Friday, May 29, 2009
Tight glucose control raises ICU mortality
| Intensively controlling blood glucose in critically ill patients increases mortality, researchers have found. The study, published in the New England Journal of Medicine, contradicts prior research which favored tight glucose control in surgical intensive care unit (ICU) patients and has prompted calls for guidelines to be revised. “Far from reducing mortality, the tighter range actually resulted in a 2.6 percent increase in mortality in a broad range of critically ill patients,” said lead author of the NICE-SUGAR* trial, Professor Simon Finfer. “The international guidelines need to be urgently reviewed and critical care practitioners need to consider this evidence and probably not target such tight glucose control in their patients.” The NICE-SUGAR study was a large, randomized controlled trial conducted in 6,104 critically ill patients in 42 hospitals across four countries. Patients were randomly assigned to undergo either intensive control (with a target blood glucose range of 81 to 108 mg/dL or 4.5 to 6 mmol/L) or conventional control (target blood glucose range of 180 mg/dL or 10 mmol/L or less). The primary endpoint was death from any cause within 90 days after randomization. [N Engl J Med 2009; 360(13):1283-97] Intensive blood glucose control resulted in 78 more deaths than the conventional control group (829 versus 751, an absolute increase of 2.6 percent; P=0.02). Severe hypoglycemia was also predictably higher in the intensive control group (206 cases out of 3,016 patients versus 15 cases out of 3,014 patients in the control group; P<0.001). However, there was no significant difference between treatment groups in the median length of hospital or ICU stay, the median number of days of mechanical ventilation or renal replacement therapy. “Intensive therapy often ends up with unacceptably high rates of hypoglycemia [and] that is counter-productive,” said Dr. Richard Chen, who is head of the division of endocrinology and director of the diabetes center at Changi General Hospital, Singapore. “Because of this, most ICUs do not attempt to lower blood glucose to below 6.1 mmol/L, but prefer to keep it just below 10 mmol/L, which the NICE-SUGAR study has shown to be safer.” A joint statement by the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) was issued in response to the NICE-SUGAR study. Although supporting the data, they also advised caution, stating: “The NICE-SUGAR study should not lead to an abandonment of the concept of good glucose management in the hospital setting. Uncontrolled high blood glucose can lead to serious problems for hospitalized patients, such as dehydration and increased propensity to infection.” Finfer and his colleagues are by no means advocating abandoning glucose control entirely, but they emphasize that targeting very low blood glucose may be harmful in critically ill patients. Based on their data, Finfer – who is senior staff specialist in intensive care at the Royal North Shore Hospital of Sydney, Australia – recommends targeting blood glucose to 10 mmol/L. This was the target used in the conventional control arm of the study, which resulted in lower mortality. Although not intensively normalizing blood glucose, it would still be viewed as “good” glucose control, and some two-thirds of conventional control patients required intravenous insulin to achieve it. “Good glycemic control in the critically ill is still necessary, as it lowers risk of concomitant sepsis,” added Chen. “The key is not to be too over-zealous.” Complete recommendations regarding glucose control will be published later this year in Endocrine Practice and Diabetes Care, but for now, the ADA and AACE are aligning themselves with the NICE-SUGAR trial. “Until more information is available, it seems reasonable for clinicians to treat critical care patients with the less intensive – yet good – glucose control strategies used in the conventional arm of the NICE-SUGAR trial,” they conclude. * NICE-SUGAR: Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation. Source : http://www.mims.com/Page.aspx?menuid=RecentHL&RecentHeaderID=92 |
Saturday, May 23, 2009
World Health Organization Issues Guidelines on Hand Hygiene in Healthcare
May 6, 2009 — The World Health Organization (WHO) has issued Guidelines on Hand Hygiene in Health Care, offering a thorough review of evidence on hand hygiene in healthcare and specific recommendations to improve hygiene practices and reduce transmission of pathogenic microorganisms to patients and healthcare workers (HCWs). The guidelines target hospital administrators and public health officials as well as HCWs, and they are designed to be used in any setting in which healthcare is delivered either to a patient or to a specific group, including all settings where healthcare is permanently or occasionally performed, such as home care by birth attendants. Individual adaptation of the recommendations is encouraged, based on local regulations, settings, needs, and resources. Hand Hygiene Indications Indications for hand hygiene are as follows: • Wash hands with soap and water when visibly dirty, when soiled with blood or other body fluids, or after using the toilet. • Handwashing with soap and water is preferred when exposure to potential spore-forming pathogens, such as Clostridium difficile, is strongly suspected or proven. • In all other clinical situations, use an alcohol-based handrub as the preferred means for routine hand antisepsis, if hands are not visibly soiled. Wash hands with soap and water if alcohol-based handrub is not available. • Hand hygiene is needed before and after touching the patient; before touching an invasive device used for patient care, whether gloves are used; after contact with body fluids or excretions, mucous membranes, nonintact skin, or wound dressings; if moving from a contaminated body site to another body site on the same patient; after touching inanimate surfaces and objects in the immediate vicinity; and after removing gloves. • Hand hygiene is needed before handling medication or preparing food using an alcohol-based handrub or handwashing with water and either plain or antimicrobial soap. • Soap and alcohol-based handrub should not be used together. Hand Hygiene Techniques Specific recommendations for hand hygiene technique are as follows: • Rub a palmful of alcohol-based handrub over all hand surfaces until dry. • When washing hands, wet hands with water and apply enough soap to cover all surfaces; rinse hands with water and dry thoroughly with a single-use towel. Whenever possible, use clean, running water. Avoid hot water, which may increase the risk for dermatitis. • Use