December 2010 FAQs
December 2010 FAQs
Should antibiotics be used in all patients with COPD exacerbations?
Should antibiotics be used in all patients with COPD exacerbations?
According to a national health survey, chronic obstructive pulmonary disease (COPD) affected about 12 million US citizens in 2001.1 It is the fourth leading cause of death in the US, and its exacerbations account for about 600,000 annual hospitalizations. 1,2 This condition is characterized by airflow limitation that is not fully reversible and is progressive in nature. 1,3 Reduced elasticity and narrowing of the small airways results in chronic obstruction. Major risk factors for COPD include cigarette smoking, environmental tobacco smoke, occupational chemicals and inhalants, and indoor as well as outdoor air pollution. Chronic obstructive pulmonary disease is most prominent in smokers, males, and individuals over 40 years of age. Airway limitation is best measured by spirometry. The most common spirometric measurements include forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1/FVC. Based on these spirometric measures and symptoms, COPD can be classified into 1 of 4 stages: mild, moderate, severe, or very severe. Components of COPD management include assessing and monitoring disease, reducing risk factors, maintaining stable COPD, and managing exacerbations.
According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), a COPD exacerbation is an acute event characterized by worsening in baseline dyspnea, cough, and/or sputum that requires a change in COPD treatment.3 Although the most common causes of acute exacerbations include infection (bacterial or viral) and air pollution, approximately 30% of cases have an unknown etiology. Exacerbations are primarily managed with inhaled bronchodilators and oral glucocorticoids with more severe cases requiring oxygen therapy and hospitalization. Antibiotic use is recommended for patients who present with increased sputum purulence, increased sputum volume, and increased dyspnea. Due to bacterial colonization of the respiratory tract, sputum culture is not always considered a reliable indicator of respiratory infections in COPD patients.1 Recent literature suggests that new onset bacterial infections in COPD patients are associated with high sputum and serum inflammatory markers such as sputum interleukin-8 (IL-8), neutrophil elastase, tumor necrosis factor-α (TNF- α), and increased serum C-reactive protein (CRP).4 A 2007 study by Stolz demonstrated successful treatment outcomes in patients who received antibiotic treatment based on elevated serum levels of procalcitonin, an inflammatory marker.5 Since only about 50% of all COPD exacerbations are due to bacterial infections and since antibiotic resistance is a concern, the question of when to use antibiotics remains controversial.2
Antibiotic use in hospitalized COPD patients
A recent retrospective, cohort study explored antibiotic use and treatment outcomes in hospitalized patients with COPD exacerbations. 2 The main objective of the study was to compare outcomes in patients who received an antibiotic during the first 2 days of hospital stay to those who received antibiotics later than the first 2 days, or not at all. Data were obtained from over 84,000 patients across 413 US hospitals.
Patients over the age of 40 with a principal diagnosis of an acute exacerbation of COPD or respiratory failure paired with a secondary diagnosis of COPD with acute exacerbation were included.2 Patients with asthma, other infections, and those directly admitted to the ICU were excluded. Primary outcomes included a composite measure of the initiation of mechanical ventilation after 2 days in the hospital, in-hospital mortality, and readmission for COPD 30 days after discharge. Secondary outcomes included hospital costs, length of stay, allergic reactions, and diarrhea.
In the overall study population, the median age was 69 years, 71% were white, 61% were female, and over 70% of the patients had not had a COPD exacerbation in the past year.2 A quinolone antibiotic was used in 60% of patients, a cephalosporin in 37%, and a macrolide in 38% of patients. Compared to patients who received no or late antibiotic treatment, fewer patients treated with antibiotic therapy during the first 2 days of their hospital stay experienced the composite outcome of treatment failure (11.75% vs. 9.77%, p <0.001). The odds of developing treatment failure was significantly lower with early antibiotic treatment compared to no/late antibiotic treatment (odds ratio [OR] 0.87, 95% CI 0.82 to 0.92). Results of individual outcomes are summarized in the table.
Table. Incidence (95% confidence interval) of individual outcomes by treatment .2
Outcome Early antibiotic (n=67,229) No/late antibiotic (n=17,392) p-value Mechanical ventilation 1.07% (1.06 to 1.08) 1.8% (1.78-1.82) <0.001 In-hospital mortality 1.04% (1.03 to 1.05) 1.59% (1.57-1.61) <0.001 Readmission within 30 days due to COPD 7.91% (7.89 to 7.94) 8.79% (8.74-8.83) <0.001 Readmission within 30 days due to diarrhea 0.23% (0.22 to 0.23) 0.13% (0.12-0.13) 0.01 C. difficile diarrhea 0.19% (0.187 to 0.193) 0.09% (0.086-0.094) 0.003
COPD=chronic obstructive pulmonary disease
The median length of stay (4 days for both groups) was not significantly different between the 2 groups.2 Unadjusted analysis of cost demonstrated a significantly lower median total cost for patients who received early antibiotics compared to those who received no/late antibiotics ($4925 vs. $5084, p <0.001). However, a covariate adjusted analysis, demonstrated higher costs for patients treated with antibiotics.
