Tag Archives: critical care

Acute Med, All Updates, ICU, Resus

Hyperglycaemia & mortality in sepsis – lactate dependent?

Leave a comment

I like this paper for introducing a new concept to me. For years the critical care community has recognised the link between hyperglycaemia and mortality, leading to early recommendations of intensive insulin regimens subsequently shown not to be of benefit. Now it appears that the association between hyperglycaemia and mortality may be less relevant in patients with a normal lactate.
In a study of adult nondiabetic critically ill patients, hyperglycaemia had a significant association with increased mortality risk using simple univariate analysis. When they adjusted for concurrent hyperlactataemia however, hyperglycaemia was not significantly associated with increased mortality risk.
The authors discuss several known or postulated aspects of interplay between lactate and glucose in sepsis:

  • Hyperlactataemia appears to inhibit glucose uptake by muscle cells and decrease activity of the GLUT-4 transporters
  • Hyperlactataemia has also been shown to increase insulin resistance directly
  • Glucose and lactate levels tend to be elevated simultaneously in severe sepsis at baseline.
  • Experimentally it has been estimated that 45% of infused (radiolabelled) lactate is either converted into glucose via gluconeogenesis or is transformed into glycogen via the Cori cycle, representing a higher proportion of glucose formation from lactate than in nonseptic controls.
  • It is possible that elevated glucose and lactate levels in sepsis both may be measures of the same phenomenon: glucose accumulates due to the sympathomimetic response to a systemic infection with increased catecholamine levels leading to increased activity of the Na+K+-ATPase, resulting in accumulation of adenosine diphosphate (ADP). Increased levels of ADP in turn augment glycogenolysis.
  • Mitochondrial metabolism cannot meet the increased cellular energy needs of sepsis, resulting in accumulation of ADP and leading to cytosolic glycolysis and lactate production, even in an aerobic environment.

The augmented glycolysis of sepsis (and during adrenergic therapy such as epinephrine/adrenaline or albuterol/salbutamol) is one of the causes of a raised lactate to consider when applying the LACTATES mnemonic I like to use.
Hyperlactatemia affects the association of hyperglycemia with mortality in nondiabetic adults with sepsis
Acad Emerg Med. 2012 Nov;19(11):1268-75
[EXPAND Click for abstract]


BACKGROUND: Admission hyperglycemia has been reported as a mortality risk factor for septic nondiabetic patients; however, hyperglycemia’s known association with hyperlactatemia was not addressed in these analyses.

OBJECTIVES: The objective was to determine whether the association of hyperglycemia with mortality remains significant when adjusted for concurrent hyperlactatemia.

METHODS: This was a post hoc, nested analysis of a retrospective cohort study performed at a single center. Providers had identified study subjects during their emergency department (ED) encounters; all data were collected from the electronic medical record (EMR). Nondiabetic adult ED patients hospitalized for suspected infection, two or more systemic inflammatory response syndrome (SIRS) criteria, and simultaneous lactate and glucose testing in the ED were enrolled. The setting was the ED of an urban teaching hospital from 2007 to 2009. To evaluate the association of hyperglycemia (glucose > 200 mg/dL) with hyperlactatemia (lactate ≥ 4.0 mmol/L), a logistic regression model was created. The outcome was a diagnosis of hyperlactatemia, and the primary variable of interest was hyperglycemia. A second model was created to determine if coexisting hyperlactatemia affects hyperglycemia’s association with mortality; the main outcome was 28-day mortality, and the primary risk variable was hyperglycemia with an interaction term for simultaneous hyperlactatemia. Both models were adjusted for demographics; comorbidities; presenting infectious source; and objective evidence of renal, respiratory, hematologic, or cardiovascular dysfunction.

RESULTS: A total of 1,236 ED patients were included, and the median age was 77 years (interquartile range [IQR] = 60 to 87 years). A total of 115 (9.3%) subjects were hyperglycemic, 162 (13%) were hyperlactatemic, and 214 (17%) died within 28 days of their initial ED visits. After adjustment, hyperglycemia was significantly associated with simultaneous hyperlactatemia (odds ratio [OR] = 4.14, 95% confidence interval [CI] = 2.65 to 6.45). Hyperglycemia and concurrent hyperlactatemia were associated with increased mortality risk (OR = 3.96, 95% CI = 2.01 to 7.79), but hyperglycemia in the absence of simultaneous hyperlactatemia was not (OR = 0.78, 95% CI = 0.39 to 1.57).

CONCLUSIONS: In this cohort of septic adult nondiabetic patients, mortality risk did not increase with hyperglycemia unless associated with simultaneous hyperlactatemia. The previously reported association of hyperglycemia with mortality in nondiabetic sepsis may be due to the association of hyperglycemia with hyperlactatemia.

[/EXPAND]

All Updates, ICU, PHARM, Resus, Ultrasound

Echo for cardiac arrest outcome prediction

Leave a comment

A meta-analysis of studies evaluation transthoracic echo as a means of predicting return of spontaneous circulation in cardiac arrest (ROSC) provides some likelihood ratios to what we already know: absence of sonographic cardiac activity means a very low chance of ROSC.

The authors report a pooled negative LR of 0.18 (95% CI = 0.10 to 0.31), and a positive likelihood ratio of 4.26 (95% CI = 2.63 to 6.92).