the towel to turn off the tap or faucet, and do not reuse the towel. • Liquid, bar, leaf, or powdered soap is acceptable; bars should be small and placed in racks that allow drainage. Surgical Hand Preparation Specific recommendations for surgical hand preparation are as follows: • Before beginning surgical hand preparation, remove jewelry. Artificial nails are prohibited. • Sinks should be designed to reduce the risk for splashes. • Visibly soiled hands should be washed with plain soap before surgical hand preparation, and a nail cleaner should be used to remove debris from underneath the fingernails, preferably under running water. • Brushes are not recommended. • Before donning sterile gloves, surgical hand antisepsis should be performed with a suitable antimicrobial soap or alcohol-based handrub, preferably one that ensures sustained activity. Alcohol-based handrub should be used when quality of water is not assured. • When using an antimicrobial soap, scrub hands and forearms for the length of time recommended by the maker, usually 2 to 5 minutes. • When using an alcohol-based surgical handrub, follow the maker's instructions; apply to dry hands only; do not combine with alcohol-based products sequentially; use enough product to keep hands and forearms wet throughout surgical hand preparation; and allow hands and forearms to dry thoroughly before donning sterile gloves. Selecting Hand Hygiene Agents Some specific recommendations for selection and handling of hand hygiene agents are as follows: • Provide effective hand hygiene products with low potential to cause irritation. • Ask for HCW input regarding skin tolerance, feel, and fragrance of any products being considered. • Determine any known interaction between products used for cleaning hands, skin care products, and gloves used in the institution. • Provide appropriate, accessible, well-functioning, clean dispensers at the point of care, and do not add soap or alcohol-based formulations to a partially empty dispenser. Skin Care Recommendations Some specific recommendations for skin care are as follows: • Educate HCWs about hand-care practices designed to reduce the risk for irritant contact dermatitis and other skin damage. • Provide alternative hand hygiene products for HCWs with confirmed allergies to standard products. • Provide HCWs with hand lotions or creams to reduce the risk for irritant contact dermatitis. • Use of antimicrobial soap is not recommended when alcohol-based handrub is available. Soap and alcohol-based handrub should not be used together. Recommendations for Glove Use Some specific recommendations for use of gloves are as follows: • Glove use does not replace the need for hand hygiene. • Gloves are recommended in situations in which contact with blood or other potentially infectious materials is likely. • Remove gloves after caring for a patient, and do not reuse. • Change or remove gloves if moving from a contaminated body site to either another body site within the same patient or the environment. "In hand hygiene promotion programmes for HCWs, focus specifically on factors currently found to have a significant influence on behaviour, and not solely on the type of hand hygiene products," the guidelines authors write. "The strategy should be multifaceted and multimodal and include education and senior executive support for implementation. Educate HCWs about the type of patient-care activities that can result in hand contamination and about the advantages and disadvantages of various methods used to clean their hands." Four of the guidelines authors have disclosed various financial relationships with GOJO, Clorox, and GlaxoSmithKline, and other companies and institutions. A complete description of their disclosures is available in the original article. The other guidelines authors have disclosed no relevant financial relationships. WHO Guidelines on Hand Hygiene in Health Care. May 2009. Clinical Context
In 2004, WHO convened a group of international experts in infection control to prepare guidelines for hand hygiene in healthcare. In 2002, the Centers for Disease Control and Prevention Guideline for Hand Hygiene in Health-Care Settings was adopted. Following a systematic review of the literature and task force meetings, the Advanced Draft of the WHO Guidelines on Hand Hygiene in Health Care was published in 2006. An Executive Summary of the Advanced Draft of the Guidelines is available separately (http://www.who.int/gpsc/tools/en/). Pilot testing of the advanced draft occurred, with subsequent updating and finalization of the guidelines. The WHO Guidelines on Hand Hygiene in Health Care includes a review of scientific data, consensus recommendations, process and outcome measurements, proposals for large scale promotion of hand hygiene, patient participation in promotion of hand hygiene, and a review of national and subnational guidelines. The recommendations are expected to be valid until 2011 and will be updated every 2 to 3 years. Study Highlights
Clinical Implications
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Thursday, May 21, 2009
10 Steps Before You Refer: Heart Failure
IntroductionCongestive heart failure (CHF) is an increasingly widespread condition, the prognosis for moderate and severe heart failure is almost identical to colorectal cancer[1] and worse than breast[2] or prostate cancer.[3] CHF has an overall population prevalence of approximately 1–3% rising to approximately 10% in the very elderly CHF accounts for about 5% of all medical admissions and approximately 2% of total healthcare expenditure.[4] Nearly one million new cases are diagnosed annually worldwide, making it the most rapidly growing cardiovascular disorder. The consequences of heart failure for primary care are profound. CHF has been reported to be second only to hypertension as a cardiovascular reason for a surgery appointment.[5] Despite improvements in medical management, undertreatment is common, many patients with CHF still do not receive treatment optimised according to current guidelines.[4,6] The introduction of the 2009/10 heart failure Quality Outcomes Framework (QOF) additions will bring financial incentives for the prescribing of beta blockers for patients with a diagnosis of heart failure. This will apply to all diagnosed heart failure patients. There are, however, no additional QOF points for optimising medication or maximum tolerated levels, therefore, patient care will rely on good practice and receiving treatment according to current guidelines. The prevalence of heart failure nationally in QOF is just over 1%. Because of the increase in survival after acute myocardial infarction and ageing of the population, the number of patients with heart failure will increase rapidly in most industrialised countries. Heart failure will continue to be a challenge to healthcare. The profile of heart failure management has been raised with the publication of the Coronary Heart Disease (CHD) National Service Framework (NSF) Chapter 6 in 2000[7] and the National Institute for Health and Clinical Excellence (NICE) Heart Failure Clinical Guideline 2003.