Tag Archives: sepsis

Acute Med, All Updates, ICU, Resus

Hyperglycaemia & mortality in sepsis – lactate dependent?

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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
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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.

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Acute Med, All Updates, ICU, Kids, Resus

Etomidate & sepsis

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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

Infectious biomarkers in the critically ill

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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
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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.

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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

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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
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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.

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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
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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.

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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
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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.

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

Acute Med, All Updates, ICU, Resus

The opposite of acute kidney injury?

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Prescribing in the critically ill patient can be a challenge due to a number of factors impacting on pharmacology:

  • variable enteral absorption and interaction with enteral feed
  • less protein binding in hypoalbuminaemic states
  • extravascular volume expansion with fluid loading and capillary leak can alter the volume of distribution
  • altered hepatic metabolism of drugs
  • impaired renal excretion
  • accumulation of toxic metabolites
  • removal by renal replacement therapy
  • interaction with other drugs

There’s another factor to bear in mind, though, which has been recently highlighted in the context of antibiotic prescription: that of Augmented Renal Clearance (ARC).
Some ICU patients have supraphysiologic renal function. Several studies have demonstrated significant numbers of ICU patients with higher than normal creatinine clearance. This is thought to be due to varying combinations of the following factors:

  • Low systemic vascular resistance and increased cardiac output leading to increased renal blood flow
  • Above factors enhanced by aggressive fluid and vasoactive therapy in pursuit of haemodynamic targets
  • These lead to increase delivery of solute to the kidneys and increased clearance

This can have implications for prescribing: the serum creatinine will not identify these patients, but it is possible that ARC will result in less effective therapy for a given dose of a renally-excreted drug, for example beta-lactam antibiotics.
An editorial by critical care physician Dr Andrew Shorr highlights the inadequacy of basing prescribing recommendations on data from the ex-vivo interaction between drug and pathogen:

‘To believe that all patients will respond in the same fashion and with the same trajectory is to become handcuffed by the median response noted in clinical trials……….The central fallacy of the bug-drug approach is that it misses the key role of the host.’

Sub-therapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations
Chest. 2011 Dec 22. [Epub ahead of print] Free Full Text
Antibiotics in the critically ill: the bug, drug, host triad
Chest. 2012 Jul 1;142(1):8-10 Free Full Text

Acute Med, All Updates, ICU, Resus, Ultrasound

Is diastolic worse than systolic dysfunction in sepsis?

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Septic myocardial dysfunction is a well recognised contributor to shock in sepsis but for many of us we assume this to be gross systolic impairment. Interestingly a recent study highlights that patients with severe sepsis and septic shock frequently have diastolic dysfunction1. They found that diastolic dysfunction was the strongest independent predictor of early mortality, even after adjusting for the APACHE-II score and other predictors of mortality.
In this study, 9.1% of severe sepsis/septic shock patients had isolated systolic dysfunction, 14.1% had combined systolic and diastolic dysfunction, and 38% had isolated diastolic dysfunction.
Importantly, the authors point out that although diastolic dysfunction is associated with age, hypertension, diabetes mellitus, and ischaemic heart disease, diastolic dysfunction is a stronger independent predictor of mortality than age and the other co-morbidities. However, a limitation of the study acknowledged by the authors is that it did not include follow-up echocardiography examinations, so we do not know whether sepsis was responsible for a transient diastolic dysfunction or whether the observed diastolic dysfunction was a pre-existing condition.
Both troponin and NT-ProBNP elevations also predicted mortality.
Want to know how to measure diastolic dysfunction? These authors measured mitral annular early-diastolic peak velocity, or the e’-wave (called ‘e prime’). It is a way of seeing how fast myocardial tissue relaxes in diastole, and if its peak velocity is slow (in this case < 8cm/s) there is diastolic dysfunction. We measure speed using Doppler, and in this case we’re looking at the speed of heart tissue (as opposed to the blood cells within the heart chambers) so we do ‘Tissue Doppler Imaging’, or TDI. You need an echo machine with pulsed-wave Doppler, and you need to be able to get an apical view. This is explained really nicely here2 but if you don’t have the time or the echopassion to read a whole article on TDI watch this one minute video (BY emergency physicians FOR emergency physicians!) on diastology, where TDI measurement of e’ is shown from 45 seconds into the video.
For reference, there is some more detail on diastolic function measurements at the Echobasics site.