They conclude that focused transthoracic echo is a fairly effective (although not definitive) test for predicting death if no cardiac activity is noted during resuscitation, and recommend interpreting the echo in the light of the test characteristics and the clinical pre-test probability, as one should do for all imaging investigations:


“An elderly patient with an unwitnessed cardiac arrest already has very poor odds for survival. Confirmation of asystole on echo lowers those pretest odds by a factor of 5.6 and therefore might lead to termination of resuscitation. However, in the case of a 50-year-old rescued from drowning, detection of cardiac contractility on echo would increase his already fair odds of survival by a factor of 4.3, prompting continued aggressive resuscitation.”

Only five relatively small studies contributed to the findings. A more definitive answer to this question should be provided in the future by the multi-centre REASON 1 trial.

Objectives:  The objective was to determine if focused transthoracic echocardiography (echo) can be used during resuscitation to predict the outcome of cardiac arrest.

Methods:  A literature search of diagnostic accuracy studies was conducted using MEDLINE via PubMed, EMBASE, CINAHL, and Cochrane Library databases. A hand search of references was performed and experts in the field were contacted. Studies were included for further appraisal and analysis only if the selection criteria and reference standards were met. The eligible studies were appraised and scored by two independent reviewers using a modified quality assessment tool for diagnostic accuracy studies (QUADAS) to select the papers included in the meta-analysis.

Results:  The initial search returned 2,538 unique papers, 11 of which were determined to be relevant after screening criteria were applied by two independent researchers. One additional study was identified after the initial search, totaling 12 studies to be included in our final analysis. The total number of patients in these studies was 568, all of whom had echo during resuscitation efforts to determine the presence or absence of kinetic cardiac activity and were followed up to determine return of spontaneous circulation (ROSC). Meta-analysis of the data showed that as a predictor of ROSC during cardiac arrest, echo had a pooled sensitivity of 91.6% (95% confidence interval [CI] = 84.6% to 96.1%), and specificity was 80.0% (95% CI = 76.1% to 83.6%). The positive likelihood ratio for ROSC was 4.26 (95% CI = 2.63 to 6.92), and negative likelihood ratio was 0.18 (95% CI = 0.10 to 0.31). Heterogeneity of the results (sensitivity) was nonsignificant (Cochran’s Q: χ(2) = 10.63, p = 0.16, and I(2) = 34.1%).

Conclusions:  Echocardiography performed during cardiac arrest that demonstrates an absence of cardiac activity harbors a significantly lower (but not zero) likelihood that a patient will experience ROSC. In selected patients with a higher likelihood of survival from cardiac arrest at presentation, based on established predictors of survival, echo should not be the sole basis for the decision to cease resuscitative efforts. Echo should continue to be used only as an adjunct to clinical assessment in predicting the outcome of resuscitation for cardiac arrest.

Bedside Focused Echocardiography as Predictor of Survival in Cardiac Arrest Patients: A Systematic Review
Acad Emerg Med. 2012 Oct;19(10):1119-1126

Acute Med, All Updates, ICU, Kids, Resus

Etomidate & sepsis

Leave a comment

A meta-analysis attempts to quantify etomidate’s effect on mortality and adrenal suppression. Of course, we all know a meta-analysis can only be as reliable as the original data it’s analysing. I think editorialists Lauzier and Turgeon have a point with their statement:

“Given the widespread use of etomidate in the emergency room, we believe that a RCT designed to evaluate the safety of etomidate as a hypnotic agent for endotracheal intubation of patients with sepsis is not only ethical but also urgently warranted”

For a critique of the paper and subsequent discussion, check out the Academic Life in EM blog post by Brian Hayes


OBJECTIVE: To evaluate the effects of single-dose etomidate on the adrenal axis and mortality in patients with severe sepsis and septic shock.

DESIGN: A systematic review of randomized controlled trials and observational studies with meta-analysis.

SETTING: Literature search of EMBASE, Medline, Cochrane Database, and Evidence-Based Medical Reviews.

SUBJECTS: Sepsis patients who received etomidate for rapid sequence intubation.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: We conducted a systematic review of randomized controlled trials and observational studies with meta-analysis assessing the effects of etomidate on adrenal insufficiency and all-cause mortality published between January 1950 and February 2012. We only examined studies including septic patients. All-cause mortality served as our primary end point, whereas the prevalence of adrenal insufficiency was our secondary end point. Adrenal insufficiency was determined using a cosyntropin stimulation test in all studies. We used a random effects model for analysis; heterogeneity was assessed with the I statistic. Publication bias was evaluated with Begg’s test. Five studies were identified that assessed mortality in those who received etomidate. A total of 865 subjects were included. Subjects who received etomidate were more likely to die (pooled relative risk 1.20; 95% confidence interval 1.02-1.42; Q statistic, 4.20; I2 statistic, 4.9%). Seven studies addressed the development of adrenal suppression associated with the administration of etomidate; 1,303 subjects were included. Etomidate administration increased the likelihood of developing adrenal insufficiency (pooled relative risk 1.33; 95% confidence interval 1.22-1.46; Q statistic, 10.7; I2 statistic, 43.9%).

CONCLUSIONS: Administration of etomidate for rapid sequence intubation is associated with higher rates of adrenal insufficiency and mortality in patients with sepsis.

Etomidate is associated with mortality and adrenal insufficiency in sepsis: A meta-analysis Crit Care Med. 2012 Nov;40(11):2945-53

Acute Med, All Updates, ICU, Resus

Not just in ARDS

Leave a comment

A ‘lung protective’ ventilation strategy that includes low tidal volumes has been shown to improve outcomes in patients with ARDS. Many also advocate it as sensible practice for any ventilated patient as a means of minimising the chances of ventilator-induced lung injury and hopefully improving outcome. A recent meta-analysis provides further evidence to support that recommendation:


Context Lung-protective mechanical ventilation with the use of lower tidal volumes has been found to improve outcomes of patients with acute respiratory distress syndrome (ARDS). It has been suggested that use of lower tidal volumes also benefits patients who do not have ARDS.