[8] The heart failure publications have supported the development of community heart failure services, and heart failure specialist nurse roles. The development of the General Practitioner with Special Interest (GPSI) in cardiology qualification and the accreditation in community echocardiography in 2004 has enabled the development of community heart failure services. The training and development of the workforce in primary care has led to improvements in the treatment and management of heart failure patients. A referral to a community specialist heart failure service or secondary care will still be relevant in certain instances, however, the 10 steps will assist in the decision to continue the management in primary care or refer for expert advice and a future management plan. 1. Make the DiagnosisTake a history to assist in determining the diagnosis of heart failure – a history of CHD (previous myocardial infarction), murmur, valve replacement, rheumatic fever, thyroid disease, atrial fibrillation and hypertension are conditions that would predispose a heart failure diagnosis. Establish the number of units of alcohol per week (consider alcoholic cardiomyopathy). The patient's smoking history should be noted as this may suggest chronic obstructive pulmonary disease (COPD) as an alternative diagnosis and spirometry should be undertaken to rule out COPD and asthma as a cause for breathlessness. Weigh and measure the patient, observe for possible cachexia hidden by the oedema. Enquire about shortness of breath, on exertion, at rest or at night. The New York Heart Association (NYHA) classification scale (Table 1) can be used to classify symptom severity. Examine for any ankle, leg or abdominal oedema. Consider an alternative cause (low protein diet, renal disease, venous stasis). Examine the patient for a raised jugular venous pressure (JVP) and listen to the heart for added heart sounds or murmur. Measure the blood pressure, which may be normal or low, and take the pulse to assess whether it is irregular or fast. Could the patient be in fast atrial fibrillation which has precipitated heart failure? Clinical assessment alone is unreliable since the symptoms and signs of heart failure may be insensitive and non-specific, however, when used in a systematic manner it can be effective in determining a diagnosis of heart failure and potentially reduce the effect on the echocardiogram service by excluding patients who are not likely to have heart failure (Figure 1).[9]
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Wednesday, May 13, 2009
New Guidelines Address Treatment of Hospitalized Patients With High Blood Glucose Levels
May 11, 2009 — A consensus statement of the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) issues clinical recommendations on the proper treatment of hospitalized patients with high blood glucose levels. The new guidelines, which target healthcare professionals, supporting staff, hospital administrators, and others involved in improved management of hyperglycemia in inpatient settings, are published in the May/June issue of Endocrine Practice and in the May issue of Diabetes Care. "Although the costs of illness-related stress hyperglycemia are not known, they are likely to be considerable in light of the poor prognosis of such patients," write Etie S. Moghissi, MD, FACP, FACE, from the University of California in Los Angeles, and colleagues. "There is substantial observational evidence linking hyperglycemia in hospitalized patients (with or without diabetes) to poor outcomes. Cohort studies as well as a few early randomized controlled trials (RCTs) suggested that intensive treatment of hyperglycemia improved hospital outcomes." In 2004, the American College of Endocrinology (ACE) and the AACE, in collaboration with the ADA and other medical organizations, developed recommendations for treatment of inpatient hyperglycemia. These guidelines generally endorsed tight glycemic control in critical care units. In 2005, the ADA annual Standards of Medical Care included recommendations for treatment of inpatient hyperglycemia. In 2006, the ACE and ADA collaborated on a joint "Call to Action" for inpatient glycemic control, highlighting several barriers to systematic implementation in hospitals. Questions to Be Considered The main objectives of the AACE and ADA in preparing this updated consensus statement were to identify reasonable, achievable, and safe glycemic targets and to describe the protocols, procedures, and system improvements needed to facilitate their implementation. After extensive review of the most current literature, members of the consensus panel considered the following questions: 1. Does improving glycemic control for inpatients with hyperglycemia improve clinical outcomes? 2. What glycemic targets should be recommended for different patient populations? 3. In specific clinical situations, which available treatment options can safely and effectively achieve optimal glycemic targets? 4. What safety issues are associated with inpatient management of hyperglycemia? 5. What systems need to be in place to implement these recommendations? 6. Is it cost-effective to treat hyperglycemia in hospitalized patients? 7. What are the best strategies to shift management of hyperglycemia to outpatient care? 8. What additional research is needed? Recommendations for Critically Ill Patients Specific clinical recommendations for critically ill patients are as follows: • For treatment of persistent hyperglycemia, beginning at a threshold of no greater than 180 mg/dL (10.0 mmol/L), insulin therapy should be started. • For most critically ill patients, a glucose range of 140 to 180 mg/dL (7.8 - 10.0 mmol/L) is recommended once insulin therapy has been started. • To achieve and maintain glycemic control in critically ill patients, the preferred method is intravenous insulin infusions. • Validated insulin infusion protocols that are shown to be safe and effective and to have low rates of hypoglycemia are recommended. • To reduce hypoglycemia and to achieve optimal glucose control, frequent glucose monitoring is essential in patients receiving intravenous insulin. Recommendations for Patients Who Are Not Critically Ill Specific clinical recommendations for noncritically