Extracorporeal liver support in acute liver failure

Critically ill patients may receive cardiovascular, respiratory, and renal support, but systems that perform some of the functions of the liver are less routinely used. Extracorporeal liver support can be provided by artificial systems or bioartificial systems:

  • Artificial liver support systems aim to replace the detoxification functions of the liver, based on albumin dialysis, and consist of membrane separation associated with columns or suspensions of sorbents, including charcoal and anion or cation exchange resins.
  • Bioartificial systems incorporate either human hepatoblastoma cells or porcine hepatocytes into bioreactors that are intended to perform both liver detoxification and synthetic functions. A porous barrier between the patient’s blood or plasma isolates cells from immunoglobulins and leucocytes, avoiding immune rejection. Smaller particles such as toxins, metabolites and synthesized proteins are free to cross the barrier.

Three artificial liver support system types and two bioartificial liver systems have undergone randomised controlled trials. A meta-analysis examined the effect of extracorporeal liver support on mortality

Molecular Adsorbent Recirculating System

BACKGROUND: Extracorporeal liver support (ELS) systems offer the potential to prolong survival in acute and acute-on-chronic liver failure. However, the literature has been unclear on their specific role and influence on mortality. This meta-analysis aimed to test the hypothesis that ELS improves survival in acute and acute-on-chronic liver failure.
METHODS: Clinical trials citing MeSH terms ‘liver failure’ and ‘liver, artificial’ were identified by searching MEDLINE, Embase and the Cochrane registry of randomised controlled trials (RCTs) between January 1995 and January 2010. Only RCTs comparing ELS with standard medical therapy in acute or acute-on-chronic liver failure were included. A predefined data collection pro forma was used and study quality assessed according to Consolidated Standards of Reporting Trials (CONSORT) criteria. Risk ratio was used as the effect size measure according to a random-effects model.
RESULTS: The search strategy revealed 74 clinical studies including 17 RCTs, five case-control studies and 52 cohort studies. Eight RCTs were suitable for inclusion, three addressing acute liver failure (198 participants) and five acute-on-chronic liver failure (157 participants). The mean CONSORT score was 14 (range 11-20). Overall ELS therapy significantly improved survival in acute liver failure (risk ratio 0·70; P = 0·05). The number needed to treat to prevent one death in acute liver failure was eight. No significant survival benefit was demonstrated in acute-on-chronic liver failure (risk ratio 0·87; P = 0·37).
CONCLUSION: ELS systems appear to improve survival in acute liver failure. There is, however, no evidence that they improve survival in acute-on-chronic liver failure.

Systematic review and meta-analysis of survival following extracorporeal liver support
Br J Surg. 2011 May;98(5):623-31

CHEST study to evaluate starch

No results to report here, just a heads up that the CHEST study is underway: a randomised controlled trial of 7000 patients comparing of 6% hydroxyethyl starch (130/0.4) with 0.9% sodium chloride for all fluid resuscitation needs whilst in the intensive care unit (ICU).  This is how the authors explain the rationale for the study:

Much of the evidence currently available to inform clinicians on the efficacy and safety of starch solutions for fluid resuscitation involves studies conducted using older, high molecular weight and high molar substitution starches. Meta-analyses of these studies suggest that when comparing starches to other fluids, the relative risk of mortality ranges from 1.00 (95% CI 0.80–1.25) to 1.35 (95% CI 0.94–1.95) and for kidney failure 1.50 (95% CI 1.20–1.87). There are insufficient data, however, on the newer low molecular weight, low molar substitution starches. To date, most published studies on these newer generation starches have been conducted in perioperative settings with small sample sizes and limited follow-up. They have been designed to examine surrogate outcomes and not important patient outcomes such as mortality or renal failure.

It is possible to overdo the starch

These are some of the same people who brought us the SAFE study on albumin and the NICE-SUGAR study on glycaemic control, so this will be one to watch. It is anticipated that recruitment will be completed by December 2011.