Objective To determine whether use of lower tidal volumes is associated with improved outcomes of patients receiving ventilation who do not have ARDS.

Data Sources MEDLINE, CINAHL, Web of Science, and Cochrane Central Register of Controlled Trials up to August 2012.

Study Selection Eligible studies evaluated use of lower vs higher tidal volumes in patients without ARDS at onset of mechanical ventilation and reported lung injury development, overall mortality, pulmonary infection, atelectasis, and biochemical alterations.

Data Extraction Three reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus.

Data Synthesis Twenty articles (2822 participants) were included. Meta-analysis using a fixed-effects model showed a decrease in lung injury development (risk ratio [RR], 0.33; 95% CI, 0.23 to 0.47; I2, 0%; number needed to treat [NNT], 11), and mortality (RR, 0.64; 95% CI, 0.46 to 0.89; I2, 0%; NNT, 23) in patients receiving ventilation with lower tidal volumes. The results of lung injury development were similar when stratified by the type of study (randomized vs nonrandomized) and were significant only in randomized trials for pulmonary infection and only in nonrandomized trials for mortality. Meta-analysis using a random-effects model showed, in protective ventilation groups, a lower incidence of pulmonary infection (RR, 0.45; 95% CI, 0.22 to 0.92; I2, 32%; NNT, 26), lower mean (SD) hospital length of stay (6.91 [2.36] vs 8.87 [2.93] days, respectively; standardized mean difference [SMD], 0.51; 95% CI, 0.20 to 0.82; I2, 75%), higher mean (SD) PaCO2 levels (41.05 [3.79] vs 37.90 [4.19] mm Hg, respectively; SMD, −0.51; 95% CI, −0.70 to −0.32; I2, 54%), and lower mean (SD) pH values (7.37 [0.03] vs 7.40 [0.04], respectively; SMD, 1.16; 95% CI, 0.31 to 2.02; I2, 96%) but similar mean (SD) ratios of PaO2 to fraction of inspired oxygen (304.40 [65.7] vs 312.97 [68.13], respectively; SMD, 0.11; 95% CI, −0.06 to 0.27; I2, 60%). Tidal volume gradients between the 2 groups did not influence significantly the final results.

Conclusions Among patients without ARDS, protective ventilation with lower tidal volumes was associated with better clinical outcomes. Some of the limitations of the meta-analysis were the mixed setting of mechanical ventilation (intensive care unit or operating room) and the duration of mechanical ventilation.

Association Between Use of Lung-Protective Ventilation With Lower Tidal Volumes and Clinical Outcomes Among Patients Without Acute Respiratory Distress Syndrome – A Meta-analysis
JAMA. 2012;308(16):1651-1659

All Updates, ICU, Kids, PHARM, Resus

Don't bronchodilators work in infants?

Leave a comment

Inpatient paediatric teams can be scornful when bronchodilators are given by ED staff to wheezing infants, correctly referring to the lack of evidence of clinical benefit(1). There is however a persisting meme out there I’ve heard on a number of occasions that ‘young infants don’t have the receptors so inhaled beta agonists will never work.’ I’d love to know where this comes from.
Apparently, beta 2-receptors are present from the 16th gestational week(2). Pulmonary function testing of ventilated, very-low-birth-weight babies has shown that some consistently responded to beta-agonists whereas others did not(3). A newly published study reports that a quarter of mechanically ventilated infants with bronchiolitis were responders to inhaled albuterol, defined as a reduction in respiratory system resistance more than 30% below baseline(4).
In summary: beta-agonist bronchodilators have not been shown to improve clinical outcomes in wheezing infants. However some infants with some wheezing disorders will show a response in terms of pulmonary function. The receptors are there, and in life-threatening presentations bronchodilators should certainly be considered.
1. Short acting beta agonists for recurrent wheeze in children under 2 years of age
Cochrane Database Syst Rev. 2002;(3):CD002873
[EXPAND Click to read abstract]


BACKGROUND: Wheeze is a common symptom in infancy and is a common cause for both primary care consultations and hospital admission. Beta2-adrenoceptor agonists (b2-agonists) are the most frequently used as bronchodilator but their efficacy is questionable.
OBJECTIVES: To determine the effectiveness of b2-agonist for the treatment of infants with recurrent and persistent wheeze.
SEARCH STRATEGY: Relevant trials were identified using the Cochrane Airways Group database (CENTRAL), Medline and Pubmed. The database search used the following terms: Wheeze or asthma and Infant or Child and Short acting beta-agonist or Salbutamol (variants), Albuterol, Terbutaline (variants), Orciprenaline, Fenoterol

SELECTION CRITERIA: Randomised controlled trials comparing the effect of b2-agonist against placebo in children under 2 years of age who had had two or more previous episodes of wheeze, not related to another form of chronic lung disease.
DATA COLLECTION AND ANALYSIS: Eight studies met the criteria for inclusion in this meta-analysis. The studies investigated patients in three settings: at home (3 studies), in hospital (2 studies) and in the pulmonary function laboratory (3 studies). The main outcome measure was change in respiratory rate except for community based studies where symptom scores were used.