ill patients are as follows: • For most noncritically ill patients receiving insulin therapy, the premeal blood glucose target should generally be less than 140 mg/dL (<> • In stable patients in whom tight glycemic control was previously achieved, more rigorous targets may be appropriate. • In terminally ill patients or in those with severe comorbidities, less stringent targets may be appropriate. • For achieving and maintaining glucose control, the preferred method is scheduled subcutaneous administration of insulin, with basal, nutritional, and correction components. • Prolonged treatment with sliding-scale insulin as the only therapeutic agent is discouraged. • For most hospitalized patients who require treatment of hyperglycemia, noninsulin antihyperglycemic agents are not appropriate. • Day-to-day decisions concerning treatment of hyperglycemia must be based on clinical judgment and ongoing evaluation of clinical status. Safety Recommendations Specific recommendations geared toward improving safety in management of inpatient hyperglycemia are as follows: • Major safety issues include overtreatment and undertreatment of hyperglycemia. • Hospital staff must be educated to engage the support of those involved in the care of inpatients with hyperglycemia. • In patients with anemia, polycythemia, hypoperfusion, or use of some medications, caution is needed when interpreting results of point-of-care glucose meters. • To promote a rational systems approach to inpatient glycemic management, buy-in and financial support from hospital administration are required. The guidelines also propose a selected number of research questions and topics to guide the management of inpatient hyperglycemia in different hospital settings. "Appropriate inpatient management of hyperglycemia is cost-effective," the guidelines authors conclude. "Preparation for transition to the outpatient setting should begin at the time of hospital admission. Discharge planning, patient education, and clear communication with outpatient providers are critical for ensuring a safe and successful transition to outpatient glycemic management." Some of the guidelines authors have disclosed various financial relationships with sanofi-aventis U.S. LLC; Amylin Pharmaceuticals, Inc;Takeda Pharmaceuticals North America, Inc; AstraZeneca; GlaxoSmithKline; Johnson & Johnson Services, Inc; Eli Lilly & Co; Medtronic, Inc; Novo Nordisk A/S; Halozyme Therapeutics; MannKind Corporation; Abbott Laboratories; F. Hoffman La Roche Ltd. (Roche); and/or Merck & Co. Endocr Pract. 2009;15:1-15. Diabetes Care. Published online May 8, 2009. Clinical Context
Hyperglycemia is common in the inpatient setting, and reducing high blood glucose levels is associated with better patient outcomes. However, a study by Finfer and colleagues, which was published in the March 26, 2009, issue of The New England Journal of Medicine, found that more intense glucose treatment could actually result in higher mortality rates in critically ill patients. Compared with a cohort of patients randomly assigned to a target blood glucose level of 180 mg/dL or less, participants randomly selected to target glucose levels of 81 to 108 mg/dL experienced a 14% increase in the risk for death. Rates of hypoglycemia were much higher in the intensive vs standard-control group, and intensive therapy did not significantly alter the duration of hospital stay, the need for renal replacement therapy, or the number of days of mechanical ventilation. The current review examines the sum of evidence for the management of hyperglycemia in inpatient settings and makes treatment recommendations. Study Highlights
Clinical Implications
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Sunday, May 3, 2009
Vasopressor Support in Septic Shock
AbstractWhen fluid administration fails to restore an adequate arterial pressure and organ perfusion in patients with septic shock, therapy with vasopressor agents should be initiated. The ultimate goals of such therapy in patients with shock are to restore effective tissue perfusion and to normalize cellular metabolism. Although arterial pressure is the end point of vasopressor therapy, and the restoration of adequate pressure is the criterion of effectiveness, BP does not always equate to blood flow; so, the precise BP goal to target is not necessarily the same in all patients. There has been longstanding debate about whether one catecholamine vasopressor agent is superior to another, but different agents have different effects on pressure and flow. The argument about which catecholamine is best in a given situation is best transformed into a discussion about which agent is best suited to implement the therapeutic strategy chosen. Despite the complex pathophysiology of sepsis, an underlying approach to its hemodynamic support can be formulated that takes both pressure and perfusion into account when choosing therapeutic interventions. The efficacy of hemodynamic therapy in sepsis should be assessed by monitoring a combination of clinical and hemodynamic parameters. How to optimize regional blood and microcirculatory blood flow remains uncertain. Thus, specific end points for therapy are debatable and are likely to evolve. Nonetheless, the idea that clinicians should define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis remains a fundamental principle. Septic shock results when infectious agents or infection-induced mediators in the bloodstream produce hemodynamic decompensation. Its pathogenesis involves a complex interaction among pathologic vasodilation, relative and absolute hypovolemia, myocardial dysfunction, and altered blood flow distribution due to the inflammatory response to infection; even after the restoration of intravascular volume, microcirculatory abnormalities may persist and lead to the maldistribution of cardiac output.12 About half of the patients who succumb to septic shock die of multiple organ system failure, and most other nonsurvivors have progressive hypotension with low systemic vascular resistance that is refractory to therapy with vasopressor agents.1 Although myocardial dysfunction is not uncommon, death from myocardial failure is rare.3 The initial priority in managing septic shock is to maintain a reasonable mean arterial pressure and cardiac output to keep the patient alive while the source of infection is identified and addressed. Another therapeutic goal is to interrupt the pathogenic sequence leading to septic shock. While these latter goals are being pursued, adequate organ system perfusion and function must be maintained, guided by cardiovascular monitoring. This review will focus on vasopressor support for patients with septic