Despite the limitations of the retrospective study design and use of administrative data, the authors concluded that use of antibiotics is beneficial and causes minimal risk in patients who require hospitalization for acute COPD exacerbations. 2 Commentary on this study and its conclusion was made by several readers. Dr. Hurley commented that a diagnosis of pneumonia could have been missed since data on chest x-rays were not collected. For patients who did not receive antibiotics, undiagnosed pneumonia could explain the higher incidence of mortality.6 Additionally, subgroups of smokers and non-smokers were not analyzed which could have provided additional information about treatment failure. Another commentary by Suissa et al. discussed the imbalance between groups as to when treatment failure was measured. For those who received antibiotics on hospital day 2, treatment failure was not measured until hospital day 4; whereas for those who did not receive antibiotics, treatment failure could have been counted on day 3.7 Finally, Albrich and colleagues identified limitations including differences in comorbidties in the 2 groups, a smaller sample size in the no/late antibiotic group, and concerns with grouping together those patients who received no antibiotics and those who received antibiotics later than 2 days of hospitalization to evaluate adverse effects.8 Further issues that were not addressed by the study were the risk of antibiotic resistance and identifying which patient subgroups benefit most from antibiotic use. The benefit of antibiotic use in patients with severe compared to less severe disease was not assessed. Additionally, Dr. Albrich disagreed with the conclusion that all patients with COPD exacerbations should receive antibiotics based on recent literature associating bacterial infections to increased inflammatory markers.
The study reviewed here demonstrates that antibiotic use can be beneficial for patients hospitalized due to COPD exacerbations. However, due to the retrospective design and lack of subgroup analysis, the question of whether all patients should receive antibiotics is still unanswered. Current guidelines recommend using antibiotics for patients who present with an increase in sputum production, purulence, and dyspnea. However, further study is required to determine whether only certain subgroups of these symptomatic patients, such as those with high procalcitonin levels or other inflammatory markers and those with greater disease severity and symptoms, should be treated with antibiotics.
- Williams DM, Bourdet SV. Chronic obstructive pulmonary disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2008: 495-517.
- Rothberg MB, Pekow PS, Lahti M, et al. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA. 2010;303(20):2035-2042.
- Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. http://pharmacoclin.hug-ge.ch/formation/GOLD_WR_06.pdf. Accessed November 7 , 2010.
- Sethi S, Wrona C, Eschberger K, et al. Inflammatory profile of new bacterial strain exacerbations of chronic obstructive pulmonary disease. Am J Respir Care Med. 2008;177(5):491-497.
- Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD. Chest. 2007;131(7):9-19.
- Hurley JC. Antibiotic therapy in patients hospitalized with acute obstructive pulmonary disease. JAMA. 2010; 304(12):1325.
- Suissa S, Ernst P. Antibiotic therapy in patients hospitalized with acute obstructive pulmonary disease. JAMA. 2010; 304(12):1325-6.
- Albrich WC, Muller B, Harbarth S. Antibiotic therapy in patients with acute obstructive pulmonary disease. JAMA. 2010; 304(12):1326.
What does the ACC/ACG/AHA 2010 Expert Consensus Document recommend regarding the concomitant use of PPIs and thienopyridines?
What does the ACC/ACG/AHA 2010 Expert Consensus Document recommend regarding the concomitant use of PPIs and thienopyridines?
In November 2010, the American College of Cardiology (ACC), the American College of Gastroenterology (ACG), and the American Heart Association (AHA) issued a 2010 Expert Consensus Document focused on the concomitant use of proton pump inhibitors and thienopyridines (clopidogrel and prasugrel). 1 The document is an update of the 2008 consensus statement, which recommended the use of proton pump inhibitors (PPIs) to reduce gastrointestinal (GI) bleeding in patients taking clopidogrel and aspirin.2 Recent data suggest an interaction between PPIs and thienopyridines (see FAQ October 2009 – Interaction between PPIs and thienopyridines). An overview of the consensus statement is summarized below. Clinicians are encouraged to review the full update at http://circ.ahajournals.org/cgi/reprint/CIR.0b013e318202f701.