PURPOSE: The intravenous fluid 6% hydroxyethyl starch (130/0.4) (6% HES 130/0.4) is used widely for resuscitation but there is limited information on its efficacy and safety. A large-scale multi-centre randomised controlled trial (CHEST) in critically ill patients is currently underway comparing fluid resuscitation with 6% HES 130/0.4 to 0.9% sodium chloride on 90-day mortality and other clinically relevant outcomes including renal injury. This report describes the study protocol.
METHODS: CHEST will recruit 7,000 patients to concealed, random, parallel assignment of either 6% HES 130/0.4 or 0.9% sodium chloride for all fluid resuscitation needs whilst in the intensive care unit (ICU). The primary outcome will be all-cause mortality at 90 days post-randomisation. Secondary outcomes will include incident renal injury, other organ failures, ICU and hospital mortality, length of ICU stay, quality of life at 6 months, health economic analyses and in patients with traumatic brain injury, functional outcome. Subgroup analyses will be conducted in four predefined subgroups. All analyses will be conducted on an intention-to-treat basis.
RESULTS AND CONCLUSIONS: The study run-in phase has been completed and the main trial commenced in April 2010. CHEST should generate results that will inform and influence prescribing of this commonly used resuscitation fluid.

The Crystalloid versus Hydroxyethyl Starch Trial: protocol for a multi-centre randomised controlled trial of fluid resuscitation with 6% hydroxyethyl starch (130/0.4) compared to 0.9% sodium chloride (saline) in intensive care patients on mortality
Intensive Care Med. 2011 May;37(5):816-823

Hyperbaric O2 for the sick and the well with CO poisoning

A French study, large by hyperbaric oxygen trial standards, did not confirm that hyperbaric oxygen therapy improves recovery from pure CO poisoning. In addition, in comatose patients, repeating hyperbaric oxygen therapy resulted in worse outcomes compared to one session.

I don't care if it doesn't work - something looking like a retro-sci-fi time machine is COOL.

INTRODUCTION: Although hyperbaric oxygen therapy (HBO) is broadly used for carbon monoxide (CO) poisoning, its efficacy and practical modalities remain controversial.
OBJECTIVES: To assess HBO in patients poisoned with CO.
DESIGN: Two prospective randomized trial on two parallel groups.
SETTING: Critical Care Unit, Raymond Poincaré Hospital, Garches, France.
SUBJECTS: Three hundred eighty-five patients with acute domestic CO poisoning.
INTERVENTION: Patients with transient loss of consciousness (trial A, n = 179) were randomized to either 6 h of normobaric oxygen therapy (NBO; arm A0, n = 86) or 4 h of NBO plus one HBO session (arm A1, n = 93). Patients with initial coma (trial B, n = 206) were randomized to either 4 h of NBO plus one HBO session (arm B1, n = 101) or 4 h of NBO plus two 2 HBO sessions (arm B2, n = 105). PRIMARY ENDPOINT: Proportion of patients with complete recovery at 1 month.
RESULTS: In trial A, there was no evidence for a difference in 1-month complete recovery rates with and without HBO [58% compared to 61%; unadjusted odds ratio, 0.90 (95% CI, 0.47-1.71)]. In trial B, complete recovery rates were significantly lower with two than with one HBO session [47% compared to 68%; unadjusted odds ratio, 0.42 (CI, 0.23-0.79)].
CONCLUSION: In patients with transient loss of consciousness, there was no evidence of superiority of HBO over NBO. In comatose patients, two HBO sessions were associated with worse outcomes than one HBO session.

Hyperbaric oxygen therapy for acute domestic carbon monoxide poisoning: two randomized controlled trials
Intensive Care Med. 2011 Mar;37(3):486-92

Pre-hospital Airtraq use often failed

The Airtraq seems nifty when you try it on a manikin, but until now the question of whether it would be a useful pre-hospital tool was unanswered. This Austrian study provides helpful data:

OBJECTIVES: The optical Airtraq laryngoscope (Prodol Meditec, Vizcaya, Spain) has been shown to have advantages when compared with direct laryngoscopy in difficult airway patients. Furthermore, it has been suggested that it is easy to use and handle even for inexperienced advanced life support providers. As such, we sought to assess whether the Airtraq may be a reliable alternative to conventional intubation when used in the prehospital setting.
DESIGN, SETTING, AND PATIENTS: Prospective, randomized control trial in emergency patients requiring endotracheal intubation provided by anesthesiologists or emergency physicians responding with an emergency medical service helicopter or ground unit associated with the Department of Anesthesiology, General Hospital, Wiener Neustadt, Austria.
MEASUREMENTS AND MAIN RESULTS: During the 18-month study period, 212 patients were enrolled. When the Airtraq was used as first-line airway device (n=106) vs. direct laryngoscopy (n=106), success rate was 47% vs. 99%, respectively (p<.001). Reasons for failed Airtraq intubation were related to the fiber-optic characteristic of this device (i.e., impaired sight due to blood and vomitus, n=11) or to assumed handling problems (i.e., cuff damage, tube misplacement, or inappropriate visualization of the glottis, n=24). In 54 of 56 patients where Airtraq intubation failed, direct laryngoscopy was successful on the first attempt; in the remaining two and in one additional case of failed direct laryngoscopy, the airway was finally secured employing the Fastrach laryngeal mask. There was no correlation between success rates and body mass index, age, indication for airway management, emergency medical service unit, or experience of the physicians. CONCLUSIONS: Based on these results, the use of the Airtraq laryngoscope as a primary airway device cannot be recommended in the prehospital setting without significant clinical experience obtained in the operation room. We conclude that the clinical learning process of the Airtraq laryngoscope is much longer than reported in the anesthesia literature.

Use of the Airtraq laryngoscope for emergency intubation in the prehospital setting: A randomized control trial
Crit Care Med. 2011 Mar;39(3):489-93

Salt or sugar on the brain

A meta-analysis suggests hypertonic saline may be more effective at lowering intracranial pressure than mannitol. An accompanying editorial cleverly entitled ‘Salt or sugar on the brain: Does it matter except for taste?’ suggests one reason hypertonic saline (HTS) has not replaced mannitol in clinical practice is that too many different regimens of HTS, in terms of concentration, dose, bolus vs. continuous infusions, and plus or minus supplementation of colloids, have been utilised. Because only 112 patients with 184 episodes of increased ICP were treated with each medication in this meta-analysis, the editorialist agrees with the authors in suggesting a larger randomised study is needed.

OBJECTIVES: Randomized trials have suggested that hypertonic saline solutions may be superior to mannitol for the treatment of elevated intracranial pressure, but their impact on clinical practice has been limited, partly by their small size. We therefore combined their findings in a meta-analysis.
DATA SOURCES: We searched for relevant studies in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and ISI Web of Knowledge.
STUDY SELECTION: Randomized trials were included if they directly compared equiosmolar doses of hypertonic sodium solutions to mannitol for the treatment of elevated intracranial pressure in human subjects undergoing quantitative intracranial pressure measurement.
DATA EXTRACTION: Two investigators independently reviewed potentially eligible trials and extracted data using a preformed data collection sheet. Disagreements were resolved by consensus or by a third investigator if needed. We collected data on patient demographics, type of intracranial pathology, baseline intracranial pressure, osms per treatment dose, quantitative change in intracranial pressure, and prespecified adverse events. Our primary outcome was the proportion of successfully treated episodes of elevated intracranial pressure.
DATA SYNTHESIS: Five trials comprising 112 patients with 184 episodes of elevated intracranial pressure met our inclusion criteria. In random-effects models, the relative risk of intracranial pressure control was 1.16 (95% confidence interval, 1.00-1.33), and the difference in mean intracranial pressure reduction was 2.0 mm Hg (95% confidence interval, -1.6 to 5.7), with both favoring hypertonic saline over mannitol. A mild degree of heterogeneity was present among the included trials. There were no significant adverse events reported.
CONCLUSIONS: We found that hypertonic saline is more effective than mannitol for the treatment of elevated intracranial pressure. Our meta-analysis is limited by the small number and size of eligible trials, but our findings suggest that hypertonic saline may be superior to the current standard of care and argue for a large, multicenter, randomized trial to definitively establish the first-line medical therapy for intracranial hypertension.

Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: A meta-analysis of randomized clinical trials
Crit Care Med. 2011 Mar;39(3):554-9

Norepinephrine increases preload

Noradrenaline (norepinephrine) may improve blood pressure in part through its venoconstriction effects, providing more venous return to the heart which increases cardiac output. A study of septic shock patients supports this.
An accompanying editorial by Drs Milzman and Napoli comments: “This study tells us something we probably already knew, that norepinephrine (NE) has the ability to provide venoconstriction, increase central venous pressure, provide a marginal increase in cardiac output, and improve the MAP in patients with septic shock. Importantly, it also demonstrates that Passive Leg Raise (PLR) continues to be a good predictor of preload responsiveness even in the presence of low doses of NE.”

OBJECTIVE: To assess the effects of norepinephrine on cardiac preload, cardiac index, and preload dependency during septic shock.
DESIGN: Prospective interventional study.
SETTING: Medical Intensive Care Unit.
PATIENTS: We included 25 septic shock patients (62 ± 13 yrs old, Simplified Acute Physiology Score II 53 ± 12, lactate 3.5 ± 2.1 mmol/L, all receiving norepinephrine at baseline at 0.24 [25%-75% interquartile range: 0.12-0.48] μg/kg/min) with a positive passive leg raising test (defined by an increase in cardiac index ≥10%) and a diastolic arterial pressure ≤40 mm Hg.
INTERVENTIONS: We performed a passive leg raising test (during 1 min) at baseline. Immediately after, we increased the dose of norepinephrine (to 0.48 [0.36-0.71] μg/kg/min) and, when the hemodynamic status was stabilized, we performed a second passive leg raising test (during 1 min). We finally infused 500 mL saline.
MEASUREMENTS AND MAIN RESULTS: Increasing the dose of norepinephrine significantly increased central venous pressure (+23% ± 12%), left ventricular end-diastolic area (+9% ± 6%), E mitral wave (+19% ± 23%), and global end-diastolic volume (+9% ± 6%). Simultaneously, cardiac index significantly increased by 11% ± 7%, suggesting that norepinephrine had recruited some cardiac preload reserve. The second passive leg raising test increased cardiac index to a lesser extent than the baseline test (13% ± 8% vs. + 19% ± 6%, p < .05), suggesting that norepinephrine had decreased the degree of preload dependency. Volume infusion significantly increased cardiac index by 26% ± 15%. However, cardiac index increased by <15% in four patients (fluid unresponsive patients) while the baseline passive leg raising test was positive in these patients. In three of these four patients, the second passive leg raising test was also negative, i.e., the second passive leg raising test (after norepinephrine increase) predicted fluid responsiveness with a sensitivity of 95 [76-99]% and a specificity of 100 [30-100]%.
CONCLUSIONS: In septic patients with a positive passive leg raising test at baseline suggesting the presence of preload dependency, norepinephrine increased cardiac preload and cardiac index and reduced the degree of preload dependency.

Norepinephrine increases cardiac preload and reduces preload dependency assessed by passive leg raising in septic shock patients
Crit Care Med 2011;39(4):689-94

Cardiac arrest drugs and pupils

Although not predictive immediately post-cardiac arrest in the emergency department, dilated unreactive pupils two or three days later on the ICU may indicate a hopeless prognosis. We know from our experience with adrenaline (epinephrine) infusions that this drug does not prevent pupils from reacting to light, but what about atropine?

A letter by Dr Sophie MacDougall-Davis in Resuscitation describes a 66 year old male patient admitted to the ICU after an intraoperative PEA arrest during which he received 3 mg intravenous atropine. Post arrest and post anaesthesia he was awake with no neurological deficit, but eight hours after the cardiac arrest his pupils remained fixed and dilated, and were dilated with only a very slight reaction the next morning and remained sluggish at forty-eight hours, normalising at seventy-two hours. A possible reason for its prolonged action may be uptake of atropine from the plasma into the aqueous humor of the eye, followed by its slow release.
Dr MacDougall-Davis cautions:

When assessing pupils in comatose cardiac arrest survivors, the potential for atropine to have a prolonged effect on pupil size and reactivity should be considered.