shock. Hemodynamic therapy for sepsis can be conceptualized in three broad categories: fluid resuscitation, vasopressor therapy, and inotropic therapy. Although many vasoactive agents have both vasopressor and inotropic actions, the distinction is made on the basis of the intended goals of therapy; vasopressor actions raise BP, while inotropic actions raise cardiac output. This is not to minimize the importance of assessing the effects of vasoactive agents on perfusion, as should be made clear from the discussion below. General ApproachSeptic shock requires early, vigorous resuscitation. An integrated approach directed at rapidly restoring systemic oxygen delivery and improving tissue oxygenation has been demonstrated4 to improve survival significantly in patients with septic shock. While the specific approach that is utilized may vary, there are critical elements that should be incorporated into any resuscitative effort. Therapy should be guided by parameters that reflect the adequacy of tissue and organ perfusion. Fluid infusion should be vigorous and titrated to clinical end points of volume repletion. Systemic oxygen delivery should be supported by ensuring arterial oxygen saturation, maintaining adequate levels of hemoglobin, and using vasoactive agents that are directed to physiologic and clinical end points. In shock states, the estimation of BP using a cuff may be inaccurate, and the use of an arterial cannula provides a more appropriate and reproducible measurement of arterial pressure.56 These catheters also allow beat-to-beat analysis so that decisions regarding therapy can be based on immediate and reproducible BP information, facilitating the administration of large quantities of fluids and potent vasopressor and inotropic agents to critically ill patients.1 Although patients with shock and mild hypovolemia may be treated successfully with rapid fluid replacement alone, hemodynamic monitoring may be useful in providing a diagnostic hemodynamic assessment in patients with moderate or severe shock. In addition, because hemodynamics can change rapidly in patients with sepsis, and because noninvasive evaluation is frequently incorrect in estimating filling pressures and cardiac output, hemodynamic monitoring is often useful for monitoring the response to therapy. Goals and Monitoring of Vasopressor TherapyWhen fluid administration fails to restore an adequate arterial pressure and organ perfusion, therapy with vasopressor agents should be initiated.6 The ultimate goals of hemodynamic therapy in patients with shock are to restore effective tissue perfusion and to normalize cellular metabolism. In patients with septic shock, tissue hypoperfusion results not only from decreased perfusion pressure attributable to hypotension but also from abnormal shunting of a normal or increased cardiac output.1 Cellular alterations may also occur. Hemodynamic support of sepsis thus requires the consideration of both global and regional perfusion. Arterial pressure is the end point of vasopressor therapy, and the restoration of adequate pressure is the criterion of effectiveness. BP, however, does not always equate to blood flow, and the precise level of mean arterial BP to aim for is not necessarily the same in all patients. Animal studies78 have suggested that below a mean arterial BP of 60 mm Hg, autoregulation in the coronary, renal, and CNS vascular beds is compromised, and flow may become linearly dependent on BP. Loss of autoregulation can occur at different levels in different organs, however, and the degree to which septic patients retain intact autoregulation is uncertain. Some patients (especially those with preexisting hypertension) may require higher BPs to maintain adequate perfusion. The precise BP goal to target in patients with septic shock remains uncertain. Most experts agree, largely on the basis of the animal studies cited above and on physiologic reasoning, that in septic patients with evidence of hypoperfusion, the mean arterial pressure should be maintained at > 60 mm Hg6 or 65 mm Hg.9 There are no data from randomized clinical trials demonstrating that failure to maintain BP at this level worsens outcome, but it seems unlikely that such a clinical trial will be conducted soon. It should be recognized that individual patients may have BPs that are somewhat lower than these thresholds without hypoperfusion; it is the scenario of hypotension with shock that merits vasopressor support. Some investigators, however, have argued that higher BP targets are warranted. The renal circulation may be especially sensitive to perfusion pressure, and vasopressor therapy to augment renal perfusion pressure has been shown to increase urine output and/or creatinine clearance in a number of open-label clinical series1011121314151617; the targeted mean BP varied, but was as high as 75 mm Hg. Improvements in renal function with increased perfusion pressure, however, have not been demonstrated in prospective, randomized studies. Randomized trials1819 comparing norepinephrine titrated to either 65 or 85 mm Hg in patients with septic shock have found no significant differences in metabolic variables or renal function. It is important to supplement end points such as BP with an assessment of regional and global perfusion. Bedside clinical assessment provides a good indication of global perfusion. Indications of decreased perfusion include oliguria, clouded sensorium, delayed capillary refill, and cool skin. Some caution is necessary in interpreting these signs in septic patients, however, since organ dysfunction can occur in the absence of global hypoperfusion. Clinical assessments can be supplemented by other measures, such as serum lactate levels and mixed venous oxygen saturation. Elevated lactate levels in patients with sepsis may result from global hypoperfusion or from cellular metabolic alterations, which may or may not represent tissue hypoxia,20 but its prognostic value, particularly of the trend in lactate concentrations, has been well established in septic shock patients.212223 Mixed venous oxyhemoglobin saturation reflects the balance between oxygen delivery and consumption, and can be elevated in septic patients due to the maldistribution of blood flow, so values must be interpreted in the context of the wider hemodynamic picture. Low values, however, suggest increased oxygen extraction and therefore potentially incomplete resuscitation. A 2001 study4 showed that the monitoring of central venous oxygen saturation can be a valuable guide to early resuscitation. The correlation between central venous oxygen saturation and mixed venous oxyhemoglobin saturation is reasonable,24 but may not always be reliable.25 