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

The 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
Click for abstract

Hyperglycaemia & mortality in sepsis – lactate dependent?

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
Click for abstract

Etomidate & sepsis

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

Infectious biomarkers in the critically ill

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
Click for Abstract

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

More on the meaning of lactate values

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
Click for abstract

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
Click for abstract

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
Click for abstract

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

The opposite of acute kidney injury?

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

Is diastolic worse than systolic dysfunction in sepsis?

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

Vasopressin – what it does and doesn’t do

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

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

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

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

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