More information from the New Scientist Website
Many local and national guidelines for the management of anaphylaxis exist, but did you know there was a World Allergy Organization, and it has a very detailed guideline on this important life threatening condition?
Some interesting snippets from the guideline are included here
Anaphylaxis and cardiac disease
- Anaphylaxis can precipitate acute myocardial infarction in susceptible individuals: in patients with ischemic heart disease, the number and density of cardiac mast cells is increased, including in the atherosclerotic plaques. Mediators released during anaphylaxis contribute to vasoconstriction and coronary artery spasm.
- Epinephrine is not contraindicated in the treatment of anaphylaxis in patients with known or suspected cardiovascular disease, or in middle-aged or elderly patients without any history of coronary artery disease who are at increased risk of ACS only because of their age. Through its beta-1 adrenergic effects, epinephrine actually increases coronary artery blood flow because of an increase in myocardial contractility and in the duration of diastole relative to systole.
- Glucagon has noncatecholamine-dependent inotropic and chronotropic cardiac effects, and is sometimes needed in patients taking a beta-adrenergic blocker who have hypotension and bradycardia and who do not respond optimally to epinephrine.
- Anticholinergic agents are sometimes needed in beta-blocked patients, for example, atropine in those with persistent bradycardia or ipratropium in those with epinephrine-resistant bronchospasm.
How quickly can untreated anaphylaxis kill you?
Studies show median times to cardiorespiratory arrest after exposure to the offending stimulus were 5 minutes after administration of contrast media or drugs, 15 minutes after an insect sting, and 30 minutes after food ingestion.
What about confirming the diagnosis with serum tryptase measurements?
- Blood samples for measurement of tryptase levels are optimally obtained 15 minutes to 3 hours after symptom onset.
- Blood samples for measurement of histamine levels are optimally obtained 15–60 minutes after symptom onset. These tests are not specific for anaphylaxis.
- Increased serum tryptase levels are often found in patients with anaphylaxis from insect stings or injected medications, and in those who are hypotensive
- However, levels are often within normal limits in patients with anaphylaxis triggered by food and in those who are normotensive
- Serial measurement of tryptase levels during an anaphylactic episode, and measurement of a baseline level after recovery are reported to be more useful than measurement at only one point in time.
- Normal levels of either tryptase or histamine do not rule out the clinical diagnosis of anaphylaxis
How does epinephrine help?
- Epinephrine is life-saving because of its alpha-1 adrenergic vasoconstrictor effects in most body organ systems (skeletal muscle is an important exception) and its ability to prevent and relieve airway obstruction caused by mucosal edema, and to prevent and relieve hypotension and shock.
- Other relevant properties in anaphylaxis include its beta-1 adrenergic agonist inotropic and chronotropic properties leading to an increase in the force and rate of cardiac contractions, and its beta-2 adrenergic agonist properties such as decreased mediator release, bronchodilation and relief of urticaria
- Epinephrine in a dose of 0.01 mg/kg of a 1:1,000 (1 mg/mL) solution injected promptly by the intramuscular route is effective and safe in the initial treatment of anaphylaxis. In other anaphylaxis scenarios, this low first-aid dose is unlikely to be effective. For example, if shock is imminent or has already developed, epinephrine needs to be given by slow intravenous infusion, ideally with the dose titrated according to noninvasive continuous cardiac monitoring.
What is the empty ventricle syndrome?
- Patients with anaphylaxis should not suddenly sit, stand, or be placed in the upright position.
- Instead, they should be placed on the back with their lower extremities elevated or, if they are experiencing respiratory distress or vomiting, they should be placed in a position of comfort with their lower extremities elevated.
- This accomplishes 2 therapeutic goals: 1) preservation of fluid in the circulation (the central vascular compartment), an important step in managing distributive shock; and 2) prevention of the empty vena cava/empty ventricle syndrome, which can occur within seconds when patients with anaphylaxis suddenly assume or are placed in an upright position.
