Something I’ve been teaching for years – but never actually done – has been described in a case report from Oman.
A 2 year old child suffered a respiratory arrest due to an inhaled foreign body, which led to a bradyasystolic cardiac arrest. She was intubated by the resuscitation team who could not achieve any ventilation through the tube. The tube was removed and reinserted by an ‘expert’ (there is no mention of capnometry, for what it’s worth) and the same problem persisted.
The life-saving manouevre was to insert the tracheal tube further down into the right main bronchus and then withdraw to the trachea. This forced the obstructing object distally so that one-lung ventilation was then possible, resulting in return of spontaneous circulation and oxygen saturations in the mid-80’s. The object – a broken piece of plastic – was removed bronchoscopically and happily the child made an uneventful recovery.
Is this technique in your list of life-saving tricks? Hopefully, it is now.
A child is alive because a doctor was able to ‘think outside the guidelines’ in an incredibly high pressure situation. Rigid adherence to ACLS procedures here would have been futile. The guidelines save lives, but a few more can be saved when care can be individualised to the clinical situation by a thinking clinician.
Well done Dr Mishra and colleagues.
Sudden near-fatal tracheal aspiration of an undiagnosed nasal foreign body in a small child
Emerg Med Australas. 2011 Dec;23(6):776-8
[And here’s something else to consider if you have no airway equipment with you and your basic choking algorithm isn’t working]
Category Archives: Resus
Life-saving medicine
Prehospital fluids for head injury – keep it simple
Just in case you thought you might be missing some recent gem on what we should be giving patients with traumatic brain injury in the field: a team from Melbourne has reviewed the literature and concluded isotonic crystalloids (Ringer’s or Saline) are as good as anything else.
The early management of patients who have sustained traumatic brain injury is aimed at preventing secondary brain injury through avoidance of cerebral hypoxia and hypoperfusion. Especially in hypotensive patients, it has been postulated that hypertonic crystalloids and colloids might support mean arterial pressure more effectively by expanding intravascular volume without causing problematic cerebral oedema. We conducted a systematic review to investigate if hypertonic saline or colloids result in better outcomes than isotonic crystalloid solutions, as well as to determine the safety of minimal volume resuscitation, or delayed versus immediate fluid resuscitation during prehospital care for patients with traumatic brain injury. We identified nine randomized controlled trials and one cohort study examined the effects of hypertonic solutions (with or without colloid added) for prehospital fluid resuscitation. None has reported better survival and functional outcomes over the use of isotonic crystalloids. The only trial of restrictive resuscitation strategies was underpowered to demonstrate its safety compared with aggressive early fluid resuscitation in head injured patients, and maintenance of cerebral perfusion remains the top priority.
Review article: Prehospital fluid management in traumatic brain injury
Emerg Med Australas. 2011 Dec;23(6):665-76
Ultrasound for pneumonia
Lung ultrasound done by a single keen individual had better test characteristics than CXR in diagnosing pneumonia as defined by discharge diagnosis.
The lung ultrasound was considered to be positive for pneumonia if it showed consolidation (including air bronchograms) or a focal interstitial syndrome (localised increased density of ‘B’ lines)
Objective The aim of this study was to evaluate the diagnostic accuracy of bedside lung ultrasound and chest radiography (CXR) in patients with suspected pneumonia compared with CT scan and final diagnosis at discharge.
Design A prospective clinical study.
Methods Lung ultrasound and CXR were performed in sequence in adult patients admitted to the emergency department (ED) for suspected pneumonia. A chest CT scan was performed during hospital stay when clinically indicated.
Results 120 patients entered the study. A discharge diagnosis of pneumonia was confirmed in 81 (67.5%). The first CXR was positive in 54/81 patients (sensitivity 67%; 95% CI 56.4% to 76.9%) and negative in 33/39 (specificity 85%; 95% CI 73.3% to 95.9%), whereas lung ultrasound was positive in 80/81 (sensitivity 98%; 95% CI 93.3% to 99.9%) and negative in 37/39 (specificity 95%; 95% CI 82.7% to 99.4%). A CT scan was performed in 30 patients (26 of which were positive for pneumonia); in this subgroup the first CXR was diagnostic for pneumonia in 18/26 cases (sensitivity 69%), whereas ultrasound was positive in 25/26 (sensitivity 96%). The feasibility of ultrasound was 100% and the examination was always performed in less than 5 min.
Conclusions Bedside chest ultrasound is a reliable tool for the diagnosis of pneumonia in the ED, probably being superior to CXR in this setting. It is likely that its wider use will allow a faster diagnosis, conducive to a more appropriate and timely therapy.
Lung ultrasound is an accurate diagnostic tool for the diagnosis of pneumonia in the emergency department
Emerg Med J. 2012 Jan;29(1):19-23
Potassium levels and AMI death
An association is demonstrated between abnormal (both high and low) serum potassium levels and in-hospital mortality in patients with acute myocardial infarction. These findings do not necessarily imply a causal relationship, since abnormal potassium levels might be a marker of increased risk of death due to other illness factors rather than a risk of death per se.