The adequacy of regional perfusion is usually assessed clinically.1 Methods for measuring regional perfusion more directly have been under investigation, with a focus on the splanchnic circulation, which is especially susceptible to ischemia and may drive organ failure.26 Measurements of oxygen saturation in the hepatic vein have revealed oxygen desaturation in a subset of septic patients, suggesting that the hepatosplanchnic oxygen supply may be inadequate in some patients, even when more global parameters appear to be adequate.27 Direct visualization of the sublingual circulation28 or sublingual capnometry29 may be useful to monitor the restoration of microvascular perfusion in patients with sepsis. Adrenergic AgentsThere has been longstanding debate about whether one catecholamine vasopressor agent is superior to another. While these discussions are enlightening in that they tend to highlight differences in pharmacology among the agents, sometimes the arguments tend to focus on the agents themselves when actually it is the therapeutic strategy that differs. Different catecholamine agents have different effects on α-adrenergic and β-adrenergic receptors, as shown in Figure 1 . The hemodynamic actions of these receptors are well known, with α-adrenergic receptors promoting vasoconstriction, β1-adrenergic receptors increasing heart rate and myocardial contractility, and β2-adrenergic receptors causing peripheral vasodilation. The result of these differential effects on adrenergic receptors is that the different agents have different effects on pressure and flow, as shown in Figure 2 . Conceived in these terms, the argument about which catecholamine is best to use in a given situation is transformed into a discussion about which agent is best suited to implement the therapeutic strategy chosen. This may or may not make the choice easier, but it does emphasize the need to define the goals and end points of therapy, and to identify how those end points will be monitored. Individual Vasopressor AgentsDopamineDopamine, the natural precursor of norepinephrine and epinephrine, has distinct dose-dependent pharmacologic effects. At doses of <>30 At doses of 5 to 10 μg/kg/min, β1-adrenergic effects predominate, increasing cardiac contractility and heart rate. At doses of > 10 μg/kg/min, α1-adrenergic effects predominate, leading to arterial vasoconstriction and an increase in BP. There is a great deal of overlap in these effects, particularly in critically ill patients. Dopamine increases mean arterial pressure and cardiac output, primarily due to an increase in stroke volume, and to a lesser extent to an increase in heart rate.3132333435363738394041 In open-label trials,3132333435363738394041 dopamine (median dose, 15 μg/kg/min) increased mean arterial pressure by 24% in septic patients who remained hypotensive after receiving optimal fluid resuscitation. Dopamine has been shown to increase oxygen delivery, but its effects on calculated or measured oxygen consumption have been mixed, suggesting that tissue oxygenation may not always be improved, perhaps due to a failure to improve microcirculatory flow.32334243 The effect of dopamine on splanchnic perfusion has also been mixed. Increases in splanchnic blood flow have been reported,313234444546 but have not always been associated with increases in splanchnic oxygen consumption, beneficial effects on gastric intramucosal pH, or improvement in hepatosplanchnic energy balance. Low doses of dopamine increase renal blood flow and glomerular filtration rate in laboratory animals and healthy volunteers, supporting the idea that dopamine can reduce the risk of renal failure in critically ill patients by increasing renal blood flow. This notion has now been put to rest by a definitive clinical trial47 that randomized 328 critically ill patients with early renal dysfunction to low-dose (“renal”) dopamine (2 μg/kg/min) or placebo. No difference was found in either the primary outcome (peak serum creatinine level), other renal outcomes (increase in creatinine level, need for renal replacement, and urine output), or secondary outcomes (survival to either ICU or hospital discharge, ICU or hospital stay, or arrhythmias).47 Dopamine use was associated with increased mortality in patients with shock in an observational cohort study48 of 198 European ICUs and remained a significant predictor after multivariate analysis. Given the limitations of observational studies, this finding will need to be confirmed by prospective studies. A large prospective randomized clinical trial comparing dopamine to norepinephrine in patients with septic shock is ongoing. Dopamine effectively increases mean arterial pressure in patients who remain hypotensive after optimal volume expansion, largely as a result of increasing cardiac index, so it may be chosen in patients with compromised cardiac function or cardiac reserve. Its major side effects are tachycardia and arrhythmogenesis, both of which are more prominent than with other vasopressor agents. There is also concern about the potential for decreased prolactin release, lymphocyte apoptosis, and consequent immunosuppression.4950 NorepinephrineNorepinephrine is a potent α-adrenergic agonist with less pronounced β-adrenergic agonist effects. Norepinephrine increases mean arterial pressure by vasoconstriction, with a small increase (10 to 15%) in cardiac output and stroke volume.101112165152 Filling pressures are either unchanged1011121653 or modestly increased (1 to 3 mm Hg).1517323436 Norepinephrine is more potent than dopamine and may be more effective at reversing hypotension in septic shock patients. In open-label trials,111216173452535455 norepinephrine administration at doses ranging from 0.01 to 3.3 μg/kg/min has been shown to increase mean arterial pressure in patients who remained hypotensive after fluid resuscitation and dopamine. The large doses of the drug required in some patients may be due to α-receptor down-regulation in sepsis.56 In the only randomized trial36 comparing vasopressor agents, 32 volume-resuscitated septic patients were given either dopamine or norepinephrine to achieve and maintain normal hemodynamic and oxygen transport parameters for at least 6 h. Dopamine administration was successful in only 31% of patients, whereas norepinephrine administration (mean [± SD] dose, 1.5 ± 1.2 μg/kg/min) was successful in 93% (p <>36 The vasoconstrictive effects of norepinephrine can have detrimental effects on renal hemodynamics in patients with hypotension and hypovolemia, with a potential for renal ischemia.575859 The situation may differ in adequately resuscitated patients with hyperdynamic septic shock.15 Norepinephrine has a