MAIN RESULTS: The studies were markedly heterogeneous and between study comparisons were limited. Improvement in respiratory rate, symptom score and oxygen saturation were noted in one study in the emergency department following two salbutamol nebulisers but this had no impact on hospital admission. There was a reduction in bronchial reactivity following salbutamol. There was no significant benefit from taking regular inhaled salbutamol on symptom scores recorded at home.

REVIEWER’S CONCLUSIONS: There is no clear benefit of using b2-agonists in the management of recurrent wheeze in the first two years of life although there is conflicting evidence. At present, further studies should only be performed if the patient group can be clearly defined and there is a suitable outcome parameter capable of measuring a response.

[/EXPAND]
2. The beta-2-agonists in asthma in infants and young children
Arch Pediatr. 2002 Aug;9 Suppl 3:384s-389s
[EXPAND Click to read abstract]


Beta 2-agonists, by inducing a fast and long relaxation of the bronchial smooth muscle, are considered as the more potent bronchodilators. beta 2-receptors are present from the 16th gestational week, explaining a possible bronchial response in the youngest children. beta 2-agonists do not induce any bronchodilator response in healthy children. Short-acting beta 2-agonists (salbutamol or albuterol, terbutaline) are indicated for asthma attacks, as needed in chronic asthma, and for prevention of symptoms during effort. They are safe and secure. The more efficient route of administration in preschool children is pressurized metered-dose inhaler used with a spacer device. Therefore, whatever the route of inhalation chosen (inhalation, injection, or continuous nebulization in acute asthma attack), more specified indications and doses are needed in young children. Long-acting beta 2-agonists (formoterol, salmeterol) are not authorized in France in children under 4 to 5 years of age depending on the drug used. Because of new oral formulations and recent considerations about their use in asthma attack, instead of short-acting beta 2-agonists, their indication in preschool asthmatic children might be reconsidered.

[/EXPAND]
3. Use of a beta-agonist in ventilated, very-low-birth-weight babies: a longitudinal evaluation
Dev Pharmacol Ther. 1990;15(2):61-7
[EXPAND Click to read abstract]


To determine if there is a specific postnatal (PNA) or postconceptional age (PCA) at which ventilated preterm infants respond to beta-agonists, we evaluated 15 infants with a mean gestational age of 26.5 +/- 1.5 weeks and mean birth weight of 0.89 +/- 0.23 kg who required mechanical ventilation at 10 days of age. Weekly pulmonary function testing (PFT) was performed before and 1 h after administration of albuterol. Taking the group as a whole, as well as individual babies, regression analysis showed no relationship between positive response and either PNA or PCA. Evaluation of individual infants, however, showed that some consistently responded to beta-agonists whereas others did not. We recommend individual PFT to identify those infants who will benefit from use of beta-agonists.

[/EXPAND]
4. Pulmonary mechanics following albuterol therapy in mechanically ventilated infants with bronchiolitis
J Asthma. 2012 Sep;49(7):688-96
[EXPAND Click to read abstract]


BACKGROUND AND AIMS: Bronchiolitis is a common cause of critical illness in infants. Inhaled β(2)-agonist bronchodilators are frequently used as part of treatment, despite unproven effectiveness. The purpose of this study was to describe the physiologic response to these medications in infants intubated and mechanically ventilated for bronchiolitis.

MATERIALS AND METHODS: We conducted a prospective trial of albuterol treatment in infants intubated and mechanically ventilated for bronchiolitis. Before and for 30 minutes following inhaled albuterol treatment, sequential assessments of pulmonary mechanics were determined using the interrupter technique on repeated consecutive breaths.

RESULTS: Fifty-four infants were enrolled. The median age was 44 days (25-75%; interquartile range (IQR) 29-74 days), mean hospital length of stay (LOS) was 18.3 ± 13.3 days, mean ICU LOS was 11.3 ± 6.4 days, and mean duration of mechanical ventilation was 8.5 ± 3.5 days. Fifty percent (n = 27) of the infants were male, 81% (n = 44) had public insurance, 80% (n = 41) were Caucasian, and 39% (n = 21) were Hispanic. Fourteen of the 54 (26%) had reduction in respiratory system resistance (Rrs) that was more than 30% below baseline, and were defined as responders to albuterol. Response to albuterol was not associated with demographic factors or hospitalization outcomes such as LOS or duration of mechanical ventilation. However, increased Rrs, prematurity, and non-Hispanic ethnicity were associated with increased LOS.

CONCLUSIONS: In this population of mechanically ventilated infants with bronchiolitis, relatively few had a reduction in pulmonary resistance in response to inhaled albuterol therapy. This response was not associated with improvements in outcomes.

[/EXPAND]

Acute Med, All Updates, ICU, Resus

Hydroxyethyl Starch vs Saline

Leave a comment

Another nail in the coffin of starch solutions for critical care patients was banged in by Prof Myburgh and colleagues who published the results of the CHEST randomised trial this week(1). 7000 Australasian ICU patients received either 6% HES (130/0.4) in 0.9% saline (HES group) or 0.9% saline (saline group). There was no difference in mortality but there was more renal dysfunction, rash, and pruritis in the HES group.
This can be combined with another recent starch vs crystalloid paper demonstrating adverse outcomes from starch(2) to make the case that there is no role for these pharmaceuticals in resuscitation or critical care.
1. Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care
N Engl J Med. 2012 Oct 17. [Epub ahead of print] Free Full Text
[EXPAND Click for abstract]


Background The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported.

Methods We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy.