- Patients with this syndrome are at high risk for sudden death. They are unlikely to respond to epinephrine regardless of route of administration, because it does not reach the heart and therefore cannot be circulated throughout the body
Should we give antihistamines, beta 2 agonists, and steroids?
The evidence base for use of these second line medications in the initial management of anaphylaxis, is extrapolated mainly from their use in treatment of other diseases such as urticaria (antihistamines) or acute asthma (beta-2 adrenergic agonists and glucocorticoids). Concerns have been raised that administering one or more second-line medications potentially delays prompt injection of epinephrine, the first-line treatment
Is ‘biphasic anaphylaxis’ a real phenomenon we should be concerned about?
- Biphasic anaphylaxis occurs when symptoms recur within 1–72 hours (usually within 8–10 hours) after the initial symptoms have resolved, despite no further exposure to the trigger.
- It occurs in up to 23% of adults and up to 11% of children.
- After apparent resolution of symptoms, duration of monitoring in a medically supervised setting should be individualized. For example, patients with moderate respiratory or cardiovascular compromise should be monitored for at least 4 hours, and if indicated, for 8–10 hours or longer.
- Protracted uniphasic anaphylaxis is uncommon, but can last for days.
World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis
World Allergy Organization Journal 2011;4(2):13-37 Full Text
The illustrated World Allergy Organization (WAO) Anaphylaxis Guidelines were created in response to absence of global guidelines for anaphylaxis. Uniquely, before they were developed, lack of worldwide availability of essentials for the diagnosis and treatment of anaphylaxis was documented. They incorporate contributions from more than 100 allergy/immunology specialists on 6 continents. Recommendations are based on the best evidence available, supported by references published to the end of December 2010. The Guidelines review patient risk factors for severe or fatal anaphylaxis, co-factors that amplify anaphylaxis, and anaphylaxis in vulnerable patients, including pregnant women, infants, the elderly, and those with cardiovascular disease. They focus on the supreme importance of making a prompt clinical diagnosis and on the basic initial treatment that is urgently needed and should be possible even in a low resource environment. This involves having a written emergency protocol and rehearsing it regularly; then, as soon as anaphylaxis is diagnosed, promptly and simultaneously calling for help, injecting epinephrine (adrenaline) intramuscularly, and placing the patient on the back or in a position of comfort with the lower extremities elevated. When indicated, additional critically important steps include administering supplemental oxygen and maintaining the airway, establishing intravenous access and giving fluid resuscitation, and initiating cardiopulmonary resuscitation with continuous chest compressions. Vital signs and cardiorespiratory status should be monitored frequently and regularly (preferably, continuously). The Guidelines briefly review management of anaphylaxis refractory to basic initial treatment. They also emphasize preparation of the patient for self-treatment of anaphylaxis recurrences in the community, confirmation of anaphylaxis triggers, and prevention of recurrences through trigger avoidance and immunomodulation. Novel strategies for dissemination and implementation are summarized. A global agenda for anaphylaxis research is proposed.
This month has also seen the publication guidelines from the UK’s National Institute for Health & Clinical Excellence, entitled ‘Anaphylaxis: assessment to confirm an anaphylactic episode and the decision to refer after emergency treatment for a suspected anaphylactic episode’
Their guideline summary is as follows:
After a suspected anaphylactic reaction in adults or young people aged 16 years or older, take timed blood samples for mast cell tryptase testing as follows:
- a sample as soon as possible after emergency treatment has started
- a second sample ideally within 1–2 hours (but no later than 4 hours) from the onset of symptoms.
After a suspected anaphylactic reaction in children younger than 16 years, consider taking blood samples for mast cell tryptase testing as follows if the cause is thought to be venom-related, drug-related or idiopathic:
- a sample as soon as possible after emergency treatment has started
- a second sample ideally within 1–2 hours (but no later than 4 hours) from the onset of symptoms.
