Tag Archives: sepsis

Understanding Elevated Lactate

I find clinicians are quick to consider sepsis and hypoperfusion/ischaemia as causes of a raised lactate, but slow to include other causes in their differential.
Although an elevated lactate has been shown to be associated with worse outcomes in numerous studies, not all causes of a raised lactate are sinister. It’s therefore important to diagnose the cause both to allow the right treatment and to avoid assuming an inappropriately poor prognosis.
This 12 minute video offers an approach to diagnosing the cause of elevated lactate based on an understanding of lactate physiology using a simple visual aid – a ‘lactate map’ and a memorable acronym.

Reference
1. Reid C, Rees V, Collyer-Merritt H. Non-septic hyperlactataemia in the emergency department. Emerg Med J. 2010 May;27(5):411–2

ARISE study: EGDT no better than standard care

periph-vasoactive-iconThe second of three major trials assessing early goal directed therapy (EGDT) in sepsis – the Australasian ARISE Trial – has been published.
ARISE tested the hypothesis that EGDT, as compared with usual care, would decrease 90-day all-cause mortality among patients presenting to the emergency department with early septic shock in diverse health care settings.
There was no difference in all-cause mortality at 90 days between EGDT and standard care, in keeping with the results from ProCESS.
Why are the results so different from Rivers’ original EGDT study? The authors explain:


“although our results differ from those in the original trial, they are consistent with previous studies showing that bias in small, single-center trials may lead to inflated effect sizes”

This cautions us all against making major practice changes based on one single centre study. In critical care we’ve learned this before with subjects like tight glycaemic control and Activated Protein C. However I do believe that the things we know to be of benefit – early recognition, source control, antibiotics, and fluids – are effective in making ‘standard’ care “as good as” EGDT because of heightened awareness of the condition and its treatment, and Rivers’ initial study and the subsequent Surviving Sepsis Campaign Guidelines have played a major role in raising that awareness.
The ARISE study is appraised by Wessex’s The Bottom Line and discussed on the one and only EMCrit podcast.
The ARISE Investigators and the ANZICS Clinical Trials Group.
Goal-Directed Resuscitation for Patients with Early Septic Shock
N Engl J Med. 2014 Oct;:141001063014008.Full Text
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Background
Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain.

Methods In this trial conducted at 51 centers (mostly in Australia or New Zealand), we randomly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care. The primary outcome was all-cause mortality within 90 days after randomization.

Results Of the 1600 enrolled patients, 796 were assigned to the EGDT group and 804 to the usual-care group. Primary outcome data were available for more than 99% of the patients. Patients in the EGDT group received a larger mean (±SD) volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group (1964±1415 ml vs. 1713±1401 ml) and were more likely to receive vasopressor infusions (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7.0%), and dobutamine (15.4% vs. 2.6%) (P<0.001 for all comparisons). At 90 days after randomization, 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group, for rates of death of 18.6% and 18.8%, respectively (absolute risk difference with EGDT vs. usual care, -0.3 percentage points; 95% confidence interval, -4.1 to 3.6; P=0.90). There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay.

Conclusions In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days.

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Blood pressure target in septic shock

ABP-iconA study comparing mean arterial pressure (MAP) targets of 80 to 85 mm Hg (high-target group) with 65 to 70 mm Hg (low-target group) n 776 septic shock patients – the SEPSISPAM study – did not show a difference in the primary endpoint of 28 day mortality. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group. In my view this supports an approach that targets MAP based on the individual patient’s history rather than a blanket one-number-fits-all approach. The MAPs actually achieved in the low-target group were between 70-75 mm of Hg.
For a more thorough review check out the great PulmCCM blog.
High versus Low Blood-Pressure Target in Patients with Septic Shock.
N Engl J Med. 2014 Mar 18. [Epub ahead of print] Free Full Text
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Background: The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.
Methods: In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support.
Results: At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality.
Conclusions: Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days.