Risk of GI bleeding
There are several risk factors for GI bleeding with antiplatelet therapy.1 There is a strong correlation with an upper GI bleed and a history of bleeding or peptic ulcer disease. Additional risk factors include older age, use of medications including steroids, anticoagulants, and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as Helicobacter pylori infection. Several observational studies have evaluated the risk of GI bleeding with thienopyridines and randomized controlled trials have assessed bleeding as an endpoint. In head-to-head trials, the risk of GI bleeding was higher with aspirin compared to clopidogrel. Dual therapy with clopidogrel and aspirin was associated with an increased risk of GI bleed. The CURE and ACTIVE trials assessed the risk of GI bleed with dual therapy with clopidogrel and aspirin.3,4 The relative risk (RR) of GI bleeding in the CURE trial was 1.78 (95% confidence interval (CI) 1.25 to 2.54).3 Similar results were shown in the ACTIVE trial [RR 1.96 (95% CI 1.46 to 2.63)].4
PPIs and clopidogrel/prasugrel efficacy
Several observational studies have been conducted which assessed the effect of PPIs on clinical cardiovascular (CV) outcomes in patients prescribed clopidogrel.1 Of the 10 published studies, 5 showed a small but significant association between PPI use and CV events, while the remaining 5 showed no significant association. O'Donoghue and colleagues analyzed 2 randomized controlled trials to determine the clinical efficacy of clopidogrel or prasugrel with or without a PPI.5 Over 13,600 patients were randomized to either clopidogrel or prasugrel after percutaneous coronary intervention (PCI). The composite outcome of CV death, myocardial infarction (MI), or stroke was not affected by the use of PPIs in either the clopidogrel group [adjusted hazard ratio (HR) 0.94 (95% CI 0.8 to 1.11)] or the prasugrel group [HR 1 (95% 0.84 to 1.2)]. There was no difference in the PPI used, which included omeprazole, lansoprazole, esomeprazole, and pantoprazole. In addition, the CREDO trial showed that PPIs were associated with an increase in CV events with or without clopidogrel.6
Gilard and colleagues conducted a randomized controlled trial to determine if the concomitant use of omeprazole reduces pharmacological action of clopidogrel.7 In this study, 3,761 patients undergoing elective coronary stent implantation and receiving standardized, dual antiplatelet therapy with aspirin and clopidogrel were randomized to omeprazole or placebo. There was no significant difference between the groups in the composite outcome of MI, stroke, coronary artery bypass graft, PCI, and CV death. Fewer GI adverse effects were seen in the patients that received omeprazole (see FAQ May 2008 – Drug interaction between omeprazole and clopidogrel ).
Pharmacokinetic and pharmcodynamic studies, which used platelet assays as surrogate endpoints, suggest that the available PPIs inhibit cytochrome P450 2C19 to differing extents.1 However, published observational studies have not shown a difference in CV events among the various PPIs.
The Expert Consensus Document provides the following 11 recommendations.1
- Clopidogrel reduces major CV events compared with placebo or aspirin.
- Dual antiplatelet therapy with clopidogrel and aspirin, compared with aspirin alone, reduces major CV events in patients with established ischemic heart disease and reduces coronary artery stent thrombosis, but is not routinely recommended for patients with prior ischemic stroke because of the risk of bleeding.
- Clopidogrel alone, aspirin alone, and their combination are all associated with increased risk of GI bleeding.
- Patients with prior GI bleeding are at highest risk of recurrent bleeding on antiplatelet therapy. Additional risk factors include advanced age, concomitant use of steroids, anticoagulants, and NSAIDs (including aspirin), and H. pylori infection. The risk of GI bleeding increases as the number of risk factors increase.
- A PPI or histamine H2 receptor antagonist (H2RA) reduces the risk of upper GI bleeding compared to no therapy; PPIs reduce GI bleeding to a greater extent.
- PPIs are recommended to reduce GI bleeding among patients with a history of upper GI bleeding. PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy.
- Routine use of either a PPI or H2RA is not recommended for patients at lower risk for upper GI bleeding.
- Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and GI complications.
- Pharmacokinetic and pharmacodynamic studies suggest that concomitant use of clopidogrel and a PPI reduces the antiplatelet effects of clopidogrel. The strongest evidence is for omeprazole and clopidogrel. It is not established that changes in surrogate endpoints translate into clinically meaningful differences.
- Observational studies and a single randomized clinical trial have shown inconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs. A clinically important interaction cannot be excluded, particularly in certain subgroups, such as poor metabolizers of clopidogrel.
- The role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and PPIs has not yet been established.
The ACC/ACG/AHA 2010 Expert Consensus Document provides clinicians with guidance on the use of concomitant PPIs and thienopyridines. It is appropriate to use PPIs to reduce GI bleeding among patients with a history of upper GI bleeding; however, use of either a PPI or H2RA is not recommended for patients at lower risk for upper GI bleeding. The document is silent on the definition of high- and low-risk patients, as well as if 1 PPI is preferred over another. Healthcare providers must use clinical judgment and weigh the benefits and risks, both CV events and GI bleeding, when placing a patient on concurrent PPI and thienopyridine therapy.
- Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Circulation. 2010; doi: 10.1161/CIR.0b013e318202f701.
- Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008;118(18):1894-1909.
- Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
- Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360(20):2066-2078.
- O'Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009;374(9694):989-997.
- Aronow HD, Steinhubl SR, Brennan DM, Berger PB, Topol EJ, CREDO Investigators. Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coronary intervention: Insights from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J. 2009;157(2):369-374.
- Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin (OCLA). J Am Coll Cardiol. 2008;51(3):256-260.
What changes have been made to the AHA guidelines for cardiopulmonary resuscitation?
What changes have been made to the AHA guidelines for cardiopulmonary resuscitation?