Patients who have had emergency treatment for suspected anaphylaxis should be observed for 6–12 hours from the onset of symptoms, depending on their response to emergency treatment
After emergency treatment for suspected anaphylaxis, offer people a referral to a specialist allergy service (age-appropriate where possible) consisting of healthcare professionals with the skills and competencies necessary to accurately investigate, diagnose, monitor and provide ongoing management of, and patient education about, suspected anaphylaxis.
After emergency treatment for suspected anaphylaxis, offer people (or, as appropriate, their parent and/or carer) an appropriate adrenaline injector as an interim measure before the specialist allergy service appointment.
Before discharge a healthcare professional with the appropriate skills and competencies should offer people (or, as appropriate, their parent and/or carer) the following:
- information about anaphylaxis, including the signs and symptoms of an anaphylactic reaction
- information about the risk of a biphasic reaction
- information on what to do if an anaphylactic reaction occurs (use the adrenaline injector and call emergency services)
Anaphylaxis: assessment to confirm an anaphylactic episode and the decision to refer after emergency treatment for a suspected anaphylactic episode
CG134 Anaphylaxis: NICE guideline
A large multinational study challenges the practice of routine thromboprophylaxis for hospitalised acutely ill medical patients. Enoxaparin plus graduated compression stockings did not reduce 30 day mortality compared with stockings alone. There was no significant difference in the rates of major bleeding.
Background Although thromboprophylaxis reduces the incidence of venous thromboembolism in acutely ill medical patients, an associated reduction in the rate of death from any cause has not been shown.
Methods We conducted a double-blind, placebo-controlled, randomized trial to assess the effect of subcutaneous enoxaparin (40 mg daily) as compared with placebo — both administered for 10±4 days in patients who were wearing elastic stockings with graduated compression — on the rate of death from any cause among hospitalized, acutely ill medical patients at participating sites in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia. Inclusion criteria were an age of at least 40 years and hospitalization for acute decompensated heart failure, severe systemic infection with at least one risk factor for venous thromboembolism, or active cancer. The primary efficacy outcome was the rate of death from any cause at 30 days after randomization. The primary safety outcome was the rate of major bleeding during and up to 48 hours after the treatment period.
Results A total of 8307 patients were randomly assigned to receive enoxaparin plus elastic stockings with graduated compression (4171 patients) or placebo plus elastic stockings with graduated compression (4136 patients) and were included in the intention-to-treat population. The rate of death from any cause at day 30 was 4.9% in the enoxaparin group as compared with 4.8% in the placebo group (risk ratio, 1.0; 95% confidence interval [CI], 0.8 to 1.2; P=0.83). The rate of major bleeding was 0.4% in the enoxaparin group and 0.3% in the placebo group (risk ratio, 1.4; 95% CI, 0.7 to 3.1; P=0.35).
Conclusions The use of enoxaparin plus elastic stockings with graduated compression, as compared with elastic stockings with graduated compression alone, was not associated with a reduction in the rate of death from any cause among hospitalized, acutely ill medical patients. (Funded by Sanofi; LIFENOX ClinicalTrials.gov number, NCT00622648.)
Low-Molecular-Weight Heparin and Mortality in Acutely Ill Medical Patients
N Engl J Med 2011; 365:2463-2472
Comments Off on Treating sepsis – have we got it the wrong way round?
In our understanding of the pathophysiology of sepsis, we often attribute organ damage and death to the excessive host response to infection, including the popular phrase ‘cytokine storm’. This has been nicely described as ‘friendly fire’ by Prof Derek Angus, who points out that this central tenet of sepsis understanding may in some cases be flawed1; it has led to research on drugs that suppress parts of these inflammatory pathways, although none have yet proven effective. An elegant study on patients dying from sepsis showed clear evidence of immunosuppression compared with controls2.
Editorialist Peter Ward3 proposes an area for future research: whether such derangements can be reversed by treatment with agents such as interleukins 7 or 15, which might combat the T-cell depletion state in sepsis.
The authors point out that all the patients included in the study died on ICU, some after a considerable duration of illness, and they emphasise that early deaths from sepsis in previously healthy patients with infections of highly virulent organisms are associated with an extremely exuberant immunoinflammatory response.