Results A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001).

Conclusions In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy

[/EXPAND]
2. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis
N Engl J Med. 2012 Jul 12;367(2):124-34
[EXPAND Click for abstract]


BACKGROUND: Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.

METHODS: In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer’s acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization.

RESULTS: Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer’s acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer’s acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.

CONCLUSIONS: Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer’s acetate.

[/EXPAND]

Acute Med, All Updates, ICU, PHARM, Resus

What's with all the chloride? An assault on salt

Leave a comment

I continue to be bewildered at my ED colleagues’ overwhelming preference for 0.9% saline as a resuscitation fluid regardless of clinical presentation. However, I have to acknowledge a lack of robust high level clinical evidence demonstrating its relative harm compared with more balanced solutions such as Hartmann’s / Ringer’s lactate or one of the more scarcely available Plasma-Lyte solutions.
Human and animal studies have demonstrated that saline exacerbates hyperchloraemia and metabolic acidosis and has renal effects including renal vasoconstriction and decreased glomerular filtration rate. A large observational study on surgical patients suggested that saline therapy increases the risk of patients requiring acute dialysis compared with Plasma-Lyte administration(1).
A new study in JAMA provides some further clinical evidence that saline has harmful renal effects(2). It was a before-and-after observational study, in which the change was a restriction in chloride-rich fluids so that they were made available only after prescription by the attending specialist for specific conditions (eg, hyponatraemia, traumatic brain injury, and cerebral oedema). Four of the authors published another study on the metabolic effects of this changed fluid strategy, presumably on the same or an overlapping cohort of patients, which I blogged about here.
Significant findings were that the chloride-restrictive strategy was associated with a significantly lower increase in serum creatinine level during ICU stay, a decrease in the incidence of renal injury and failure (according to the RIFLE definitions), and a decrease in renal replacement therapy. These effects persisted after adjusting for known contributors to acute kidney injury.
As this is not a randomised trial cause and effect cannot be assumed, but this is consistent with other work.
In summary, keep pushing the saline if you want to increase your patients’ risk of acute kidney injury and the need for dialysis, whilst rendering them acidotic. You may even decrease their gut perfusion(3) and give them abdominal discomfort and subjective decreased cognitive ability(4). Alternatively, give Hartmann’s / Ringer’s lactate… although bear in mind that might not be such a good choice in the context of hyponatraemia, alkalaemia, cerebral oedema, or traumatic brain injury.
1. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte
Ann Surg. 2012 May;255(5):821-9
[EXPAND Click for abstract]


OBJECTIVE: To assess the association of 0.9% saline use versus a calcium-free physiologically balanced crystalloid solution with major morbidity and clinical resource use after abdominal surgery.

BACKGROUND: 0.9% saline, which results in a hyperchloremic acidosis after infusion, is frequently used to replace volume losses after major surgery.

METHODS: An observational study using the Premier Perspective Comparative Database was performed to evaluate adult patients undergoing major open abdominal surgery who received either 0.9% saline (30,994 patients) or a balanced crystalloid solution (926 patients) on the day of surgery. The primary outcome was major morbidity and secondary outcomes included minor complications and acidosis-related interventions. Outcomes were evaluated using multivariable logistic regression and propensity scoring models.

RESULTS: For the entire cohort, the in-hospital mortality was 5.6% in the saline group and 2.9% in the balanced group (P < 0.001). One or more major complications occurred in 33.7% of the saline group and 23% of the balanced group (P < 0.001). In the 3:1 propensity-matched sample, treatment with balanced fluid was associated with fewer complications (odds ratio 0.79; 95% confidence interval 0.66-0.97). Postoperative infection (P = 0.006), renal failure requiring dialysis (P < 0.001), blood transfusion (P < 0.001), electrolyte disturbance (P = 0.046), acidosis investigation (P < 0.001), and intervention (P = 0.02) were all more frequent in patients receiving 0.9% saline.

CONCLUSIONS: Among hospitals in the Premier Perspective Database, the use of a calcium-free balanced crystalloid for replacement of fluid losses on the day of major surgery was associated with less postoperative morbidity than 0.9% saline.

[/EXPAND]
2. Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults
JAMA. 2012 Oct 17;308(15):1566-72
[EXPAND Click for abstract]


CONTEXT: Administration of traditional chloride-liberal intravenous fluids may precipitate acute kidney injury (AKI).

OBJECTIVE: To assess the association of a chloride-restrictive (vs chloride-liberal) intravenous fluid strategy with AKI in critically ill patients.

DESIGN, SETTING, AND PATIENTS: Prospective, open-label, sequential period pilot study of 760 patients admitted consecutively to the intensive care unit (ICU) during the control period (February 18 to August 17, 2008) compared with 773 patients admitted consecutively during the intervention period (February 18 to August 17, 2009) at a university-affiliated hospital in Melbourne, Australia.

INTERVENTIONS: During the control period, patients received standard intravenous fluids. After a 6-month phase-out period (August 18, 2008, to February 17, 2009), any use of chloride-rich intravenous fluids (0.9% saline, 4% succinylated gelatin solution, or 4% albumin solution) was restricted to attending specialist approval only during the intervention period; patients instead received a lactated solution (Hartmann solution), a balanced solution (Plasma-Lyte 148), and chloride-poor 20% albumin.

MAIN OUTCOME MEASURES: The primary outcomes included increase from baseline to peak creatinine level in the ICU and incidence of AKI according to the risk, injury, failure, loss, end-stage (RIFLE) classification. Secondary post hoc analysis outcomes included the need for renal replacement therapy (RRT), length of stay in ICU and hospital, and survival.

