation. This demonstrates the lethal potential of uncontrolled systemic inflammation.


The Physiologic Characteristics of Septic Shock

Severe sepsis and septic shock have been implicated in one of every four deaths worldwide, and the incidence of these conditions is steadily rising. The mortality rate averages about 30-50%, and varies with age and the number of associated organ failures. The mortality rate is not related to the site of infection or the causative organism, including multidrug-resistant organisms. This observation is evidence that inflammation, not infection, is the principal determinant of outcome in severe sepsis and septic shock.

Hemodynamic Alterations

  • The principal hemodynamic problem is systemic vasodilatation (involving both arteries and veins), which reduces ventricular preload and ventricular afterload. The vascular changes are attributed to the enhanced production of nitric oxide (a free radical) in vascular endothelial cells.
  • Oxidant injury in the vascular endothelium (from neutrophil attachment and degranulation) leads to fluid extravasation and hypovolemia, which adds to the decreased ventricular filling from venodilation.
  • Proinflammatory cytokines promote cardiac dysfunction (both systolic and diastolic dysfunction); however, the cardiac output is usually increased as a result of tachycardia and volume resuscitation.
  • Despite the increased cardiac output, splanchnic blood flow is typically reduced in septic shock. This can lead to disruption of the intestinal mucosa, thereby creating a risk for translocation of enteric pathogens and endotoxin across the bowel mucosa and into the systemic circulation. This, of course, will only aggravate the inciting condition.

The typical hemodynamic pattern in septic shock includes low cardiac filling pressure (CVP or wedge pressure), a high cardiac output, and a low systemic vascular resistance (SVR). Because of the high cardiac output and peripheral vasodilatation, septic shock is also known as hyperdynamic shock or warm shock. In the advanced stages of septic shock, cardiac dysfunction is more prominent and the cardiac output is reduced, resulting in a hemodynamic pattern that resembles cardiogenic shock (i.e., high CVP, low CO, high SVR). A declining cardiac output in septic shock usually indicates a poor prognosis.

Tissue Oxygenation

The impaired energy metabolism in septic shock is not the result of inadequate tissue oxygenation, but is caused by a defect in oxygen utilization in mitochondria. This condiditon is known as cytopathic hypoxia, and the culprit is oxidant-induced inhibition of cytochrome oxidase and other proteins in the electron transport chain. A decrease in oxygen utilization would explain the observation that the PO2 in skeletal muscle is increased in patients with severe sepsis.

The proposed decrease in oxygen utilization in sepsis is not consistent with the increase in whole-body O2 consumption that is often observed in sepsis. This discrepancy can be resolved by proposing that the increased O2 consumption in sepsis is not a reflection of aerobic metabolism, but is a manifestation of the increased O2 consumption that occurs during neutrophil activation (i.e., the respiratory burst).

The discovery that tissue oxygenation is (more than) adequate in severe sepsis and septic shock has important implications because it means that efforts to improve tissue oxygenation in these conditions (e.g., with blood transfusions) are not justified.

Serum Lactate Levels

The increase in serum lactate levels in severe sepsis and septic shock is not the result of inadequate tissue oxygenation, but instead appears to be the result of enhanced production of pyruvate and inhibition of pyruvate dehydrogenase, the enzyme that converts pyruvate to acetyl coenzyme A in mitochondria. Endotoxin and other bacterial cell wall components have been implicated in the inhibition of this enzyme. This mechanism of lactate accumulation is consistent with the notion that tissue oxygenation is not impaired in severe sepsis and septic shock.


Management

The management of septic shock is outlined in Table 14-3, and is organized in "bundles", which are sets of instructions that must be followed without deviation to provide a survival benefit. The acute sepsis bundle is considered the most important, and must be completed within 6 hours after the diagnosis of septic shock. Screen Shot 2015-11-14 at 8.15.07 PM

Volume Resuscitation

Volume resuscitation is often necessary in septic shock because cardiac filling pressures are reduced from venodilatation and fluid extravasation. The volume resuscitation requires the insertion of a central venous catheter to monitor the central venous pressure (CVP).

1.Infuse 500-1,000 mL of crystalloid fluid or 300-500 mL of colloid fluid over 30 minutes.

2.Repeat as needed until the CVP reaches 8 mm Hg, or 12 mm Hg in ventilator-dependent patients.