1.The Search for Effective Therapy for Sepsis: Back to the Drawing Board?
JAMA December 21, 2011, Vol 306, No. 23, pp 2614-5
2.Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure
JAMA December 21, 2011, Vol 306, No. 23, pp 2594-2605
Context Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting.
Objectives To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression.
Design, Setting, and Participants Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009-2011). Control spleens (n = 29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n = 20) were obtained from transplant donors or from lung cancer resections.
Main Outcome Measures Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells.
Results The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28–stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, −5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, −269 to 1534) vs 58 (95% CI, −39 to 156) pg/mL; (P < .001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells.
Conclusions Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.
3.Immunosuppression in Sepsis
JAMA December 21, 2011, Vol 306, No. 23, pp 2618-9
Comments Off on Circulatory support in cardiogenic shock
An editorial1 reviewing options for circulatory support in patients with cardiogenic shock argues that traditional inotrope therapy may be replaced by newer alternatives that have a less detrimental effect on myocardial oxygen demand.
Newer inotropic agents include levosimendan, istaroxime, and omecamtiv mecarbil. Mechanical therapies include intra-aortic balloon pumps (IABP), ventricular assist devices (VAD), and extracorporeal membrane oxygenation (ECMO).
Levosimendan is an inodilator, with the following characteristics:
- stabilises the myocardial calcium-troponin C complex
- activates adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle and cardiac mitochondria,
- acts as a traditional phosphodiesterase inhibitor at higher doses
- improved cardiac output and a reduction in filling pressures compared with dobutamine
- may also improve diastolic function by increasing relaxation rate
- modulates the neuroendocrine response to heart failure by reducing brain natriuretic peptide levels
- has anti-apoptotic and anti-inflammatory effects
- renal function may also improve
- is associated with a similar risk of ventricular arrhythmias to dobutamine
- increases risk of new onset atrial fibrillation
- has conflicting literature surrounding mortality
- has shown a lack of consistent outcome benefits in studies
- may be useful in postmyocardial infarction cardiac dysfunction and septic shock through increasing coronary flow and attenuating inflammatory activation, respectively2.
Istaroxime, a novel inotrope with positive lusitropic (cardiac relaxant) effects3:
- is an inhibitor of the sodium-potassium-ATPase (resulting, like digoxin, in elevated intracellular calcium) with additional stimulatory effects on the sarcoplasmic reticulum calcium pump (SERCA)
- provides a dose-dependant increase in cardiac output without significant change in heart rate or arrhythmia
- in one study reducesd pulmonary capillary wedge pressure, increased systolic blood pressure, and reduced heart rate and left ventricular end-diastolic volume
- requires further clinical evaluation.
Omecamtiv mecarbil is a cardiac myosin activator. This new drug:
- improves myocardial contraction by increasing the hydrolysis of ATP by myosin ATPase
- this produces the power stroke between actin and myosin and subsequent shortening of sarcomere length
- in phase-2a studies in patients with systolic heart failure it demonstrated improved stroke volume without an increase in heart rate, although cardiac ischaemia emerged at high plasma concentrations4,5.
1. Do inotropes really have a future?
Anaesthesia. 2011 Nov;66(11):972-6.
2. Inotropes in cardiac patients: update 2011
Curr Opin Crit Care. 2010 Oct;16(5):432-41
PURPOSE OF REVIEW: ICU patients frequently develop low output syndromes due to cardiac dysfunction, myocardial injury, and inflammatory activation. Conventional inotropic agents seem to be useful in restoring hemodynamic parameters and improving peripheral organ perfusion, but can increase short-term and long-term mortality in these patients. Novel inotropes may be promising in the management of ICU patients, having no serious adverse effects. This review summarizes all the current knowledge about the use of conventional and new inotropic agents in various clinical entities of critically ill patients.