RESULTS Chloride administration decreased by 144 504 mmol (from 694 to 496 mmol/patient) from the control period to the intervention period. Comparing the control period with the intervention period, the mean serum creatinine level increase while in the ICU was 22.6 μmol/L (95% CI, 17.5-27.7 μmol/L) vs 14.8 μmol/L (95% CI, 9.8-19.9 μmol/L) (P = .03), the incidence of injury and failure class of RIFLE-defined AKI was 14% (95% CI, 11%-16%; n = 105) vs 8.4% (95% CI, 6.4%-10%; n = 65) (P < .001), and the use of RRT was 10% (95% CI, 8.1%-12%; n = 78) vs 6.3% (95% CI, 4.6%-8.1%; n = 49) (P = .005). After adjustment for covariates, this association remained for incidence of injury and failure class of RIFLE-defined AKI (odds ratio, 0.52 [95% CI, 0.37-0.75]; P < .001) and use of RRT (odds ratio, 0.52 [95% CI, 0.33-0.81]; P = .004). There were no differences in hospital mortality, hospital or ICU length of stay, or need for RRT after hospital discharge.
CONCLUSION The implementation of a chloride-restrictive strategy in a tertiary ICU was associated with a significant decrease in the incidence of AKI and use of RRT.

[/EXPAND]
3. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients
Anesth Analg. 2001 Oct;93(4):811-6
Free full text
[EXPAND Click for abstract]


The IV administration of sodium chloride solutions may produce a metabolic acidosis and gastrointestinal dysfunction. We designed this trial to determine whether, in elderly surgical patients, crystalloid and colloid solutions with a more physiologically balanced electrolyte formulation, such as Hartmann’s solution and Hextend, can provide a superior metabolic environment and improved indices of organ perfusion when compared with saline-based fluids. Forty-seven elderly patients undergoing major surgery were randomly allocated to one of two study groups. Patients in the Balanced Fluid group received an intraoperative fluid regimen that consisted of Hartmann’s solution and 6% hetastarch in balanced electrolyte and glucose injection (Hextend). Patients in the Saline group were given 0.9% sodium chloride solution and 6% hetastarch in 0.9% sodium chloride solution (Hespan). Biochemical indices and acid-base balance were determined. Gastric tonometry was used as a reflection of splanchnic perfusion. Postoperative chloride levels demonstrated a larger increase in the Saline group than the Balanced Fluid group (9.8 vs 3.3 mmol/L, P = 0.0001). Postoperative standard base excess showed a larger decline in the Saline group than the Balanced Fluid group (-5.5 vs -0.9 mmol/L, P = 0.0001). Two-thirds of patients in the Saline group, but none in the Balanced Fluid group, developed postoperative hyperchloremic metabolic acidosis (P = 0.0001). Gastric tonometry indicated a larger increase in the CO2 gap during surgery in the Saline group compared with the Balanced Fluid group (1.7 vs 0.9 kPa, P = 0.0394). In this study, the use of balanced crystalloid and colloid solutions in elderly surgical patients prevented the development of hyperchloremic metabolic acidosis and resulted in improved gastric mucosal perfusion when compared with saline-based solutions.
IMPLICATIONS: This prospective, randomized, blinded trial showed that, in elderly surgical patients, the use of balanced IV solutions can prevent the development of hyperchloremic metabolic acidosis and provide better gastric mucosal perfusion compared with saline-based fluids.

[/EXPAND]
4. The effect of intravenous lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers.
Anesth Analg. 1999 May;88(5):999-1003
Free full text
[EXPAND Click for abstract]


Animal studies have shown that large volumes of IV lactated Ringer’s solution (LR) decrease serum osmolality, thereby increasing cerebral water. These studies have led to recommendations to limit LR to avoid cerebral edema in neurosurgical patients. Eighteen healthy human volunteers aged 20-48 yr received 50 mL/kg LR over 1 h on one occasion and 0.9% sodium chloride (NS) on another. Venous samples were taken at baseline (T1), at infusion end (T2), and 1 h after T2 (T3). Time until first urination was noted. With LR, serum osmolality decreased by 4+/-3 mOsm/kg from T1 to T2 and increased insignificantly with NS. At T3, osmolality returned almost to baseline in the LR group. Blood pH increased from T1 to T2 with LR by 0.04+/-0.04 and decreased with NS by 0.04+/-0.04. These pH changes persisted at T3. Subjective mental changes occurred only with NS. Abdominal discomfort was more common with NS. Time until first urination was longer with NS (106+/-11 min) than with LR (75+/-10 min) (P < 0.001). In healthy humans, an infusion of large volumes of LR, but not NS, transiently decreased serum osmolality, whereas acidosis associated with NS persisted and urinary output was slower with NS.
IMPLICATIONS: Large volumes of lactated Ringer’s solution administered to healthy humans produced small transient changes in serum osmolality. Large volumes of sodium chloride did not change osmolality but resulted in lower pH.

[/EXPAND]

Acute Med, All Updates, ICU

Infectious biomarkers in the critically ill

Leave a comment

A study examining patterns of procalcitonin in a group of critically ill patients(1) showed some interesting findings:

Shock was associated with higher procalcitonin values independent of the presence of infection

Procalcitonin (PCT) levels were less in patients who developed infections later during their ICU stay compared with those who had infections when admitted to ICU.

The accompanying editorial(2) reminds us about commonly used inflammatory biomarkers.

