β-2 agonists could worsen ARDS outcome

Image: Wikipedia. I really fancy a curry now.

A previous study (BALTI-1) suggested β-2 agonists may help in ARDS by reducing extravascular lung water. A randomised trial in the UK aimed to recruit 1334 patients to compare intravenous salbutamol infused for seven days with placebo (0.9% saline). However the Data Monitoring and Ethics Committee recommended that the study stop after the second interim analysis of 273 patients because of a significant increase in mortality. It is unclear why salbutamol is harmful, and could be due to lung, cardiovascular, or other metabolic effects, such as activation of the renin-angiotensin aldosterone system affecting fluid balance.

BACKGROUND:In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS.

METHODS:We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minimisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO2/FiO2) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86.

FINDINGS:We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08).

INTERPRETATION:Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended.

FUNDING:UK Medical Research Council, UK Department of Health, UK Intensive Care Foundation.

Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial
Lancet 379(9812, 21–27 January 2012, Pages 229–235

FIRST: Fluids in Resuscitation of Severe Trauma

This is the first randomized, controlled, double-blind study comparing crystalloids with isotonic colloids in trauma. 0.9% saline was compared with hydroxyethyl starch, HES 130/0.4, as a resuscitation fluid in pre-defined subgroups of penetrating and blunt trauma. While a primary outcome measure of gastrointestinal recovery might not seem an obvious choice to some of us, previous research has indicated this to be an issue with crystalloid and the authors clearly defined this as a predefined outcome when registering the trial here.

I don't have any pictures of colloids. Here's where I work.

Colloids tend to require smaller volumes than crystalloid to achieve the same degree of plasma expansion. An interesting finding in this study is that the volume of saline administered was 1.5 times that of hydroxyethyl starch – a very similar ratio to that seen in the SAFE study which compared saline with 4% albumin in intensive care patients.

The authors assert: “..the better lactate clearance in the P-HES group indicated superior tissue resuscitation with the colloid.” There are a number of reasons why this might be a bit of stretch, including the use of epinephrine in some patients which is known to be a cause of hyperlactataemia.

This is a small study whose conclusions should be treated with caution, but which provides an important contribution to the pool of fluid resuscitation literature. If you have full text access to the British Journal of Anaesthesia, the letters pages provide excellent critiques and responses regarding potential flaws in this paper. Nevertheless, it’s one to know about – I’m sure the FIRST trial is going to be quoted for some time to come, including, I suspect, by the manufacturers of certain colloids.

Background The role of fluids in trauma resuscitation is controversial. We compared resuscitation with 0.9% saline vs hydroxyethyl starch, HES 130/0.4, in severe trauma with respect to resuscitation, fluid volume, gastrointestinal recovery, renal function, and blood product requirements.

Methods Randomized, controlled, double-blind study of severely injured patients requiring>3 litres of fluid resuscitation. Blunt and penetrating trauma were randomized separately. Patients were followed up for 30 days.

Results A total of 115 patients were randomized; of which, 109 were studied. For patients with penetrating trauma (n=67), the mean (sd) fluid requirements were 5.1 (2.7) litres in the HES group and 7.4 (4.3) litres in the saline group (P<0.001). In blunt trauma (n=42), there was no difference in study fluid requirements, but the HES group required significantly more blood products [packed red blood cell volumes 2943 (1628) vs 1473 (1071) ml, P=0.005] and was more severely injured than the saline group (median injury severity score 29.5 vs 18; P=0.01). Haemodynamic data were similar, but, in the penetrating group, plasma lactate concentrations were lower over the first 4 h (P=0.029) and on day 1 with HES than with saline [2.1 (1.4) vs 3.2 (2.2) mmol litre−1; P=0.017]. There was no difference between any groups in time to recovery of bowel function or mortality. In penetrating trauma, renal injury occurred more frequently in the saline group than the HES group (16% vs 0%; P=0.018). In penetrating trauma, maximum sequential organ function scores were lower with HES than with saline (median 2.4 vs 4.5, P=0.012). No differences were seen in safety measures in the blunt trauma patients.

Conclusions In penetrating trauma, HES provided significantly better lactate clearance and less renal injury than saline. No firm conclusions could be drawn for blunt trauma.

Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma)

Br J Anaesth. 2011 Nov;107(5):693-702

Adjacent haemofiltration catheters can remove CVC drugs

An important consideration when siting your lines in your critical care patients who require renal replacement therapy…

Dual-lumen haemodiafiltration catheters enable continuous renal replacement therapy in the critically ill and are often co-located with central venous catheters used to infuse drugs. The extent to which infusions are immediately aspirated by an adjacent haemodiafiltration catheter remains unknown. A bench model was constructed to evaluate this effect. A central venous catheter and a haemodiafiltration catheter were inserted into a simulated central vein and flow generated using centrifugal pumps within the simulated vein and haemodiafiltration circuit. Ink was used as a visual tracer and creatinine solution as a quantifiable tracer. Tracers were completely aspirated by the haemodiafiltration catheter unless the infusion was at least 1 cm downstream to the arterial port. No tracer was aspirated from catheters infusing at least 2 cm downstream. Orientation of side ports did not affect tracer elimination. Co-location of central venous and haemodiafiltration catheters may lead to complete aspiration of infusions into the haemodiafilter with resultant drug under-dosing.