RECENT FINDINGS: In recent European Society of Cardiology guidelines, inotropic agents are administered in patients with low output syndrome due to impaired cardiac contractility, and signs and symptoms of congestion. The most recommended inotropes in this condition are levosimendan and dobutamine (both class of recommendation: IIa, level of evidence: B). Recent data indicate that levosimendan may be useful in postmyocardial infarction cardiac dysfunction and septic shock through increasing coronary flow and attenuating inflammatory activation, respectively. Furthermore, calcium sensitizing by levosimendan can be effectively used for weaning of mechanical ventilation in postcardiac surgery patients and has also cardioprotective effect as expressed by the absence of troponin release in this patient population. Finally, new agents, such as istaroxime and cardiac myosin activators may be safe and improve central hemodynamics in experimental models of heart failure and heart failure patients in phase II clinical trials; however, large-scale randomized clinical trials are required.
SUMMARY: In an acute cardiac care setting, short-term use of inotropic agents is crucial for the restoration of arterial blood pressure and peripheral tissue perfusion, as well as weaning of cardiosurgery. New promising agents should be tested in randomized clinical trials.
3. Combining SERCA2a activation and Na-K ATPase inhibition: a promising new approach to managing acute heart failure syndromes with low cardiac output.
Discov Med. 2011 Aug;12(63):141-51 Free Full Text
Heart failure (HF) patients are a medically complex and heterogeneous population with multiple cardiac and non-cardiac comorbidities. Although there are a multitude of etiologic substrates and initiating and amplifying mechanisms contributing to disease progression, these pathophysiologic processes ultimately all lead to impaired myocardial function. The myocardium must both pump oxygenated, nutrient-rich blood throughout the body (systolic function) and receive deoxygenated, nutrient-poor blood returning from the periphery (diastolic function). At the molecular level, it is well-established that Ca2+ plays a central role in excitation-contracting coupling with action potentials stimulating the opening of L-type Ca2+ in the plasma membrane and ryanodine receptor 2 (RyR2) in the sarcoplasmic reticulum (SR) membrane during systole and the Na-Ca2+ exchanger and SERCA2a returning Ca2+ to the extracellular space and SR, respectively, during diastole. However, there is increasing recognition that impaired Ca2+ cycling may contribute to myocardial dysfunction. Preclinical studies and clinical trials indicate that combining SERCA2a activation and Na-K ATPase inhibition may increase contractility (inotropy) and facilitate active relaxation (lusitropy), improving both systolic and diastolic functions. Istaroxime, a novel luso-inotrope that activates SERCA2a and inhibits the Na-K ATPase, is currently in phase II clinical development and has been shown to improve systolic and diastolic functions and central hemodynamics, increase systolic but not diastolic blood pressure, and decrease substantially heart rate. Irrespective of its clinical utility, the development of istaroxime has evolved our understanding of the clinical importance of inhibiting the Na-K ATPase in order to obtain a clinically significant effect from SERCA2a activation in the setting of myocardial failure.
4. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study
Lancet. 2011 Aug 20;378(9792):667-75
BACKGROUND: Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings.
METHODS: In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223.
FINDINGS: The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0·99 by dose), associated with increases in stroke volume (15  mL), fractional shortening (8% ), and ejection fraction (7% ; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time.
INTERPRETATION: These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure.
FUNDING: Cytokinetics Inc.
5. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial
Lancet. 2011 Aug 20;378(9792):676-83
BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure.
METHODS: We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442.
FINDINGS: T45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged.
INTERPRETATION: Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent.
FUNDING: Cytokinetics Inc.
This interesting study introduces a novel technique for guiding the inflation of tracheal tube cuffs to avoid excessive cuff pressures: listening with a stethoscope over the thyroid cartilage and inflating the cuff until breath sounds change from harsh to soft.