Since the 1960s the American Heart Association (AHA) has authored guidelines for healthcare providers on appropriate management of cardiopulmonary arrest.1 The first guideline focused on use of cardiopulmonary resuscitation (CPR); today the guidelines encompass all aspects of emergency cardiovascular care including basic life support (BLS), electrical therapies such as defibrillation and cardioversion, adult and pediatric advanced cardiac life support (ACLS), acute coronary syndrome, and stroke. The 2010 update to the AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care contain several important changes from previous versions, which are summarized below.
Quality cardiopulmonary resuscitation
Cardiopulmonary resuscitation refers to interventions performed on patients with cardiopulmonary arrest that aim to achieve return of spontaneous circulation (ROSC).2 These activities typically include chest compressions and rescue breaths for patients without a pulse and spontaneous breathing, respectively. Of the 2 interventions, chest compression is associated with better outcomes. Several studies have demonstrated an increase in survival with shorter time to chest compression or improved compression technique, which has led to a change in the 2010 guidelines in the sequence of BLS events to "C-A-B" from "A-B-C".2-5 In addition, "look, listen, and feel", which refers to activities in checking the airway, has been removed from the BLS protocol. The new focus on achieving adequate chest compressions prior to clearing the patient's airway and delivering rescue breaths is an effort to decrease the time to first chest compression.2
Reasons cited in the guidelines for an increased focus on chest compressions include greater willingness and ability of first responders (often non-healthcare providers) to participate in BLS, tailoring rescue efforts to the most likely cause of adult arrest (cardiac rather than respiratory), and lack of evidence suggesting harm if assisted breathing is delayed.2 Of note, since cardiopulmonary arrest in infants usually results from respiratory causes, "A-B-C" remains the standard BLS procedure in that population unless there is a known cardiac cause.
There are also data suggesting that out-of-hospital rescue efforts involving only chest compressions may have similar efficacy as those involving both chest compressions and rescue breaths.6-10 Survival to discharge, a common measure of efficacy in cardiopulmonary arrest studies, were not statistically different in 2 retrospective studies that compared standard CPR with continuous chest compression (no breaths).6,7 Similarly, 1-month survival did not differ between groups in another retrospective study.8 One prospective study found no difference in the endpoint of 1-year survival with favorable neurologic outcome when standard CPR and continuous chest compression were compared, while another demonstrated significantly better 1-year survival with continuous chest compression compared to standard CPR in patients with apnea, shockable rhythm, and CPR initiated less than 4 minutes after a witnessed arrest.9,10 These data further reinforce the value of chest compressions compared to breath support in the setting of cardiopulmonary arrest.
The quality of chest compressions remains an important focus of the 2010 guidelines.1,2 Adequate compression technique requires a depth of at least 2 inches (a change from the previous recommendation of 1.5 to 2 inches), a rapid enough rate to ensure tissue perfusion, complete recoil to allow the heart to completely fill with blood between compressions (100 per minute), and minimal interruptions in compression for breaths, defibrillation, or checking for a pulse. Any deviation from this standard of care may decrease the effectiveness of BLS efforts. The need to achieve appropriate compression depth and rate is summarized in the new phrase "push hard, push fast". Healthcare providers with previous BLS certification may require retraining to ensure understanding of these new CPR recommendations.
Medication use in advanced cardiac life support
Several medication-related changes have been made to the 2010 ACLS guidelines.11 The first change involves the pulseless electrical activity (PEA)/asystole algorithm. For several decades, the AHA has recommended alternating bolus doses of epinephrine and atropine in patients with non-shockable PEA/asystole; however, data to support the use of atropine in this setting are limited. The drug is used to reverse cholinergic effects on heart rate and atrioventricular nodal conduction, but no prospective studies examining its efficacy in this setting have been conducted and retrospective studies are conflicting. An early case series of 8 asystole cases refractory to epinephrine found that all patients achieved a regular heart rhythm after atropine therapy.12 Subsequent studies found no benefit with atropine, or demonstrated an association with emergency medication use (including atropine) and decreased likelihood of successful resuscitation and survival after PEA or asystole.13-17 Based on the lack of efficacy data, atropine has been removed from the PEA/asystole algorithm.11 In contrast, improved ROSC (but not survival) has been seen with epinephrine.18 According to the guidelines, multiple clinical trials have demonstrated similar efficacy of vasopressin compared to epinephrine, thus justifying its continued inclusion in the PEA/asystole protocol.11
Adenosine continues to be the standard of care for treatment of narrow-complex tachycardia with a regular rhythm.11 Previous tachycardia algorithms have also recommended adenosine for regular wide-complex tachycardia thought to be due to supraventricular tachycardia (SVT) with abberancy; however, the 2010 ACLS guideline recommends use of adenosine for any regular wide-complex tachycardia. In this case, adenosine can be used to both treat and diagnose the underlying rhythm; SVT will slow or convert to sinus rhythm with adenosine, while ventricular tachycardia will not be affected. Of note, due to the risk of ventricular fibrillation the guidelines caution against use of adenosine for irregular or polymorphic wide-complex tachycardias.