Adjacent central venous catheters can result in immediate aspiration of infused drugs during renal replacement therapy
Anaesthesia. 2012 Feb;67(2):115-121

Caution with intraosseous adenosine

Two cases of failed cardioversion of SVT after tibial intraosseous administration of adenosine in infants are described in this month’s Pediatric Emergency Care. Both cases were subsequently cardioverted by intravenous adenosine. The maximum intraosseous dose given was 0.25 mg/kg. The successful IV doses were not higher than the IO doses.

It has been noted before that infants may require relatively higher doses of adenosine than children and that 0.2 mg/kg might even be considered a starting dose in infancy. I wonder if a bigger IO dose would have been effective, or whether a proximal humeral insertion site would make a difference. IO adenosine has been successfully used in infants and piglets.

This interesting case series provides a helpful caution in the management of paediatric SVT.

ABSTRACT: Supraventricular tachycardia (SVT) is a common tachyarrhythmia in the pediatric population that can necessitate immediate treatment. Adenosine has been well studied as a mainstay treatment, but the methods of adenosine administration have not been very well delineated. The intraosseous technique has presented itself as a possible method of administration. We describe 2 cases in which adenosine was administered through bone marrow infusion to convert SVT without success. The cases we describe show that intraosseous is not a reliable method of administering adenosine to stop SVT. Both patients presented with SVT refractory to vagal maneuvers and difficult intravenous placement. Intraosseous access was achieved, but administration of adenosine at increasing doses was unable to successfully convert the arrhythmia.

Intraosseous Infusion Is Unreliable for Adenosine Delivery in the Treatment of Supraventricular Tachycardia
Pediatr Emerg Care. 2012 Jan;28(1):47-8

Vasopressin – what it does and doesn’t do

The current Surviving Sepsis campaign guidelines recommend that vasopressin should not be administered as the initial vasopressor in septic shock, and that vasopressin at constant dosage of 0.03 units/min may be added to norepinephrine with anticipation of an effect equivalent to that of norepinephrine alone. European intensivists conducted a systematic review to determine vasopressin’s risks and benefits in vasodilatory shock. There was no demonstrated survival benefit but its use is associated with a significant reduction in norepinephrine requirement.

Interestingly, the authors point out: ‘Low-dose vasopressin may help to restore blood pressure in patients with hypotension refractory to catecholamines, and may favor pulmonary vasodilation and increase glomerular filtration rate and plasma cortisol levels’.

My take home: consider its use if an apparent vasodilatory shock state is refractory to catecholamines, but don’t stress if you don’t have access to it (or it will complicate practical aspects of organising resuscitation and transfer), since there’s still no clear evidence for outcome benefit.

To examine the benefits and risks of vasopressin or its analog terlipressin for patients with vasodilatory shock.

We searched the CENTRAL, MEDLINE, EMBASE, and LILACS databases (up to March 2011) as well as reference lists of articles and proceedings of major meetings; we also contacted trial authors. We considered randomized and quasirandomized trials of vasopressin or terlipressin versus placebo or supportive treatment in adult and pediatric patients with vasodilatory shock. The primary outcome for this review was short-term all-cause mortality.

We identified 10 randomized trials (1,134 patients). Six studies were considered for the main analysis on mortality in adults.

The crude short-term mortality was 206 of 512 (40.2%) in vasopressin/terlipressin-treated patients and 198 of 461 (42.9%) in controls [six trials, risk ratio (RR) = 0.91; 95% confidence interval (CI) 0.79-1.05; P = 0.21; I (2) = 0%]. There were 49 of 463 (10.6%) patients with serious adverse events in the vasopressin/terlipressin arm and 51 of 431 (11.8%) in the control arm (four trials, RR = 0.90; 95% CI 0.49-1.67; P = 0.75; I (2) = 26%). Metaregression analysis showed negative correlation between vasopressin dose and norepinephrine dose (P = 0.03).

Overall, use of vasopressin or terlipressin did not produce any survival benefit in the short term in patients with vasodilatory shock. Physicians may value the sparing effects of vasopressin/terlipressin on norepinephrine requirement given its apparent safe profile.

Vasopressin for treatment of vasodilatory shock: an ESICM systematic review and meta-analysis
Intensive Care Med. 2012 Jan;38(1):9-19

A big brain saves a little one

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]

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