Tracheal tube cuffs are commonly inflated to pressures exceeding the recommended upper limit of 30 cmH2O. We evaluated whether a stethoscope-guided method of cuff inflation results in pressures within the recommended range. Patients were randomly assigned to receive one of two methods of cuff inflation. In the standard ‘just seal’ group, air was introduced into the tracheal cuff until the audible leak at the mouth disappeared. In the stethoscope-guided group, air was introduced into the cuff until a change from harsh to soft breath sounds occurred, whilst listening with a stethoscope bell placed over the thyroid cartilage. Twenty-five patients were recruited
to each group. The median (IQR [range]) cuff pressure in the ‘just seal’ group was 34 (28–40 [18–49]) cmH2O, and in the stethoscope-guided group was 20 (20–26 [16–28]) cmH2O,
p < 0.0001. The stethoscope-guided method of tracheal tube cuff inflation is a novel, simple technique that reliably results in acceptable tracheal cuff pressures.
Clinical evaluation of stethoscope-guided inflation of tracheal tube cuffs
Anaesthesia. 2011 Nov;66(11):1012-6
A review showed that peripherally inserted central catheters were associated with higher rates of complications that standard central venous catheters
We undertook a review of studies comparing complications of centrally or peripherally inserted central venous catheters. Twelve studies were included. Catheter tip malpositioning (9.3% vs 3.4%, p = 0.0007), thrombophlebitis (78 vs 7.5 per 10 000 indwelling days, p = 0.0001) and catheter dysfunction (78 vs 14 per 10 000 indwelling days, p = 0.04) were more common with peripherally inserted catheters than with central catheter placement, respectively. There was no difference in infection rates. We found that the risks of tip malpositioning, thrombophlebitis and catheter dysfunction favour clinical use of centrally placed catheters instead of peripherally inserted central catheters, and that the two catheter types do not differ with respect to catheter- related infection rates.
Complications associated with peripheral or central routes for central venous cannulation
Anaesthesia. 2012 Jan;67(1):65-71
Comments Off on Make space for pre-hospital intubation
“Control your environment – don’t let it control you” is a reliable adage for pre-hospital providers, and its adherence can assist in in-hospital resuscitation too. Commanding control of ones space is a skill demonstrated by more seasoned paramedics compared with novices and the requirement, where possible, for 360 degrees of access around a patient is included in some Standard Operating Procedures for pre-hospital rapid sequence intubation.
Evidence for this approach is now further supported by a study demonstrating that limited surrounding space on scene was a significant risk factor for difficult pre-hospital intubation by European EMS physicians.
Other predisposing factors for difficult prehospital intubation included obesity and a short neck.
OBJECTIVES:For experienced personnel endotracheal intubation (ETI) is the gold standard to secure the airway in prehospital emergency medicine. Nevertheless, substantial procedural difficulties have been reported with a significant potential to compromise patients’ outcomes. Systematic evaluation of ETI in paramedic operated emergency medical systems (EMS) and in a mixed physician/anaesthetic nurse EMS showed divergent results. In our study we systematically assessed factors associated with difficult ETI in an EMS exclusively operating with physicians.
METHODS:Over a 1-year period we prospectively collected data on the specific conditions of all ETIs of two physician staffed EMS vehicles. Difficult ETI was defined by more than 3 attempts or a difficult visualisation of the larynx (Cormack and Lehane grade 3, or worse). For each patient ETI conditions, biophysical characteristics and factors of the surrounding scene were assessed. Additionally, physicians were asked whether they had expected difficult ETI in advance.
RESULTS:Out of 3979 treated patients 305 (7.7%) received ETI. For 276 patients complete data sets were available. The incidence of difficult ETI was 13.0%. In 4 cases (1.4%) ETI was impossible, but no patient was unable to be ventilated sufficiently. Predicting conditions for difficult intubation were limited surrounding space on scene (p<0.01), short neck (p<0.01), obesity (p<0.01), face and neck injuries (p<0.01), mouth opening<3cm (p<0.01) and known ankylosing spondylitis (p<0.01). ETI on the floor or with C-spine immobilisation in situ were of no significant influence. The incidence of unexpected difficult ETI was 5.0%.
CONCLUSIONS: In a physician staffed EMS difficult prehospital ETI occurred in 13% of cases. Predisposing factors were limited surrounding space on scene and certain biophysical conditions of the patient (short neck, obesity, face and neck injuries, and anatomical restrictions). Unexpected difficult ETI occurred in 5% of the cases.