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No Benefit From Early Goal Directed Therapy

The first of three major trials assessing early goal directed therapy (EGDT) in sepsis – the American ProCESS Trial – has been published.
It showed what many of us thought – that the specific monitoring via a central line of central venous oxygen saturation – was not necessary for improved survival.
However the trial randomised 1341 patients to one of three arms:
(1) protocolised EGDT
(2) protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions
(3) ‘usual care’ which was not standardised.
There were no differences in any of the primary or secondary outcomes between the groups.
Interestingly, in the six hours of early care that the trial dictated, the volume of intravenous fluids administered differed significantly among the groups (2.8 litres in the protocol-based EGDT group, 3.3 litres in the protocol-based standard-therapy group, and 2.3 litres in the usual-care group).
There was also a difference in the amount of vasopressor given, with more patients in the two protocol-based groups receiving vasopressors (54.9% in the protocol-based EGDT group, 52.2% in the protocol-based standard-therapy group, 44.1% in the usual-care group).
The use of intravenous fluids, vasopressors, dobutamine, and blood transfusions between 6 and 72 hours did not differ significantly among the groups.
Overall 60 day mortality was in the region of 20% for all groups.
What are the take home points here? Firstly, overall sepsis outcomes have improved over recent years, and early recognition and antibiotic administration may be the most important components of care. In the early emergency department phase of care, protocolised fluid and vasopressor therapy may not be as important as we thought. Good clinical assessment and regular review seem to be as effective and perhaps more important than any specific monitoring modality or oxygen delivery-targeted drug and blood therapy.
We all await the ARISE and ProMISE studies which may shed more light on the most important components of early sepsis care.
A Randomized Trial of Protocol-Based Care for Early Septic Shock
NEJM Mar 18 2014 (Full Text Link)
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Background: In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.

Methods: In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support.

Results: We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support.

Conclusions: In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes

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Sepsis research – let's get some answers

There’s so much debate on which components of Early Goal Directed Therapy in sepsis really make a difference. The good news is that three randomised controlled trials in the UK, Australasia, and North America, aim to answer the question, and the study design from the outset has been a collaboration that will allow the results to be pooled.
ProMISe is taking place in the UK, ProCESS in the US, and ARISE in Australasia.

sepsistrialssm

The Australasian study (ARISE) and is nearing completion. If you can recruit patients then please do. Listen to a podcast on this fantastic study with lead investigator Dr Anthony Delaney.

Beta blockers potentially beneficial in septic shock

Counterintuitive as it sounds, this is pretty cool. I blogged about these guys before when they published their findings on microcirculatory flow in septic patients given beta blockers.
It’s a small study – 77 patients with septic shock and a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of at least 65 mm Hg were randomised to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay. 77 patients received standard treatment. It should be noted the primary outcome (target heart rate) was not a patient-oriented endpoint. Interestingly though, there were no increased adverse events in the beta blocker group, which demonstrated improved left ventricular stroke work, lower lactate levels, decreased noradrenaline and fluid requirements, improved oxygenation, and a lower mortality.
Caution is appropriate here though: this study was a small, single-centre open-label trial. It will be very interesting to see if these effects are reproduced and whether they will ultimately translate to meaningful outcome benefits.
Read more about the study at the PulmCCM site.
There is also a great critical appraisal of the study at Emergency Medicine Literature of Note/a>.
Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial
JAMA. 2013 Oct 23;310(16):1683-91
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IMPORTANCE: β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects.

OBJECTIVE: To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock.

DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher.

INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment.

MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization.

RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P <  .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P < .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P < .001).
CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.