The bradycardia algorithm has also changed in terms of medication use.11 Symptomatic bradycardia with evidence of instability such as hypotension, acute chest discomfort, or altered mental status should be treated with atropine. If atropine is ineffective, an infusion of dopamine, epinephrine, or isoproterenol is now suggested by the guidelines as an equally effective alternative (rather than a less effective alternative, as stated in previous guidelines) to transcutaneous pacing.1,11 These infusions should be used temporarily prior to more definite treatment, such as pacemaker placement, and may be most useful in patients with hypotension.
Post-cardiac arrest care
A new section of the 2010 AHA guidelines focuses on care of patients during the immediate post-cardiac arrest period.19 Following the examples of success with other critical illnesses such as sepsis and acute decompensated heart failure, the guidelines now advocate a structured, comprehensive, multidisciplinary, bundled approach to post-arrest management. A new post-arrest algorithm has been developed to help institutions implement these changes. Initial objectives of focused care in this setting include optimization of cardiac function and vital organ perfusion, transport of patients to tertiary care hospitals and critical care units with adequate post-arrest treatment facilities, and identification and treatment of the underlying cause for the cardiac arrest to prevent future arrests. Specifically, the guidelines recommend:
- Achievement of adequate body temperature for survival and neurologic recovery;
- Identification and management of acute coronary syndromes;
- Optimization of mechanical ventilation to prevent lung injury;
- Support of organ function to minimize risk of injury;
- Objective assessment of prognosis for recovery;
- Provision of rehabilitation services to survivors.
The post-cardiac arrest algorithm recommends that providers consider inducing hypothermia in patients unable to follow commands after ROSC and pulmonary and hemodynamic support, especially those presenting with ventricular fibrillation.19 Multiple clinical trials, including 2 randomized trials, have demonstrated an improvement in overall survival and neurologically intact survival to hospital discharge when patients were cooled after ROSC post-ventricular fibrillation.20-23 No randomized, controlled trials have compared induced hypothermia with no hypothermia in patients with other arrhythmias, though there are some preliminary data suggesting benefit.19 The induced hypothermia protocol involves administration of 30 mL/kg cold intravenous fluid with concurrent surface cooling. The goal core temperature is 32 to 34°C as continuously monitored by esophageal, bladder, or pulmonary artery thermometers. After 12 to 24 hours patients should be gradually rewarmed by 0.25°C per hour. Important questions remain about induced hypothermia, including the optimal time to start, duration, method of cooling, and monitoring. In addition, further information is needed regarding the potential adverse effects such as coagulopathy, arrhythmia, and hyperglycemia.
Several important changes were made to the AHA cardiopulmonary resuscitation guidelines with the 2010 update. Key changes include a greater emphasis on high-quality chest compressions with a de-emphasis on rescue breaths during CPR, removal of atropine from the PEA/asystole algorithm, an expanded role for infusion of chronotropic agents for refractory bradycardia and adenosine for regular wide-complex tachycardia, and a new algorithm for post-cardiac arrest care including a strong recommendation regarding provision of induced hypothermia to comatose post-arrest patients. Clinicians involved in cardiopulmonary arrest rescue efforts should be aware of these changes and work to ensure their implementation on the institutional level.
- Field JM, Hazinski MF, Sayre MR, et al. Part 1: executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(8 Suppl 3):S640-S656.
- Berg RA, Hemphill R, Abella BS, et al. Part 5: adult basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(8 Suppl 3):S685-S705.
- Lund-Kordahl I, Olasveengen TM, Lorem T, Samdal M, Wik L, Sunde K. Improving outcome after out-of-hospital cardiac arrest by strengthening weak links of the local Chain of Survival; quality of advanced life support and post-resuscitation care. Resuscitation. 2010;81(4):422-426.
- Sayre MR, Cantrell SA, White LJ, Hiestand BC, Keseg DP, Koser S. Impact of the 2005 American Heart Association cardiopulmonary resuscitation and emergency cardiovascular care guidelines on out-of-hospital cardiac arrest survival. Prehosp Emerg Care. 2009;13(4):469-477.
- Iwami T, Nichol G, Hiraide A, et al. Continuous improvements in "chain of survival" increased survival after out-of-hospital cardiac arrests: a large-scale population-based study. Circulation. 2009;119(5):728-734.
- Olasveengen TM, Wik L, Steen PA. Standard basic life support vs. continuous chest compressions only in out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2008;52(7):914-919.
- Ong ME, Ng FS, Anushia P, et al. Comparison of chest compression only and standard cardiopulmonary resuscitation for out-of-hospital cardiac arrest in Singapore. Resuscitation. 2008;78(2):119-126.
- Bohm K, Rosenqvist M, Herlitz J, Hollenberg J, Svensson L. Survival is similar after standard treatment and chest compression only in out-of-hospital bystander cardiopulmonary resuscitation. Circulation. 2007;116(25):2908-2912.
- Iwami T, Kawamura T, Hiraide A, et al. Effectiveness of bystander-initiated cardiac-only resuscitation for patients with out-of-hospital cardiac arrest. Circulation. 2007;116(25):2900-2907.