Atropine, fixed dilated pupils and prognostication following cardiac arrest
Resuscitation. 2011 Feb;82(2):232

Video laryngoscope successes and failures

With a difficult airway, video laryngoscopes can get you out of a hole – or rather into one. However they’re not guaranteed for all eventualities; a large study of Glidescope use showed:

  • Primary intubation with the Glidescope was successful in 98% of 1,755 cases and rescued failed direct laryngoscopy in 94% of 239 cases.
  • Altered neck anatomy with presence of a surgical scar, radiation changes, or mass was the strongest predictor of Glidescope failure.



INTRODUCTION: The Glidescope video laryngoscope has been shown to be a useful tool to improve laryngeal view. However, its role in the daily routine of airway management remains poorly characterized.
METHODS: This investigation evaluated the use of the Glidescope at two academic medical centers. Electronic records from 71,570 intubations were reviewed, and 2,004 cases were identified where the Glidescope was used for airway management. We analyzed the success rate of Glidescope intubation in various intubation scenarios. In addition, the incidence and character of complications associated with Glidescope use were recorded. Predictors of Glidescope intubation failure were determined using a logistic regression analysis.
RESULTS: Overall success for Glidescope intubation was 97% (1,944 of 2,004). As a primary technique, success was 98% (1,712 of 1,755), whereas success in patients with predictors of difficult direct laryngoscopy was 96% (1,377 of 1,428). Success for Glidescope intubation after failed direct laryngoscopy was 94% (224 of 239). Complications were noticed in 1% (21 of 2,004) of patients and mostly involved minor soft tissue injuries, but major complications, such as dental, pharyngeal, tracheal, or laryngeal injury, occurred in 0.3% (6 of 2,004) of patients. The strongest predictor of Glidescope failure was altered neck anatomy with presence of a surgical scar, radiation changes, or mass.
CONCLUSION: These data demonstrate a high success rate of Glidescope intubation in both primary airway management and rescue-failed direct laryngoscopy. However, Glidescope intubation is not always successful and certain predictors of failure can be identified. Providers should maintain their competency with alternate methods of intubation, especially for patients with neck pathology.

Routine Clinical Practice Effectiveness of the Glidescope in Difficult Airway Management
Anesthesiology. 2011 Jan;114(1):34-41

Emergency tracheal intubations outside the OR

Most data regarding RSI complication rates traditionally come from the operating room setting. I and my colleagues made a small attempt address this in the UK with a publication in 2004. The latest, much larger, study on the subject from Michigan shows a 10% rate of difficult intubations and a 4.2% rate of airway complications.

BACKGROUND: There are limited outcome data regarding emergent nonoperative intubation. The current study was undertaken with a large observational dataset to evaluate the incidence of difficult intubation and complication rates and to determine predictors of complications in this setting.
METHODS: Adult nonoperating room emergent intubations at our tertiary care institution from December 5, 2001 to July 6, 2009 were reviewed. Prospectively defined data points included time of day, location, attending physician presence, number of attempts, direct laryngoscopy view, adjuvant use, medications, and complications. At our institution, a senior resident with at least 24 months of anesthesia training is the first responder for all emergent airway requests. The primary outcome was a composite airway complication variable that included aspiration, esophageal intubation, dental injury, or pneumothorax.
RESULTS: A total of 3,423 emergent nonoperating room airway management cases were identified. The incidence of difficult intubation was 10.3%. Complications occurred in 4.2%: aspiration, 2.8%; esophageal intubation, 1.3%; dental injury, 0.2%; and pneumothorax, 0.1%. A bougie introducer was used in 12.4% of cases. Among 2,284 intubations performed by residents, independent predictors of the composite complication outcome were as follows: three or more intubation attempts (odds ratio, 6.7; 95% CI, 3.2-14.2), grade III or IV view (odds ratio, 1.9; 95% CI, 1.1-3.5), general care floor location (odds ratio, 1.9; 95% CI, 1.2-3.0), and emergency department location (odds ratio, 4.7; 95% CI, 1.1-20.4).
CONCLUSIONS: During emergent nonoperative intubation, specific clinical situations are associated with an increased risk of airway complication and may provide a starting point for allocation of experienced first responders.