If you think you can cope with any more of this level of awesomeness and want these geniuses to talk to you from your smartphone in the ED then get the free One Minute Ultrasound app for Android or Apple devices.


AIMS: Systolic dysfunction in septic shock is well recognized and, paradoxically, predicts better outcome. In contrast, diastolic dysfunction is often ignored and its role in determining early mortality from sepsis has not been adequately investigated.

METHODS AND RESULTS: A cohort of 262 intensive care unit patients with severe sepsis or septic shock underwent two echocardiography examinations early in the course of their disease. All clinical, laboratory, and survival data were prospectively collected. Ninety-five (36%) patients died in the hospital. Reduced mitral annular e’-wave was the strongest predictor of mortality, even after adjusting for the APACHE-II score, low urine output, low left ventricular stroke volume index, and lowest oxygen saturation, the other independent predictors of mortality (Cox’s proportional hazards: Wald = 21.5, 16.3, 9.91, 7.0 and 6.6, P< 0.0001, <0.0001, 0.002, 0.008, and 0.010, respectively). Patients with systolic dysfunction only (left ventricular ejection fraction ≤50%), diastolic dysfunction only (e’-wave <8 cm/s), or combined systolic and diastolic dysfunction (9.1, 40.4, and 14.1% of the patients, respectively) had higher mortality than those with no diastolic or systolic dysfunction (hazard ratio = 2.9, 6.0, 6.2, P= 0.035, <0.0001, <0.0001, respectively) and had significantly higher serum levels of high-sensitivity troponin-T and N-terminal pro-B-type natriuretic peptide (NT-proBNP). High-sensitivity troponin-T was only minimally elevated, whereas serum levels of NT-proBNP were markedly elevated [median (inter-quartile range): 0.07 (0.02-0.17) ng/mL and 5762 (1001-15 962) pg/mL, respectively], though both predicted mortality even after adjusting for highest creatinine levels (Wald = 5.8, 21.4 and 2.3, P= 0.015, <0.001 and 0.13).

CONCLUSION: Diastolic dysfunction is common and is a major predictor of mortality in severe sepsis and septic shock.

1. Diastolic dysfunction and mortality in severe sepsis and septic shock
Eur Heart J. 2012 Apr;33(7):895-903
2. A clinician’s guide to tissue Doppler imaging
Circulation. 2006 Mar 14;113(10):e396-8 Free Full Text

Acute Med, All Updates, ICU, Resus

Vasopressin – what it does and doesn't do

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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.


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

DATA SOURCE:
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.

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

DATA EXTRACTION AND SYNTHESIS:
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).

CONCLUSIONS:
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

Acute Med, All Updates, ICU, Kids, Resus

Treating sepsis – have we got it the wrong way round?

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In our understanding of the pathophysiology of sepsis, we often attribute organ damage and death to the excessive host response to infection, including the popular phrase ‘cytokine storm’. This has been nicely described as ‘friendly fire’ by Prof Derek Angus, who points out that this central tenet of sepsis understanding may in some cases be flawed1; it has led to research on drugs that suppress parts of these inflammatory pathways, although none have yet proven effective. An elegant study on patients dying from sepsis showed clear evidence of immunosuppression compared with controls2.

Editorialist Peter Ward3 proposes an area for future research: whether such derangements can be reversed by treatment with agents such as interleukins 7 or 15, which might combat the T-cell depletion state in sepsis.
The authors point out that all the patients included in the study died on ICU, some after a considerable duration of illness, and they emphasise that early deaths from sepsis in previously healthy patients with infections of highly virulent organisms are associated with an extremely exuberant immunoinflammatory response.
1.The Search for Effective Therapy for Sepsis: Back to the Drawing Board?
JAMA December 21, 2011, Vol 306, No. 23, pp 2614-5
2.Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure
JAMA December 21, 2011, Vol 306, No. 23, pp 2594-2605
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Context Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting.
Objectives To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression.
Design, Setting, and Participants Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009-2011). Control spleens (n = 29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n = 20) were obtained from transplant donors or from lung cancer resections.
Main Outcome Measures Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells.
Results The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28–stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, −5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, −269 to 1534) vs 58 (95% CI, −39 to 156) pg/mL; (P < .001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells. Conclusions Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.