- SOS-KANTO study group. Cardiopulmonary resuscitation by bystanders with chest compression only (SOS-KANTO): an observational study. Lancet . 2007;369(9565):920-926.
- Neumar RW, Otto CW, Link MS, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(8 Suppl 3):S729-S767.
- Brown DC, Lewis AJ, Criley JM. Asystole and its treatment: the possible role of the parasympathetic nervous system in cardiac arrest. JACEP. 1979;8(11):448-452.
- Stueven HA, Tonsfeldt DJ, Thompson BM, Whitcomb J, Kastenson E, Aprahamian C. Atropine in asystole: human studies. Ann Emerg Med. 1984;13(9 Pt 2):815-817.
- Stiell IG, Wells GA, Hebert PC, Laupacis A, Weitzman BN. Association of drug therapy with survival in cardiac arrest: limited role of advanced cardiac life support drugs. Acad Emerg Med. 1995;2(4):264-273.
- van Walraven C, Stiell IG, Wells GA, Hébert PC, Vandemheen K. The OTAC Study Group. Do advanced cardiac life support drugs increase resuscitation rates from in-hospital cardiac arrest? Ann Emerg Med. 1998;32(5):544-553.
- Engdahl J, Bång A, Lindqvist J, Herlitz J. Can we define patients with no and those with some chance of survival when found in asystole out of hospital? Am J Cardiol. 2000;86(6):610-614.
- Dumot JA, Burval DJ, Sprung J, et al. Outcome of adult cardiopulmonary resuscitations at a tertiary referral center including results of "limited" resuscitations. Arch Intern Med. 2001;161(14):1751-1758.
- Herlitz J, Ekström L, Wennerblom B, Axelsson A, Bång A, Holmberg S. Adrenaline in out-of-hospital ventricular fibrillation. Does it make any difference? Resuscitation. 1995;29(3):195-201.
- Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(8 Suppl 3):S768-S786.
- Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549-556.
- Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-563.
- Belliard G, Catez E, Charron C, et al. Efficacy of therapeutic hypothermia after out-of-hospital cardiac arrest due to ventricular fibrillation. Resuscitation. 2007;75(2):252-259.
- Castrejón S, Cortés M, Salto ML, et al. Improved prognosis after using mild hypothermia to treat cardiorespiratory arrest due to a cardiac cause: comparison with a control group. Rev Esp Cardiol. 2009;62(7):733-741.
What are the treatment options for post-operative shivering?
What are the treatment options for post-operative shivering?
Postoperative shivering is an unpleasant side effect of recovery from anesthesia. It is characterized as involuntary mechanical oscillatory muscle movements that can be clonic in nature.1-3 These tremors can affect one or more groups of skeletal muscles, and their onset may range from 5 to 30 minutes after stopping anesthesia.3-4 It is unclear how many patients experience shivering, but the incidence can vary from 5% to 60% of patients recovering from anesthesia.3 Several risk factors are thought to increase the incidence of postoperative shivering including male gender, young age, length of surgery and anesthesia, perioperative hypothermia, and type of anesthetic used during surgery.1 Halogenated agents and thiopental appear to increase the incidence of shivering postoperatively.
While there may be several causes behind postoperative shivering, it can be effectively categorized into one of two classes: thermoregulatory and non-thermoregulatory shivering.3 Thermoregulatory shivering is a response to a drop in core body temperature, typically caused by perioperative hypothermia. The onset of hypothermia is usually a consequence of thermoregulatory inhibition by anesthetics. The causes of non-thermoregulatory shivering are not completely understood, but postoperative pain may play an important role in its onset. Often, it is the combination of anesthetic-induced hypothermia and exposure to a cold environment (such as the operating room) that results in postoperative shivering.
While discomfort and increased postoperative pain (due to surgical incision stretching) are the main clinical implications of shivering, it has been proposed that oxygen consumption and metabolic demand may also be increased.3 However, the extent of this increase and its effect on clinical status or cardiac morbidity are still unclear. Shivering also increases metabolic heat production up to 600% above baseline.
Treatment of postoperative shivering
There are several non-pharmacological approaches that can address shivering in recovering patients. Shivering caused by hypothermia can be prevented by skin surface re-warming, either by covering the patient with surgical drapes, using a forced-air warmer prior to anesthesia, raising the temperature in the operating room, or warming intravenous solutions when possible.1 Several pharmacological options can be used for preventing or treating postoperative shivering.3 These include opiates (with meperidine showing the most remarkable and consistent results), tramadol, magnesium sulfate, α2-agonists (eg, clonidine and dexmedetomidine), physostigmine, doxapram, methylphenidate, and 5-HT3 antagonists. Of note, nefopam (a centrally-acting nonopioid analgesic) and urapidil (α1-agonist and 5-HT1A agonist) are both agents that may be used in the treatment of postoperative shivering. However, neither are approved for use in the United States.