3,423 emergency tracheal intubations at a university hospital: airway outcomes and complications.
Anesthesiology. 2011 Jan;114(1):42-8

Anaesthesia's dirty laundry – let's all learn from it

NAP4 is here! Is that good? Yes. Why? Because it’s the long awaited 4th National Audit Project of the Royal College of Anaesthetists and the Difficult Airway Society in the United Kingdom – a multi-phase national survey that was designed to answer the questions;

  • What types of airway device are used during anaesthesia and how often?
  • How often do major complications, leading to serious harm, occur in association with airway management in anaesthesia, in the intensive care units and in the emergency departments of the UK?
  • What is the nature of these events and what can we learn from them, in order to reduce their frequency and consequences?

The Audit identified 33 deaths and 46 cases of death or brain damage as a result of airway complications during anaesthesia, in ICU and the emergency department over a one year period in the four countries of the United Kingdom.

Some major findings include:

  • Poor planning contributed to poor airway outcomes – often a failure to plan for failure.
  • The project identified numerous cases where awake fibreoptic intubation (afoi) was indicated but was not used. A lack of suitable equipment was prevalent on ICU.
  • Problems arose when difficult intubation was managed by multiple repeat attempts at intubation.
  • Events were reported where supraglottic airway devices (SAD) were used inappropriately. Patients who were markedly obese, often managed by junior trainees, were prominent in the group of patients who sustained non-aspiration events. Numerous cases of aspiration occurred during use of a first generation SAD in patients who had multiple risk factors for aspiration and in several in whom the aspiration risk was so high that rapid sequence induction, should have been used.
  • The proportion of obese patients in case reports submitted to NAP4 was twice that in the general population
  • When rescue techniques were necessary in obese patient they failed more often than in the non-obese.

Here’s my favourite bit so far – in keeping with what the literature has already told us about this technique:

There was a high failure rate of emergency cannula cricothyroidotomy, approximately 60%. There were numerous mechanisms of failure and the root cause was not determined; equipment, training, insertion technique and ventilation technique all led to failure. In contrast a surgical technique for emergency surgical airway was almost universally successful. The technique of cannula cricothyroidotomy needs to be taught and performed to the highest standards to maximise the chances of success, but the possibility that it is intrinsically inferior to a surgical technique should also be considered. Anaesthetists should be trained to perform a surgical airway.

  • failure to correctly interpret a capnograph trace led to several oesophageal intubations going unrecognised in anaesthesia. A flat capnograph trace indicates lack of ventilation of the lungs: the tube is either not in the trachea or the airway is completely obstructed. Active efforts should be taken to positively exclude these diagnoses. This applies equally in cardiac arrest as CPR leads to an attenuated but visible expired carbon dioxide trace.
  • at least one in four major airway events reported to NAP4 was from ICU or the emergency department. The outcome of these events was more likely to lead to permanent harm or death than events in anaesthesia. Analysis of the cases identified gaps in care that included: poor identification of at-risk patients, poor or incomplete planning, inadequate provision of skilled staff and equipment to manage these events successfully, delayed recognition of events and failed rescue due to lack of or failure of interpretation of capnography. The project findings suggest avoidable deaths due to airway complications occur in ICU and the emergency department.


  • failure to use capnography in ventilated patients likely contributed to more than 70% of ICU related deaths. Increasing use of capnography on ICU is the single change with the greatest potential to prevent deaths such as those reported to NAP4.
  • Displaced tracheostomy, and to a lesser extent displaced tracheal tubes, were the greatest cause of major morbidity and mortality in ICU. Obese patients were at particular risk of such events and adverse outcome from them. All patients on ICU should have an emergency re-intubation plan.


  • Most events in the emergency department were complications of rapid sequence induction. This was also an area of concern in ICU. RSI outside the operating theatre requires the same level of equipment and support as is needed during anaesthesia. This includes capnography and access for equipment needed to manage routine and difficult airway problems.

These are just snippets – there is much more in the report, and I’m still going through it.
The Executive Summary and all other Sections of NAP4 can be downloaded here from the Royal College of Anaesthetists