greater effect on efferent than afferent renal arteriolar resistance and increases the filtration fraction. Several studies101315173236375360 have shown increases in urine output and renal function in patients with septic shock treated with norepinephrine alone or with norepinephrine added to dobutamine. The results of studies of the effects of norepinephrine on splanchnic blood flow in patients with septic shock have been mixed. The effects of norepinephrine on both splanchnic blood flow and oxygen consumption have been unpredictable both among patients and within groups.3134 Comparisons between norepinephrine and other vasoactive agents have also been variable. One pilot study32 found that gastric mucosal intracellular pH (pHi) was significantly increased during 3 h of treatment with norepinephrine but significantly decreased during treatment with dopamine. A more recent study61 compared the effects of norepinephrine, epinephrine, and dopamine in 20 patients with septic shock. In the 10 patients with moderate shock, no differences in splanchnic blood flow or gastric-arterial Pco2 difference were observed. In the 10 patients with severe shock, the effects of norepinephrine and dopamine were similar. Epinephrine increased cardiac index more than norepinephrine, but splanchnic blood flow was lower despite this higher cardiac index.61 Norepinephrine can increase BP in patients with septic shock without causing a deterioration in cardiac index and organ function. Although the effect of the drug on oxygen transport variables and splanchnic parameters has varied in different studies, other clinical parameters of peripheral perfusion, such as urine flow and lactate concentration, are significantly improved in most studies. In a multivariate analysis62 including 97 septic shock patients, mortality was favorably influenced by the use of norepinephrine; the use of high-dose dopamine, epinephrine, or dobutamine had no significant effect. Controlled data comparing norepinephrine to other catecholaminergic agents are sparse, with only one randomized study.36 Whether using norepinephrine in septic shock patients affects mortality compared to dopamine or epinephrine will hopefully be clarified by the ongoing prospective clinical trials. PhenylephrinePhenylephrine, a selective α1-adrenergic agonist, increases BP by vasoconstriction. Its rapid onset, short duration, and primary vascular effects make it an attractive agent in the management of hypotension associated with sepsis, but there are concerns about its potential to reduce cardiac output in these patients. Few studies have evaluated the use of phenylephrine in patients with hyperdynamic sepsis. As such, guidelines on its clinical use are limited. Phenylephrine has been shown to increase BP when administered to normotensive hyperdynamic septic patients at doses of 0.5 to 8 μg/kg/min, with little change in cardiac output or stroke volume.6364 Only one small study65 of 13 patients has evaluated the effects of phenylephrine on treating patients with hypotension associated with sepsis. Phenylephrine added to either low-dose dopamine or dobutamine increased mean arterial pressure and cardiac index without a change in heart rate. A significant increase in urine output without a change in serum creatinine level was observed during phenylephrine therapy.65 The limited information available on phenylephrine therapy suggests that this drug can increase BP modestly in fluid-resuscitated septic shock patients without impairing cardiac or renal function. Phenylephrine is a second-line agent but may be a good therapeutic option when tachyarrhythmias limit therapy with other vasopressors.6 EpinephrineEpinephrine is a potent α-adrenergic and β-adrenergic agent that increases mean arterial pressure by increasing both cardiac index and peripheral vascular tone.14666768 Epinephrine increases oxygen delivery, but oxygen consumption may be increased as well.6667686970 Lactate levels can be increased after the use of epinephrine in sepsis patients, although whether this results from excess vasoconstriction and compromised perfusion or increased lactate production remains uncertain.546670 The chief concern with the use of epinephrine in patients with sepsis is the potential to decrease regional blood flow, particularly in the splanchnic circulation.54717273 In a study61 of patients with severe septic shock, epinephrine administration increased global oxygen delivery and consumption, but caused lower absolute and fractional splanchnic blood flow and lower indocyanine green clearance, thus validating the adverse effects of therapy with epinephrine alone on the splanchnic circulation. Another group has reported74 improved gastric mucosal perfusion with epinephrine compared to a norepinephrine/dobutamine combination, but subsequently the same group reported superiority of a therapy with a norepinephrine/dopexamine combination over therapy with epinephrine.75 A fairly large (n = 330) randomized clinical trial76 comparing therapy with epinephrine to that with norepinephrine with or without dobutamine has been completed, and preliminary results were reported at the European Society of Intensive Care Medicine meeting; no significant difference was found in the rates of 28-day mortality, ICU mortality, or hospital mortality. Epinephrine administration can increase BP in patients who are unresponsive to traditional agents. It increases heart rate, and has the potential to induce tachyarrhythmias, ischemia, and hypoglycemia. Because of its effects on gastric blood flow and its propensity to increase lactate concentrations, epinephrine has been considered a second-line agent, the use of which should be considered in patients failing to respond to traditional therapies.6 VasopressinVasopressin is a peptide hormone that is synthesized in the hypothalamus and is then transported to and stored in the pituitary gland. Released in response to decreases in blood volume, decreased intravascular volume, and increased plasma osmolality, vasopressin constricts vascular smooth muscle directly via V1 receptors and also increases responsiveness of the vasculature to catecholamines.7778 Vasopressin may also increase BP by the inhibition of vascular smooth muscle nitric oxide production79 and K+-ATP channels.7880 Normal levels of vasopressin have little effect on BP in physiologic conditions,77 but vasopressin helps to maintain BP during hypovolemia,81 and seems to restore impaired hemodynamic mechanisms and also to inhibit pathologic vascular responses in patients with shock.78 Increased levels of vasopressin have been documented in patients with hemorrhagic shock,82 but a growing body of evidence indicates that