White blood cells are influenced by almost every inflammatory stimulus, rendering them unhelpful in the management of severely ill patients.

Daily monitoring of CRP levels can identify ICU-acquired infections early, and some prognostic information can be provided by how rapidly CRP levels respond to treatment.

PCT rises early in severe sepsis, mainly by pneumonia and bloodstream infections, and can reflect the severity of the systemic inflammatory response syndrome to infection. PCT is more specific than CRP for infection compared with non-infectious causes of systemic inflammatory response syndrome. However PCT can also be increased in noninfectious diseases such as acute pancreatitis and cardiogenic shock.

1. Longitudinal changes in procalcitonin in a heterogenous group of critically ill patients
Crit Care Med. 2012 Oct;40(10):2781-2787
[EXPAND Click for Abstract]


OBJECTIVE: The utility of procalcitonin for the diagnosis of infection in the critical care setting has been extensively investigated with conflicting results. Herein, we report procalcitonin values relative to baseline patient characteristics, presence of shock, intensive care unit time course, infectious status, and Gram stain of infecting organism.

DESIGN: Prospective, multicenter, observational study of critically ill patients admitted to intensive care unit for >24 hrs. SETTING:: Three tertiary care intensive care units.

PATIENTS: All consenting patients admitted to three mixed medical-surgical intensive care units. Patients who had elective surgery, overdoses, and who were expected to stay <24 hrs were excluded.

INTERVENTIONS: Patients were followed prospectively to ascertain the presence of prevalent (present at admission) or incident (developed during admission) infections and clinical outcomes. Procalcitonin levels were measured daily for 10 days and were analyzed as a function of the underlying patient characteristics, presence of shock, time of infection, and pathogen isolated.

MAIN RESULTS: Five hundred ninety-eight patients were enrolled. Medical and surgical infected cohorts had similar baseline procalcitonin values (3.0 [0.7-15.3] vs. 3.7 [0.6-9.8], p = .68) and peak procalcitonin (4.5 [1.0-22.9] vs. 5.0 [0.9-16.0], p = .91). Infected patients were sicker than their noninfected counterparts (Acute Physiology and Chronic Health Evaluation II 22.9 vs. 19.3, p < .001); those with infection at admission had a trend toward higher peak procalcitonin values than did those whose infection developed in the intensive care unit (4.9 vs. 1.4, p = .06). The presence of shock was significantly associated with elevations in procalcitonin in cohorts who were and were not infected (both groups p < .003 on days 1-5).

CONCLUSIONS: Procalcitonin dynamics were similar between surgical and medical cohorts. Shock had an association with higher procalcitonin values independent of the presence of infection. Trends in differences in procalcitonin values were seen in patients who had incident vs. prevalent infections.

[/EXPAND]
2. The many facets of procalcitonin in the critically ill population
Crit Care Med. 2012 Oct;40(10):2903-5

Acute Med, All Updates, ICU, Resus

More on the meaning of lactate values

Leave a comment

A newly published study(1) reminds us that we need to do better than just identify a raised lactate in patients with sepsis; we need to make sure it’s not increasing when they leave the ED (if we can). An incremental rise is associated with mortality.

The authors comment:


We found that the prognostic value of lactate continues to rise across a wide range of values, from 0 to 20 mmol/L…. These data suggest that grouping patients into less granular and larger groups, such as low, intermediate, and high, potentially underutilizes the prognostic value of the test. Furthermore, we did not find any value of lactate, up to a maximum value of 20 mmol/L, where mortality failed to increase with an increase in lactate concentration.

The paper does not state whether the lactate was arterial or venous, although either can be used. The Surviving Sepsis Campaign provides this comment:


In the course of the Campaign the question has been raised many times as to whether an arterial or venous lactate sample is appropriate. While there is no consensus of settled literature on this question, an elevated lactate of any variety is typically abnormal, although this may be influenced by other conditions..

This relationship between lactate trend and mortality has also been demonstrated in a study of all patients admitted to hospital (with or without sepsis), which also showed good correlation between arterial and venous lactate(2).

Lactate clearance has been shown to be an acceptable alternative to central venous oxygen saturation as a goal for therapy in ED severe sepsis patients(3), which is good because it provides one less reason for a central line.

Always remember the good emergency physician / critical care practitioner will consider other causes of a raised lactate, particularly when things don’t add up. I invented the ‘LACTATES’ acronym to help me remember them(4), and it’s come in handy several times.

Craving more info on lactate? Check out the EMCrit site with its great lactate reference sheet.

1. Prognostic Value of Incremental Lactate Elevations in Emergency Department Patients With Suspected Infection
Acad Emerg Med. 2012 Aug;19(8):983-5
[EXPAND Click for abstract]


Objectives:  Previous studies have confirmed the prognostic significance of lactate concentrations categorized into groups (low, intermediate, high) among emergency department (ED) patients with suspected infection. Although the relationship between lactate concentrations categorized into groups and mortality appears to be linear, the relationship between lactate as a continuous measurement and mortality is uncertain. This study sought to evaluate the association between blood lactate concentrations along an incremental continuum up to a maximum value of 20 mmol/L and mortality.

Methods:  This was a retrospective cohort analysis of adult ED patients with suspected infection from a large urban ED during 2007–2010. Inclusion criteria were suspected infection evidenced by administration of antibiotics in the ED and measurement of whole blood lactate in the ED. The primary outcome was in-hospital mortality. Logistic and polynomial regression were used to model the relationship between lactate concentration and mortality.