If CVP measurements are not available, a volume of at least 20 mL/kg (crystalloid fluid) can be used for the volume resuscitation.

After the initial period of volume resuscitation, the infusion rate of intravenous fluids should be reduced to avoid unnecessary fluid accumulation. A positive fluid balance is associated with increased mortality in septic shock, so attention to avoid fluid accumulation will improve the chances of a favorable outcome.

Vasopressors

If hypotension persists after the initial volume resuscitation, infusion of a vasoconstrictor drug (vasopressor) like norepinephrine or dopamine should begin. Vasoconstrictor drugs must be infused through a central venous catheter, and the goal is to achieve a mean arterial pressure (MAP) >=65 mm Hg.

Norepinephrine is favored by many because it is more likely to raise the blood pressure than dopamine, and is less likely to promote arrhythmias. However, neither agent has proven superior to the other for improving the outcome in septic shock.

When hypotension is refractory to norepinephrine and dopamine, vasopressin may be effective in raising the blood pressure (Vasopressin is used as an additional pressor rather than a replacement for norepinephrine or dopamine). Vasopressin is a pure vasoconstrictor that can promote splanchnic and digital ischemia, especially at high dose rates. Although vasopressin may help in raising the blood pressure, the accumulated experience with vasopressin shows no influence on outcomes in septic shock.

Corticosteroids

Corticosteroids have two actions that are potentially beneficial in septic shock: they have antiinflammatory activity, and they magnify the vasoconstrictor response to catecholamines. Unfortunately, after more than 50 years of investigations, there is no convincing evidence that steroids provide any benefit in the treatment of septic shock. Yet steroids therapy continues to be popular in septic shock. The following comments reflect the current recommendations regarding steroid therapy in spetic shcok.

1.Steroid therapy should be considered in cases of septic shock where the blood pressure is poorly responsive to intravenous fluids and vasopressor therapy. Evidence of adrenal insufficiency (by the rapid ACTH stimulation test) is not required.

2.Intravenous hydrocortisone is preferred to dexamethasone (because of the mineralocorticoid effects of hydrocortisone), and the dose should not exceed 300 mg daily (to limit the risk of infection).

3.Steroid therapy should be continued as long as vasopressor therapy is required.

Antimicrobial Therapy

For the pharmacotherapy of antimicrobial therapy please view the thread of Systematic Approach for Selection of Antimicrobials at http://www.tomhsiung.com/wordpress/2014/03/systematic-approach-for-selection-of-antimicrobials/

Management of Gout (Medications)

October 25, 2012 Adverse Drug Reactions, Drug Informatics, Pharmacotherapy No comments , , , ,

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are the drugs of choice in most patients with acute gout who do not have underlying health problems. However, aspirin should not be used because it can alter uric acid levels and potentially prolong and intensify an acute attack.

Avoid NSAIDs in patients who have a history of peptic ulcer disease or GI bleeding, patients with renal insufficiency, patients with abnormal hepatic function, patients taking warfarin (selective COX-2 inhibitors can be used but used cautiously), and patients in the intensive care unit who are predisposed to gastritis. In patients with diabetes and those who are receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.

NSAIDs are prescribed at full dosage for 2-5 days to control the acute attack, and the dose is reduced to approximately one half to one fourth of that amount once the acute attack is controlled. Taper the dose down over approximately 2 weeks. But the consistent low-dose of NSAIDs used for 6-24 months may help to prevent the occurring of acute gout attack during the chronic lowering uric acid treatment.

Gout symptoms should be absent for at least 2 days before the NSAID is discontinued.

Colchicine

Although colchicine was once the treatment of choice for acute gout, it is now a second-line approach because of its narrow therapeutic window and risk of toxicity.

Colchicine therapy must be initiated within 24 hours of onset of the acute attack to be effective. Dosing recommendation for colchicine in acute gout therapy have been modified in recent years because of an increased awareness of its toxicities. The most recent recommendations have been trending toward lowered daily and cumulative doses. The favored regimen is low-dose colchicine 1.8 mg total over 1 hour (1.2 mg PO initially then 0.6 mg q1hr, total not to exceed 1.8 mg over 1 hour-period).