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Beta blockade in sepsis

tachy-iconWhat do septic patients need if they remain shocked after fluid resuscitation? Catecholamines right? Let’s stimulate some adrenoceptors and support that circulation!
Sydney’s Prof Myburgh has told us why adrenaline (epinephrine) and noradrenaline (norepinephrine) are the go-to vasoactive choices, and Prof Singer from London likes to remind us about the detrimental effects of these drugs – the pros and cons are listed here. Tachycardia is associated with worse outcomes in sepsis, and the balance of oxygen supply and demand can be difficult to achieve. Beta blocking drugs could reduce tachycardia, but there does seem to be something counter-intuitive about giving both beta-blockers and catecholamines in the same patient. You might expect that beta blockers would cause fall in cardiac output and worsen tissue perfusion.
A small study previously showed possible helpful effects of beta blockers in children with burns. The potential benefits may extend beyond control of heart rate to anti-inflammatory / anti-catabolic effects. A recent publication evaluated beta blockers in adult patients with septic shock, which appears to be a pilot study for an ongoing randomised controlled trial.
They included patients who had been fluid resuscitated and who required noradrenaline, and treated them with a titrated esmolol infusion commenced at 25 mg/hr, with an upper dose limit of 2,000 mg/hr, to maintain a predefined HR range between 80 and 94 beats per minute. Esmolol was chosen because of its half-life of approximately 2 min, so any adverse effects could be rapidly reversed. They examined the macrocirculation using pulmonary artery catheterisation and the microcirculation using sublingual microvascular blood flow imaging.
Most of the patients had pneumonia, and interestingly, all patients received intravenous hydrocortisone (200mg/d) as a continuous infusion.
In this small cohort of patients, they found that titrating the heart rate to less than 95 bpm was associated with maintenance of stroke volume and preservation of microvascular blood flow. Although cardiac output fell because of the lower HR, stroke volume, MAP, and lactate levels were unchanged while noradrenaline requirements were reduced.

Increased vascular reactivity to norepinephrine following nonselective β-blockade is supported by volunteer and animal studies, and postulated mechanisms include:

  • blockade of a peripheral β2-mediated vasodilatory effect of noradrenaline
  • decreased clearance of infused noradrenaline
  • a centrally mediated effect on reflex activity
  • inhibition of vascular endothelial nitric oxide synthase activity

Microvascular Effects of Heart Rate Control With Esmolol in Patients With Septic Shock: A Pilot Study
Crit Care Med. 2013 Sep;41(9):2162-2168
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OBJECTIVE: β-blocker therapy may control heart rate and attenuate the deleterious effects of β-stimulating catecholamines in septic shock. However, their negative chronotropy and inotropy may potentially lead to an inappropriately low cardiac output, with a subsequent compromise of microvascular blood flow. The purpose of the present pilot study was to investigate the effects of reducing heart rate to less than 95 beats per minute in patients with septic shock using the β-1 adrenoceptor blocker, esmolol, with specific focus on systemic hemodynamics and the microcirculation.

DESIGN: Prospective, observational clinical study.

SETTING: Multidisciplinary ICU at a university hospital.

MEASUREMENTS AND MAIN RESULTS: After 24 hours of initial hemodynamic optimization, 25 septic shock patients with a heart rate greater than or equal to 95 beats per minute and requiring norepinephrine to maintain mean arterial pressure greater than or equal to 65 mm Hg received a titrated esmolol infusion to maintain heart rate less than 95 beats per minute. Sublingual microcirculatory blood flow was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 24 hours after esmolol administration. Heart rates targeted between 80 and 94 beats per minute were achieved in all patients. Whereas cardiac index decreased (4.0 [3.5; 5.3] vs 3.1 [2.6; 3.9] L/min/m; p < 0.001), stroke volume remained unchanged (34 [37; 47] vs 40 [31; 46] mL/beat/m; p = 0.32). Microcirculatory blood flow in small vessels increased (2.8 [2.6; 3.0] vs 3.0 [3.0; 3.0]; p = 0.002), while the heterogeneity index decreased (median 0.06 [interquartile range 0; 0.21] vs 0 [0; 0]; p = 0.002). PaO2 and pH increased while PaCO2 decreased (all p < 0.05). Of note, norepinephrine requirements were significantly reduced by selective β-1 blocker therapy (0.53 [0.29; 0.96] vs 0.41 [0.22; 0.79] µg/kg/min; p = 0.03).