Results:  A total of 2,596 patients met inclusion criteria and were analyzed. The initial median lactate concentration was 2.1 mmol/L (interquartile range [IQR] = 1.3 to 3.3 mmol/L) and the overall mortality rate was 14.4%. In the cohort, 459 patients (17.6%) had initial lactate levels >4 mmol/L. Mortality continued to rise across the continuum of incremental elevations, from 6% for lactate <1.0 mmol/L up to 39% for lactate 19–20 mmol/L. Polynomial regression analysis showed a strong curvilinear correlation between lactate and mortality (R = 0.72, p < 0.0001).
Conclusions:  In ED patients with suspected infection, we found a curvilinear relationship between incremental elevations in lactate concentration and mortality. These data support the use of lactate as a continuous variable rather than a categorical variable for prognostic purposes.

[/EXPAND]
2. Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review
Scand J Trauma Resusc Emerg Med. 2011 Dec 28;19:74 Free Full Text
[EXPAND Click for abstract]


BACKGROUND: Using blood lactate monitoring for risk assessment in the critically ill patient remains controversial. Some of the discrepancy is due to uncertainty regarding the appropriate reference interval, and whether to perform a single lactate measurement as a screening method at admission to the hospital, or serial lactate measurements. Furthermore there is no consensus whether the sample should be drawn from arterial, peripheral venous, or capillary blood. The aim of this review was: 1) To examine whether blood lactate levels are predictive for in-hospital mortality in patients in the acute setting, i.e. patients assessed pre-hospitally, in the trauma centre, emergency department, or intensive care unit. 2) To examine the agreement between arterial, peripheral venous, and capillary blood lactate levels in patients in the acute setting.

METHODS: We performed a systematic search using PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL up to April 2011. 66 articles were considered potentially relevant and evaluated in full text, of these ultimately 33 articles were selected.

RESULTS AND CONCLUSION: The literature reviewed supported blood lactate monitoring as being useful for risk assessment in patients admitted acutely to hospital, and especially the trend, achieved by serial lactate sampling, is valuable in predicting in-hospital mortality. All patients with a lactate at admission above 2.5 mM should be closely monitored for signs of deterioration, but patients with even lower lactate levels should be considered for serial lactate monitoring. The correlation between lactate levels in arterial and venous blood was found to be acceptable, and venous sampling should therefore be encouraged, as the risk and inconvenience for this procedure is minimal for the patient. The relevance of lactate guided therapy has to be supported by more studies.

[/EXPAND]
3. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial
JAMA. 2010 Feb 24;303(8):739-46
[EXPAND Click for abstract]


CONTEXT: Goal-directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department.

OBJECTIVE: To test the hypothesis of noninferiority between lactate clearance and central venous oxygen saturation (ScvO2) as goals of early sepsis resuscitation.

DESIGN, SETTING, AND PATIENTS: Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals.

INTERVENTIONS: We randomly assigned patients to 1 of 2 resuscitation protocols. The ScvO2 group was resuscitated to normalize central venous pressure, mean arterial pressure, and ScvO2 of at least 70%; and the lactate clearance group was resuscitated to normalize central venous pressure, mean arterial pressure, and lactate clearance of at least 10%. The study protocol was continued until all goals were achieved or for up to 6 hours. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment.

MAIN OUTCOME MEASURE: The primary outcome was absolute in-hospital mortality rate; the noninferiority threshold was set at Delta equal to -10%.

RESULTS: Of the 300 patients enrolled, 150 were assigned to each group and patients were well matched by demographic, comorbidities, and physiological features. There were no differences in treatments administered during the initial 72 hours of hospitalization. Thirty-four patients (23%) in the ScvO2 group died while in the hospital (95% confidence interval [CI], 17%-30%) compared with 25 (17%; 95% CI, 11%-24%) in the lactate clearance group. This observed difference between mortality rates did not reach the predefined -10% threshold (intent-to-treat analysis: 95% CI for the 6% difference, -3% to 15%). There were no differences in treatment-related adverse events between the groups.

CONCLUSION: Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality.

[/EXPAND]
4. Non-septic hyperlactataemia in the emergency department
Emerg Med J. 2010 May;27(5):411-2

All Updates, ICU, PHARM, Resus

From BURP to BILP: backwards internal laryngeal pressure

Leave a comment

A burns patient whose tracheal tube was accidentally dislodged and ended up placed in the oesophagus on day 2 of his ICU stay continued to spontaneously ventilate and maintain saturations on a midazolam infusion. The oesophageal tube was left in during laryngoscopy (after propofol but no muscle relaxant due to anticipated difficult airway) which revealed a cormack-lehane grade 3 view. The operator’s hand which was holding a bougie rested on the oesophageal tube, which displaced it backwards. This resulted in backwards displacement of the larynx and improved the glottic view to 2b, facilitating intubation.
The discovery of this ‘backwards internal laryngeal pressure’ manoeuvre led the authors to make the recommendation that during difficult intubation an inadvertently placed oesophageal tube should be left in place to allow a BILP manouevre, but removed if it impedes the passage of the tracheal tube.
I love anything that might improve success rates of critical procedures and this one could conceivably come in handy. I can just see Minh Le Cong inventing a transoesophageal posterior laryngal retractor for under 50 bucks…
The use of “Internal Laryngeal Pressure” to improve the laryngeal view following inadvertent oesophageal intubation in a patient with difficult airway
Anaesth Intensive Care. 2012 Jul;40(4):736-7