Difficult prehospital endotracheal intubation – predisposing factors in a physician based EMS
Resuscitation. 2011 Dec;82(12):1519-24
What are the best sedatives for patients with traumatic brain injury? A systematic review found no evidence that one sedative agent is better than another for improvement of neurologic outcome or mortality in critically ill adults with severe TBI. Thirteen randomised trials including around 380 patients were reviewed.
Why sedate brain injured patients anyway? Reasons include:
- minimise noxious stimuli
- improve patient comfort
- reduce metabolic requirements of the injured brain to avoid ischemic progression of the traumatic lesion in presence of increased ICP
- facilitate mechanical ventilation to control PaCo2
- avoid ICP rises due to airway instrumentation such as those induced by coughing
Sedation generally improved intracranial pressure (ICP) and cerebral perfusion pressure (CPP) vs. baseline in most trials.
Interestingly boluses or short infusions of opioids resulted in (often transient) increases in ICP and decreases in MAP and CPP in three RCTs. An accompanying editorial suggests this may be due to large opioid doses (up to 3 μg/kg of fentanyl) and consequent hypotension; hypotension itself may trigger autoregulatory cerebral vasodilatation and increase ICP and decrease CPP. Although opioids have been linked with increased ICP through decreased cerebrovascular resistance, increased cerebral blood flow or Paco2, and disturbed cerebral autoregulation, they state that in studies in which hypotension after opioid administration was prevented, an ICP increasing effect was not seen. It is important to note the small sample sizes studied and the long time period of studies included, dating back some decades.
Importantly, ketamine did not result in the increase in ICP purported by older literature.
OBJECTIVES: To summarize randomized controlled trials on the effects of sedative agents on neurologic outcome, mortality, intracranial pressure, cerebral perfusion pressure, and adverse drug events in critically ill adults with severe traumatic brain injury.
DATA SOURCES: PubMed, MEDLINE, EMBASE, the Cochrane Database, Google Scholar, two clinical trials registries, personal files, and reference lists of included articles.
STUDY SELECTION: Randomized controlled trials of propofol, ketamine, etomidate, and agents from the opioid, benzodiazepine, α-2 agonist, and antipsychotic drug classes for management of adult intensive care unit patients with severe traumatic brain injury.
DATA EXTRACTION: In duplicate and independently, two investigators extracted data and evaluated methodologic quality and results.
DATA SYNTHESIS: Among 1,892 citations, 13 randomized controlled trials enrolling 380 patients met inclusion criteria. Long-term sedation (≥24 hrs) was addressed in six studies, whereas a bolus dose, short infusion, or doubling of plasma drug concentration was investigated in remaining trials. Most trials did not describe baseline traumatic brain injury prognostic factors or important cointerventions. Eight trials possibly or definitely concealed allocation and six were blinded. Insufficient data exist regarding the effects of sedative agents on neurologic outcome or mortality. Although their effects are likely transient, bolus doses of opioids may increase intracranial pressure and decrease cerebral perfusion pressure. In one study, a long-term infusion of propofol vs. morphine was associated with a reduced requirement for intracranial pressure-lowering cointerventions and a lower intracranial pressure on the third day. Trials of propofol vs. midazolam and ketamine vs. sufentanil found no difference between agents in intracranial pressure and cerebral perfusion pressure.
CONCLUSIONS: This systematic review found no convincing evidence that one sedative agent is more efficacious than another for improvement of patient-centered outcomes, intracranial pressure, or cerebral perfusion pressure in critically ill adults with severe traumatic brain injury. High bolus doses of opioids, however, have potentially deleterious effects on intracranial pressure and cerebral perfusion pressure. Adequately powered, high-quality, randomized controlled trials are urgently warranted.
Sedation for critically ill adults with severe traumatic brain injury: A systematic review of randomized controlled trials
Crit Care Med. 2011 Dec;39(12):2743-51