CONCLUSIONS: This pilot study demonstrated that heart rate control by a titrated esmolol infusion in septic shock patients was associated with maintenance of stroke volume, preserved microvascular blood flow, and a reduction in norepinephrine requirements.

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Identifying the febrile kid who's too tachypnoeic

Body temperature raises heart rate and respiratory rate in kids, potentially affecting our interpretation of these clinical signs.
Dutch investigators developed centile charts of respiratory rates for specific body temperatures (derivation study), so that abnormally high rates could be identified as a means of predicting lower respiratory infection (validation set).
Respiratory rate increased overall by 2.2 breaths/min per 1°C rise (standard error 0.2) after accounting for age and temperature in the model, which is similar to a previous UK study that suggested a rise in respiratory rate of around 0.5-2 breaths per minute and an increase in heart rate of about 10 beats per minute for every 1 degree celcius above normal.
Cut-off values at the 97th centile were more useful in detecting the presence of LRTI than existing (Advanced Paediatric Life Support) respiratory rate thresholds.
The respiratory rate charts are available here.
Derivation and validation of age and temperature specific reference values and centile charts to predict lower respiratory tract infection in children with fever: prospective observational study
BMJ. 2012 Jul 3;345:e4224
Free Full Text Link

New Sepsis Guidelines

pumpsThe latest update of the Surviving Sepsis Campaign Guidelines has been released.
There’s too much interesting stuff to easily summarise, but luckily the full text article is available at the link below.
Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012
Crit Care Med 2013 Feb;41(2):580-637 FREE FULL TEXT

Decatecholaminization in septic shock

A subset of patients from the 2008 Vasopressin and Septic Shock Trial (VASST) trial had invasive haemodynamic monitoring measurements from pulmonary artery catheters. These data have now been analysed, revealing that vasopressin was associated with a lower heart rate compared with norepinephrine (noradrenaline) alone, without significant difference in cardiac index or stroke volume index. However, there was significantly greater use of inotropic drugs in the vasopressin group compared with the norepinephrine group.
Tachycardia and high quantities of catecholamine infusion are both associated with mortality in sepsis. The authors discuss:
“The idea of decatecholaminization, reducing both endogenous and exogenous adrenergic stimulation, is now believed to be an important treatment strategy, and the use of beta-blockers in septic shock is being considered. The early use of vasopressin or specific V1a receptor agonists in early septic shock may be another possible treatment.”
This interesting post-hoc analysis may help further define the patients in whom vasopressin is to be considered, by those clinicians who are using it in septic shock. For those that aren’t, I wouldn’t worry about it.
The cardiopulmonary effects of vasopressin compared with norepinephrine in septic shock
Chest. 2012 Sep;142(3):593-605
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BACKGROUND: Vasopressin is known to be an effective vasopressor in the treatment of septic shock, but uncertainty remains about its effect on other hemodynamic parameters.

METHODS: We examined the cardiopulmonary effects of vasopressin compared with norepinephrine in 779 adult patients with septic shock recruited to the Vasopressin and Septic Shock Trial. More detailed cardiac output data were analyzed for a subset of 241 patients managed with a pulmonary artery catheter, and data were collected for the first 96 h after randomization. We compared the effects of vasopressin vs norepinephrine in all patients and according to severity of shock (< 15 or ≥ 15 μg/min of norepinephrine) and cardiac output at baseline.
RESULTS: Equal BPs were maintained in both treatment groups, with a significant reduction in norepinephrine requirements in the patients treated with vasopressin. The major hemodynamic difference between the two groups was a significant reduction in heart rate in the patients treated with vasopressin (P < .0001), and this was most pronounced in the less severe shock stratum (treatment × shock stratum interaction, P =.03). There were no other major cardiopulmonary differences between treatment groups, including no difference in cardiac index or stroke volume index between patients treated with vasopressin and those treated with norepinephrine. There was significantly greater use of inotropic drugs in the vasopressin group than in the norepinephrine group.
CONCLUSIONS: Vasopressin treatment in septic shock is associated with a significant reduction in heart rate but no change in cardiac output or other measures of perfusion.

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