Acknowledging that a randomised trial of potassium replacement is unlikely to happen, the authors pragmatically advise:
Our data suggest that the optimal range of serum potassium levels in AMI patients may be between 3.5 and 4.5 mEq/L and that potassium levels of greater than 4.5 mEq/L are associated with increased mortality and should probably be avoided.
Context Clinical practice guidelines recommend maintaining serum potassium levels between 4.0 and 5.0 mEq/L in patients with acute myocardial infarction (AMI). These guidelines are based on small studies that associated low potassium levels with ventricular arrhythmias in the pre−β-blocker and prereperfusion era. Current studies examining the relationship between potassium levels and mortality in AMI patients are lacking.
Objective To determine the relationship between serum potassium levels and in-hospital mortality in AMI patients in the era of β-blocker and reperfusion therapy.
Design, Setting, and Patients Retrospective cohort study using the Cerner Health Facts database, which included 38 689 patients with biomarker-confirmed AMI, admitted to 67 US hospitals between January 1, 2000, and December 31, 2008. All patients had in-hospital serum potassium measurements and were categorized by mean postadmission serum potassium level (<3.0, 3.0-<3.5, 3.5-<4.0, 4.0-<4.5, 4.5-<5.0, 5.0-<5.5, and ≥5.5 mEq/L). Hierarchical logistic regression was used to determine the association between potassium levels and outcomes after adjusting for patient- and hospital-level factors.
Main Outcome Measures All-cause in-hospital mortality and the composite of ventricular fibrillation or cardiac arrest.
Results There was a U-shaped relationship between mean postadmission serum potassium level and in-hospital mortality that persisted after multivariable adjustment. Compared with the reference group of 3.5 to less than 4.0 mEq/L (mortality rate, 4.8%; 95% CI, 4.4%-5.2%), mortality was comparable for mean postadmission potassium of 4.0 to less than 4.5 mEq/L (5.0%; 95% CI, 4.7%-5.3%), multivariable-adjusted odds ratio (OR), 1.19 (95% CI, 1.04-1.36). Mortality was twice as great for potassium of 4.5 to less than 5.0 mEq/L (10.0%; 95% CI, 9.1%-10.9%; multivariable-adjusted OR, 1.99; 95% CI, 1.68-2.36), and even greater for higher potassium strata. Similarly, mortality rates were higher for potassium levels of less than 3.5 mEq/L. In contrast, rates of ventricular fibrillation or cardiac arrest were higher only among patients with potassium levels of less than 3.0 mEq/L and at levels of 5.0 mEq/L or greater.
Conclusion Among inpatients with AMI, the lowest mortality was observed in those with postadmission serum potassium levels between 3.5 and <4.5 mEq/L compared with those who had higher or lower potassium levels.
Serum Potassium Levels and Mortality in Acute Myocardial Infarction
JAMA Jan 11 2012,307(2):115-213
Steroid replacement after etomidate: no benefit
More fuel for the etomidate debate…
In essence:
- Etomidate has been a useful induction agent for RSI for many years due to its greater haemodynamic stability compared with thiopentone or propofol
- It is widely used in the USA
- It inhibits the 11β-hydroxylase enzyme that converts 11β-deoxycortisol into cortisol in the adrenal gland
- A single dose of etomidate has been demonstrated to inhibit cortisol production for up to 48 hrs
- This has led to concerns about its use in the critically ill, particular in patients with severe sepsis / septic shock
- This small study randomised patients receiving etomidate to hydrocortisone or placebo, with no significant difference in these patient-oriented outcomes: duration of mechanical ventilation, intensive care unit length of stay, or 28-day mortality
- This study suggests that replacement doses of hydrocortisone are not required after a single dose of etomidate
- No randomised study has conclusively demonstrated increased mortality due to etomidate; however while controversy and the possibility of harm remain, I personally see no reason not to use ketamine for RSI in haemodynamically compromised patients.
- Ketamine was compared with etomidate in a previous controlled trial
OBJECTIVE: To investigate the effects of moderate-dose hydrocortisone on hemodynamic status in critically ill patients throughout the period of etomidate-related adrenal insufficiency.
DESIGN: Randomized, controlled, double-blind trial (NCT00862381).
SETTING: University hospital emergency department and three intensive care units.
INTERVENTIONS: After single-dose etomidate (H0) for facilitating endotracheal intubation, patients without septic shock were randomly allocated at H6 to receive a 42-hr continuous infusion of either hydrocortisone at 200 mg/day (HC group; n = 49) or saline serum (control group; n = 50).
MEASUREMENTS AND MAIN RESULTS: After completion of a corticotrophin stimulation test, serum cortisol and 11β-deoxycortisol concentrations were subsequently assayed at H6, H12, H24, and H48. Forty-eight patients were analyzed in the HC group and 49 patients in the control group. Before treatment, the diagnostic criteria for etomidate-related adrenal insufficiency were fulfilled in 41 of 45 (91%) and 38 of 45 (84%) patients in the HC and control groups, respectively. The proportion of patients with a cardiovascular Sequential Organ Failure Assessment score of 3 or 4 declined comparably over time in both HC and control groups: 65% vs. 67% at H6, 65% vs. 69% at H12, 44% vs. 54% at H24, and 34% vs. 45% at H48, respectively. Required doses of norepinephrine decreased at a significantly higher rate in the HC group compared with the control group in patients treated with norepinephrine at H6. No intergroup differences were found regarding the duration of mechanical ventilation, intensive care unit length of stay, or 28-day mortality.