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3.Immunosuppression in Sepsis
JAMA December 21, 2011, Vol 306, No. 23, pp 2618-9

Acute Med, All Updates, ICU, Resus

AF in sepsis and risk of stroke

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Atrial fibrillation can occur in the setting of severe sepsis, and often presents a therapeutic conundrum for critical care physicians, in that it can be relatively resistant to treatment until the sepsis has resolved, and its prognostic significance is unclear. A new study on a massive dataset shows atrial fibrillation in the setting of severe sepsis is associated with an increased risk of stroke and increased hospital mortality. Patients with severe sepsis who developed new-onset AF had a greater risk of in-hospital stroke than patients with preexisting AF and individuals without a history of AF.


Context New-onset atrial fibrillation (AF) has been reported in 6% to 20% of patients with severe sepsis. Chronic AF is a known risk factor for stroke and death, but the clinical significance of new-onset AF in the setting of severe sepsis is uncertain.

Objective To determine the in-hospital stroke and in-hospital mortality risks associated with new-onset AF in patients with severe sepsis.

Design and Setting Retrospective population-based cohort of California State Inpatient Database administrative claims data from nonfederal acute care hospitals for January 1 through December 31, 2007.

Patients Data were available for 3 144 787 hospitalized adults. Severe sepsis (n = 49 082 [1.56%]) was defined by validated International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 995.92. New-onset AF was defined as AF that occurred during the hospital stay, after excluding AF cases present at admission.

Main Outcome Measures A priori outcome measures were in-hospital ischemic stroke (ICD-9-CM codes 433, 434, or 436) and mortality.

Results Patients with severe sepsis were a mean age of 69 (SD, 16) years and 48% were women. New-onset AF occurred in 5.9% of patients with severe sepsis vs 0.65% of patients without severe sepsis (multivariable-adjusted odds ratio [OR], 6.82; 95% CI, 6.54-7.11; P < .001). Severe sepsis was present in 14% of all new-onset AF in hospitalized adults. Compared with severe sepsis patients without new-onset AF, patients with new-onset AF during severe sepsis had greater risks of in-hospital stroke (75/2896 [2.6%] vs 306/46 186 [0.6%] strokes; adjusted OR, 2.70; 95% CI, 2.05-3.57; P < .001) and in-hospital mortality (1629 [56%] vs 18 027 [39%] deaths; adjusted relative risk, 1.07; 95% CI, 1.04-1.11; P < .001). Findings were robust across 2 definitions of severe sepsis, multiple methods of addressing confounding, and multiple sensitivity analyses.
Conclusion Among patients with severe sepsis, patients with new-onset AF were at increased risk of in-hospital stroke and death compared with patients with no AF and patients with preexisting AF.

Incident Stroke and Mortality Associated With New-Onset Atrial Fibrillation in Patients Hospitalized With Severe Sepsis
JAMA. 2011 Nov 13. [Epub ahead of print]

Acute Med, All Updates, ICU, Resus

Xigris withdrawn

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Pharmaceutical company Eli Lilly has announced the withdrawal of its severe sepsis drug activated protein C, or drotrecogin alfa (proprietary name Xigris). This is because the PROWESS-SHOCK study, now complete, showed no benefit in its primary endpoint of 28 day mortality when compared with placebo in septic shock patients. There was also no benefit in a subgroup of patients with protein C deficiency, and no significant increased risk of severe bleeding.
The European Medicines Agency’s Instructions are:


At this stage physicians should not initiate treatment with Xigris in new patients and should stop ongoing treatment

The US Food and Drug Administration’s Instructions are:


Xigris treatment should not be started in new patients. Xigris treatment should be stopped in patients being treated with Xigris.

All remaining Xigris product should be returned to the supplier from whom it was purchased.

The UK Intensive Care Society’s Announcement contains a link to Eli Lilly’s press release.

The Xigris website looks like this at the time of posting