Colchicine should not be used if the glomerular filtration rate (GFR) is less than 10 mL/min, and the dose should be decreased by at least half if the GFR is less than 50 mL/min. Colchicine should also be avoided in patients with hepatic dysfunction, biliary obstruction, or an inability to tolerate diarrhea.

For prophylaxis the dose of colchicine is 0.6 mg bid or lower. In patients with renal insufficiency, this dose may need to be decreased to daily or overy-other-day administration. Even in prophylactic dose, colchicines can cause marrow toxicity and neuromyopathy in the setting of renal insufficiency. Long-term use of colchicine can lead to a muscle weakness associated with elevated levels of creatine kinase due to a drug-induced neuromyopathy, particularly in patients with renal insufficiency.

Corticosteroids

Corticosteroids can be given to patients with gout who cannot use NSAIDs or coclchicine, but adrenocorticotropic hormone (ACTH) would be preferred. Steroids can be given orally, intravenously, intramuscularly, intra-articularly, or indirectly via ACTH.

ACTH 40 IU can be given to induce corticosteroid production by the patient’s own adrenal glands. Such a regimen dose not depend on the patient to properly taper prednisone. Using parenteral corticosteroids confers no advantage unless the patient cannot take oral medications.

Intra-articular, long-acting (depot) corticosteroids are particularly useful in patients with a monoarticular flare to help reduce the systemic effects of oral steroids.

Allopurinol

Allopurinol blocks xanthine oxidase and thus reduces the generation of uric acid. Therefore, it should be used in patients who overproduce uric acid. It is the most effective urate-lowering agent. However, alcohol can interfere with effectiveness of allopurinol.

Approximately 3-10% of patients taking allopurinol develop dyspepsia, headache, diarrhea, and/or pruritic maculopapular rash. Less frequently, patients taking allopurinol can develop allopurinol hypersensitivity, which carries a mortality rate of 20-30%. Features of allopurinol hypersensitivity include fever, toxic epidermal necrolysis, bone marrow suppression, eosinophilia, leukocytosis, renal failure, hepatic failure, and vasculitis. Corticosteroids are often used to treat allopurinol hypersensitivity.

Allopurinol hypersensitivity is more likely to occur in patients with renal insufficiency, patients who are taking a diuretic, and patients begun on 300 mg of allopurinol. Although allopurinol hypersensitivity is more common (although still rare) in patients with renal insufficiency, this effect dose not appear to be dose-related. Thus, a slow and careful titration of allopurinol dosing sufficient to achieve uric acid levels of less than 6 mg/dL is also recommended in these patients.

Allopurinol is also associated with the drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome affects the liver, kidney, and skin. It is a delayed-hypersensitivity response occurring 6-8 weeks after beginning allopurinol. The underlying mechanism is thought to be a cell-mediated immunity to allopurinol and its metabolites. Although occurrence is 0.4%, the rate of organ failure and death is high. Treatment is with intravenous N-acetyl cysteine and steroids. Allopurinol should be discontinued in patients who develop a rash.

In most patients, start at 100 mg per day (50 mg in patients with renal insufficiency) and adjust the dose monthly according to the uric acid level until the goal of a uric acid level of 6 mg/dL or less is achieved.

While adjusting the dosage of allopurinol in patients who are being treated with colchicine and/or anti-inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute gouty attacks for several months.

Update from Medscape Reference at http://emedicine.medscape.com/article/329958-medication#6 on Sep 6th 2013.

Pegloticase

Pegloticase is a pegylated uric acid–specific enzyme that is a polyethylene glycol conjugate of recombinant uricase. It achieves its therapeutic effect by catalyzing oxidation of uric acid to allantoin, thereby lowering serum uric acid levels. Pegloticase is indicated for gout in adults refractory to conventional therapy (ie, when serum uric acid levels have not normalized and either signs and symptoms are inadequately controlled with xanthine oxidase inhibitors or uricosurics at maximum appropriate doses or xanthine oxidase inhibitors are contraindicated).

The dosage is 8 mg IV every 2 weeks. Complications include anaphylaxis, infusion reactions, flare of gout attacks in 63-86% of patients and nephrolithiasis in 13-14%, along with arthralgias, nausea, dyspepsia, muscle spasms, pyrexia, back pain, diarrhea, and rash.[134, 135] Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a contraindication.[135]