CONCLUSION: These findings suggest that critically ill patients without septic shock do not benefit from moderate-dose hydrocortisone administered to overcome etomidate-related adrenal insufficiency.
Corticosteroid after etomidate in critically ill patients: A randomized controlled trial
Crit Care Med. 2012 Jan;40(1):29-35
Emergency percutaneous airway
An excellent thorough review of emergency needle and surgical cricothyroidotomy – collectively described as ’emergency percutaneous airway’ – reveals a number of pearls.
Regarding anatomy:
- The cricothyroid menbrane has an average height of 10 mm and a width of 11 mm
- Transverse incision in the lower half of the cricothyroid membrane is recommended to avoid the cricothyroid arteries and the vocal cords
Regarding oxygenation / ventilation via a cricothyroid needle:
- High pressure source ventilation via a needle (eg. by Sanders injector or Manujet) may cause laryngospasm, so a neuromuscular blocking agent should be considered
- Barotrauma may result from an obstructed upper airway, so efforts should be made to maintain upper airway patency where possible (eg. with a supraglottic airway)
- A device has been manufactured that provides suction-generated expiratory ventilation assistance (using oxygen flow and the Bernoulli principle) – the Ventrain
- The Fourth National Audit Project reported a much lower success rate and described several complications of attempted re-oxygenation via a narrow-bore cricothyroidotomy
- Where there is no kink-resistant cannula or suitable high-pressure source ventilation device readily available, it is probably safer to perform a wide-bore cannula puncture or surgical cricothyroidotomy.
Wide-bore cannula-over trocar devices:
- Include the Quicktrach II and Portex cricothyroidotomy kit
- Sometimes require considerable force to push the device through the cricothyroid membrane, risking compression of the airway and damage or perforation of the posterior tracheal wall.
Seldinger cricothyroidotomy kits:
- Separate the puncture and dilatation steps, minimising the risk of trauma
- Include the Melker emergency cricothyroidotomy set, available in sizes 3.0–6.0 mm ID
- Tend to be preferred by anaesthetists over the surgical and wide-bore cannula-over-trocar techniques
- Seldinger technique in human cadavers and manikin studies by those well trained, inexperienced operators have low success rates and a long performance time
What about after?
- High-pressure source ventilation may aid subsequent intubation by direct laryngoscopy as bubbles may be seen emerging from the glottis.
- The Seldinger technique has been recommended to convert a narrow-bore cannula into a cuffed wide-bore cricothyroidotomy
- While conversion of cricothyroidotomy to tracheostomy within 72 h has been advocated because of the increased risk of developing subglottic stenosis with prolonged intubation through the cricothyroid membrane, this risk may be much lower than previously believed
- The risk of conversion, although less well examined, may also be appreciable
Which technique is best?
- The recent NAP4 audit reported a success rate of only 37% for narrow-bore cannula-over-needle cricothyroidotomy, 57% for wide-bore cannula techniques and 100% for surgical cricothyroidotomy
- Simulation studies show conflicting results about whether seldinger or surgical technique is faster.
- Reported success rates of the different techniques (in simulations) also vary widely and range for surgical cricothyroidotomy from 55% to 100%, for wide-bore cannula-over-trocar from 30% to 100%, and for Seldinger technique from 60% to 100%.
The one area of some consensus is that conventional (low-pressure source) ventilation should not be used with a narrow-bore cannula; a high-pressure oxygen source and a secure pathway for the egress of gas are both mandatory to achieve adequate ventilation.
Complications may be related to technique:
- Complications of narrow-bore cannula techniques are ventilation-related and include barotrauma, subcutaneous emphysema, pneumothorax, pneumomediastinum and circulatory arrest due to impaired venous return; Cannula obstruction due to kinking also occurs.
- Seldinger technique may be complicated by kinking of the guidewire, which increases the risk of tube misplacement
- Bleeding and laryngeal fracture may complicate the surgical method, and long-term complications include subglottic stenosis, scarring and voice changes.
Equipment and strategies for emergency tracheal access in the adult patient
Anaesthesia. 2011 Dec;66 Suppl 2:65-80
Two new anaphylaxis guidelines
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
[EXPAND click for abstract]
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.
[/EXPAND]
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
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
[EXPAND Abstract]
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.
[/EXPAND]
3.Immunosuppression in Sepsis
JAMA December 21, 2011, Vol 306, No. 23, pp 2618-9
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
[EXPAND Abstract]
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.
[/EXPAND]
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
[EXPAND Abstract]
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.
[/EXPAND]
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
[EXPAND Abstract]
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 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; 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.
[/EXPAND]
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
[EXPAND Abstract]
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.
[/EXPAND]
Listen over the neck when inflating ETT cuff
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