this response is abnormal or blunted in those with septic shock. One study83 found markedly increased levels of circulating vasopressin in 12 patients with cardiogenic shock, but much lower levels in 19 patients with septic shock, which were hypothesized to be inappropriately low. One potential mechanism for this relative vasopressin deficiency would be the depletion of pituitary stores, possibly in conjunction with impaired synthesis. The depletion of vasopressin stores in the neurohypophysis evaluated by MRI has in fact been described in a small group of septic shock patients.84 A 2003 prospective cohort study85 of patients with septic shock found that vasopressin levels were almost always elevated in the initial hours of septic shock and decreased afterward; relative vasopressin deficiency, as defined by the investigators, developed in one third of patients. Given this theoretical rationale, observational studies868788 have demonstrated that the addition of a low dose of vasopressin (0.01 to 0.04 U/min) to a course of catecholamines can raise BP in patients with pressor-refractory septic shock. Two small randomized studies8990 comparing vasopressin to norepinephrine have demonstrated that the initiation of vasopressin decreases catecholamine requirements, and one of these89 showed improved renal function. Similar data are available for terlipressin, a synthetic vasopressin analog.91 There is concern, however, that vasopressin infusion in septic patients may either decrease splanchnic perfusion or redistribute blood flow away from the splanchnic mucosa.9293 Vasopressin should be thought of as replacement therapy for relative deficiency rather than as a vasopressor agent to be titrated to effect. A large randomized clinical trial (Vasopressin vs Norepinephrine in Septic Shock Study)94 has now been completed comparing vasopressin to norepinephrine therapy in 776 patients with pressor-dependent septic shock, and the preliminary results were presented at the European Society of Intensive Care Medicine meeting. Patients were randomized to receive vasopressin (0.03 U/min) or 15 μg/min norepinephrine in addition to their original vasopressor infusion; the primary end point was 28-day mortality rate; a prespecified subgroup analysis was performed in patients with less severe septic shock (norepinephrine, 5 to 14 μg/min) and more severe septic shock (norepinephrine, > 15 μg/min). For the group as a whole, there was no difference in mortality, but vasopressin appeared to be better in the less severe subgroup.94 Vasopressin (0.03 U/min) added to norepinephrine appears to be as safe and effective as norepinephrine in fluid-resuscitated patients with septic shock. Vasopressin may be more effective in patients receiving lower doses of norepinephrine than when started as rescue therapy, although the answer to the question of what therapy to administer in patients with high vasopressor requirements despite vasopressin infusion remains uncertain. Complications of Vasopressor TherapyAll of the catecholamine vasopressor agents can cause significant tachycardia, especially in patients who have received inadequate volume resuscitation. Tachyarrhythmias can occur as well. In patients with significant coronary atherosclerosis, vasopressor-induced coronary artery constriction may precipitate myocardial ischemia and infarction; this is of particular concern in patients treated with vasopressin. In the presence of myocardial dysfunction, excessive vasoconstriction can decrease stroke volume, cardiac output, and oxygen delivery. Should this occur, the dose of the vasopressor should be lowered or the addition of an inotropic agent such as dobutamine should be considered.52 Excessive doses of vasopressors can also cause limb ischemia and necrosis. The administration of vasopressors may potentially impair blood flow to the splanchnic system, and this can be manifested by stress ulceration, ileus, malabsorption, and even bowel infarction.5470 Gut mucosal integrity occupies a key position in the pathogenesis of multiple organ failure, and countercurrent flow in splanchnic microcirculation gives the gut a higher critical threshold for oxygen delivery than other organs. Thus, it makes sense to avoid episodes of intramucosal acidosis, which might be detected either by a fall in gastric mucosal pHi or an increase in gastric mucosal Pco2, if possible. Whether to monitor these parameters routinely is less certain, as pHi or gastric Pco2-directed care has not been shown to reduce mortality in patients with septic shock in prospective randomized controlled trials. Consensus RecommendationsConsensus recommendations regarding vasopressor support in patients with septic shock have been put forth by the American College of Critical Care Medicine (ACCCM)695 and the Surviving Sepsis campaign9; these recommendations differ more in wording than in substance, and are compiled in Table 1 . The Surviving Sepsis campaign will likely amend the vasopressin section to take the Vasopressin vs Norepinephrine in Septic Shock Study trial results under consideration. ConclusionThe ultimate goals of hemodynamic therapy in shock are to restore effective tissue perfusion and to normalize cellular metabolism. In patients with sepsis, both global and regional perfusion must be considered. In addition, mediators of sepsis can perturb cellular metabolism, leading to the inadequate utilization of oxygen and other nutrients despite adequate perfusion; one would not expect organ dysfunction mediated by such abnormalities to be corrected by hemodynamic therapy. Despite the complex pathophysiology of sepsis, an underlying approach to its hemodynamic support can be formulated that is particularly pertinent with respect to vasoactive agents. Both arterial pressure and tissue perfusion must be taken into account when choosing therapeutic interventions, and the efficacy of hemodynamic therapy should be assessed by monitoring a combination of clinical and hemodynamic parameters. It is relatively easy to raise BP, but somewhat harder to raise cardiac output in septic patients. How to optimize regional blood and microcirculatory blood flow remains uncertain. Thus, specific end points for therapy are debatable and are likely to evolve. Nonetheless, the idea that clinicians should define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis remains a fundamental principle. The ACCCM practice parameters695 were intended to emphasize the importance of such an approach so as to provide a foundation for the rational choice of vasoactive agents in the context of evolving monitoring techniques and therapeutic approaches. Footnotes
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