Despite the number of pharmacological options available for postoperative shivering, no "gold-standard" treatment exists. In fact, the mechanism and relative efficacy of these interventions is unclear. A number of trials have evaluated the role of several parenteral medications in postoperative shivering prophylaxis and treatment. The results of these trials are discussed below.
A meta-analysis of 27 randomized controlled trials involving over 2200 patients found clonidine to be the most frequently studied drug in the prevention of shivering.5 Other commonly studied medications included meperidine and tramadol. All the studies compared single parenteral doses of the medication to placebo or no treatment. Varying doses were investigated; however, all studies involving these agents showed that pharmacological therapy was more effective than the control intervention at preventing postoperative shivering. Data on the absence of shivering were evaluated based on the relative benefit and the number needed to treat (NNT). The average incidence of shivering in controls was 52%, although the reported range was variable, from 20% or less to over 70%.
The results of this analysis for the most commonly studied interventions are included in Table 1.5 For clonidine, the authors of the meta-analysis also looked at the dose of clonidine and its relative benefit on shivering; the dosage categories were arbitrarily set (see Table 1). For meperidine, the doses tested in the clinical trials were 0.3, 0.4, and 0.5 mg/kg, and 12.5 and 25 mg. The mg/kg doses were converted to a fixed dose, resulting in a dosage range of 12.5 to 35 mg. Based on the results of individual studies, lower doses of meperidine (<24 mg) were no more effective than controls. Tramadol dosing was treated in the same manner-the original dosing regimens were 0.5, 1, 2, and 3 mg/kg. However, individual studies found all dose levels to be more effective than controls. Of note, methylphenidate, midazolam, dolasetron, ondansetron, physostigmine, and flumazenil were all independently studied in a smaller number of trials with a limited number of patients.
Table 1. Comparison of parenteral IV agents in prevention of postoperative shivering.5 Drug and dosage Total number of patients enrolled Relative benefit (95% CI) vs control NNT Clonidine 65 to 300 mcg 978 (14 trials) 1.58 (1.43-1.74) 3.7 Clonidine 65 to 110 mcg 230 (3 trials) 1.32 (1.16-1.51) Clonidine 140 to 150 mcg 440 (5 trials) 1.83 (1.47-2.27) Clonidine 220 to 330 mcg 308 (6 trials) 1.61 (1.38-1.87) Meperidine 12.5 to 35 mg 250 (5 trials) 1.67 (1.37-2.03) 3 Tramadol 35 to 220 mg 250 (4 trials) 1.93 (1.56-2.39) 2.2
CI=confidence interval; IV=intravenous; NNT=number needed to treat.
The authors noted that all 3 agents were associated with a low NNT to avoid one episode of postoperative shivering. However, the particularly high incidence of shivering in the control groups suggests that the study populations were at a higher baseline risk for shivering, potentially limiting the generalizability of these findings and inflating the efficacy of these agents compared with controls. Regardless, several experts have conflicting opinions about the role of pharmacological prevention in clinical practice. It is argued that the best first-line prevention of postoperative shivering is through non-pharmacological methods, such as direct skin re-warming or covering the patients with surgical drapes. Furthermore, parenteral agents should be reserved for patients who shiver despite non-pharmacological methods.6
Several interventions including opioids, centrally-acting analgesics, sodium-channel blockers, α2-agonists, methylphenidate, doxapram, magnesium, and ketanserin, were evaluated in a meta-analysis of 20 randomized, placebo-controlled studies published between 1984 and 2000.2 The most frequently studied agents were meperidine, clonidine, doxapram, alfentanil, and ketanserin (an antihypertensive agent not available in the United States). Data on the absence of shivering after treatment were evaluated by calculating the relative risk and the NNT and stratified according to time of observation after drug administration. Meperidine, clonidine, ketanserin, and doxapram were found to have the most evidence in favor of their efficacy when evaluated at 5 minutes. Significance remained in favor of meperidine, clonidine, and alfentanil when shivering was assessed at 10 minutes after administration. There was not enough data about other agents to draw conclusions about their role in postoperative shivering. Some of the efficacy data regarding meperidine, clonidine, and doxapram are presented in Table 2.
Table 2. Comparison of parenteral agents in treatment of postoperative shivering.2 Drug/Dose Percent not shivering after
(RR [95% CI]): (versus control)
Relative Risk (95% CI)a NNT (95% CI)a 1 minute 5 minutes 10 minutes Meperidine 25 mg 43% vs 6% 87% vs 9% 91% vs 23% 9.55 (5.72-15.9) 1.3 (1.2-1.4) Clonidine 150 mcg NA 87% vs 12% 77% vs 26% 6.82 (3.28-14.2) 1.3 (1.1-1.6) Doxapram 100 mg 33% vs 8% 78% vs 20% NA 3.97 (2.42-6.53) 1.7 (1.4-2.3) Alfentanil 250 mcg 23% vs 4% 50% vs 9% 54% vs 22% 5.56 (2.04-15.1) 2.4 (1.7-4.0)
a At 5 minutes after treatment. CI=confidence interval; NA=not available: NNT=number needed to treat.
These data suggest that approximately 2 shivering patients need to be treated with meperidine, clonidine, or doxapram to stop shivering in one patient within 5 minutes. Also, these data suggest that meperidine, clonidine, and doxapram may have comparable efficacy at treating postoperative shivering in postsurgical patients. Although significant from the control group, the rates of patients without shivering were lowest with alfentanil. However, it is important to note that the meta-analysis relied on indirect comparisons of the agents.
Since the publication of the previous meta-analysis, several trials have been conducted comparing the efficacy of different agents in the treatment of postoperative shivering. A recent randomized, prospective, controlled trial evaluated the efficacy of intravenous doxapram 1.5 mg/kg, meperidine 0.35 mg/kg, and saline placebo in 30 postoperative adult patients.4 The study found no statistical difference between doxapram and meperidine nor between doxapram and placebo. However, meperidine was better than placebo at stopping postoperative shivering. Meperidine stopped shivering in 80% of patients, while saline placebo stopped shivering in 20% of patients (p < 0.05). Due to the small sample size, it is difficult to make a meaningful conclusion regarding the efficacy of meperidine. This study also raises the question about the clinical significance of treatment, given that 20% of patients in the placebo group stopped shivering within minutes of administration. Whether this is related to a placebo effect or if it relates to the fact that shivering is often self-resolving is not known.
Another prospective, randomized, double-blind study compared the efficacy of meperidine, clonidine, and urapidil in the treatment of postanesthetic shivering.6 The trial included 149 postoperative patients. Sixty patients developed shivering after their procedure and were randomized to treatment with intravenous meperidine 25 mg, clonidine 0.15 mg, or urapidil 25 mg. Patients received a second dose after 5 minutes if the shivering did not stop (except for clonidine, which was replaced by saline). A 25-mg dose of meperidine was used as rescue therapy if the second dose of the randomized treatment was not effective after another 5 minutes. The trial found that meperidine and clonidine were both more effective than urapidil (p<0.01). Clonidine was effective in stopping shivering in 16 of 20 patients. The 4 remaining patients required longer than 5 minutes for the shivering to resolve. Shivering ceased within 5 minutes in 18 of 20 patients treated with meperidine. A second dose of meperidine was sufficient to stop shivering in the remaining 2 patients. Only 6 of 20 patients in the urapidil group stopped shivering after the first dose, and 6 more had stopped shivering after the second dose. The treatment was not effective in 8 patients.
Postoperative shivering can sometimes be a disturbing side effect for patients recovering from surgery and may result in increased incision pain and metabolic demand. Non-pharmacological methods of preventing shivering include covering the patient with surgical drapes during the procedure, warming intravenous fluids, and raising the temperature in the operating room (>23°C) when possible. Nonetheless, postoperative shivering may still occur, and pharmacological agents have been used for the prevention and treatment of shivering. A wide variety of agents with different mechanisms of action are available for use. Unfortunately, there is no "gold-standard" drug for the treatment of postoperative shivering. Numerous trials have studied the efficacy of several agents, either in comparison to placebo or to each other, and even more trials have been conducted studying the efficacy of such agents in the prevention of postoperative shivering. Clonidine, meperidine, and tramadol all appear to be effective agents in postoperative shivering prophylaxis. However, non-pharmacologic methods such as skin re-warming may be more appropriate options for prevention of shivering.
It appears that clonidine and meperidine have the most data to support their efficacy in treatment. While most studies, including the results from a meta-analysis, show similar efficacy of both agents in stopping shivering in postoperative patients, the choice depends on the patient's clinical status and the drug's side effect profile. Those medications also have additional properties that may determine their usefulness in certain patient populations. For example, meperidine has analgesic effects, while clonidine is an antihypertensive that can be used to lower blood pressure. If pharmacological treatment is to be used in a shivering postoperative patient, the clinical status (including hemodynamic stability) of the patient should be considered along with the medication's mechanism and potential side effects.
1. Alfonsi P. Postanaesthetic shivering. Drugs. 2001; 61(15): 2193-2205.
2. Kranke P, Eberhart LH, Roewer N, Tramer MR. Pharmacological treatment of postoperative shivering: a quantitative systematic review of randomized controlled trials. Anesth Analg. 2002;949(2):453-460.
3. Witte J, Sessler DI. Perioperative shivering. Anesthesiology. 2002;96(2):467-484.
4. Shrestha AB. Comparative study on effectiveness of doxapram and pethidine for postanaesthetic shivering. J Nepal Med Assoc. 2009;48(174):116-120.
5. Kranke P, Eberhart LH, Roewer N, Tramer MR. Single-dose parenteral pharmacological interventions for the prevention of postoperative shivering: a quantitative systematic review of randomized controlled trials. Anesth Analg. 2004; 99(3):718-727.
6. Schwarzkopf KRG, Hoff H, Hartmann M, Fritz HG. A comparison between meperidine, clonidine, and urapidil in the treatment of postanesthetic shivering. Anesth Analg. 2001;92(1):257-260.