CRP helpful in risk stratifying febrile kids

In febrile children, peripheral white blood cell counts were not helpful in separating children with self limiting infections from those with serious bacterial infections, but serum C reactive protein was1: febrile children with serum C reactive protein concentrations of 20 mg/L or less have a 5% risk of serious infection, whereas those with serum concentrations greater than 80 mg/L have a risk of 72%; children with intermediate values have a risk of about 15%. According to the accompanying BMJ editorial2:
This grouping, although imperfect, provides some guidance to help clinicians deciding which children may avoid extensive evaluation and treatment.

OBJECTIVE: To collate all available evidence on the diagnostic value of laboratory tests for the diagnosis of serious infections in febrile children in ambulatory settings.

DESIGN: Systematic review.

DATA SOURCES: Electronic databases, reference tracking, and consultation with experts.

STUDY SELECTION: Studies were selected on six criteria: design (studies of diagnostic accuracy or deriving prediction rules), participants (otherwise healthy children and adolescents aged 1 month to 18 years), setting (first contact ambulatory care), outcome (serious infection), features assessed (in first contact care), and data reported (sufficient to construct a 2×2 table).

DATA EXTRACTION: Quality assessment was based on the quality assessment tool of diagnostic accuracy studies (QUADAS) criteria. Meta-analyses were done using the bivariate random effects method and hierarchical summary receiver operating characteristic curves for studies with multiple thresholds.

DATA SYNTHESIS: None of the 14 studies identified were of high methodological quality and all were carried out in an emergency department or paediatric assessment unit. The prevalence of serious infections ranged from 4.5% to 29.3%. Tests were carried out for C reactive protein (five studies), procalcitonin (three), erythrocyte sedimentation rate (one), interleukins (two), white blood cell count (seven), absolute neutrophil count (two), band count (three), and left shift (one). The tests providing most diagnostic value were C reactive protein and procalcitonin. Bivariate random effects meta-analysis (five studies, 1379 children) for C reactive protein yielded a pooled positive likelihood ratio of 3.15 (95% confidence interval 2.67 to 3.71) and a pooled negative likelihood ratio of 0.33 (0.22 to 0.49). To rule in serious infection, cut-off levels of 2 ng/mL for procalcitonin (two studies, positive likelihood ratio 13.7, 7.4 to 25.3 and 3.6, 1.4 to 8.9) and 80 mg/L for C reactive protein (one study, positive likelihood ratio 8.4, 5.1 to 14.1) are recommended; lower cut-off values of 0.5 ng/mL for procalcitonin or 20 mg/L for C reactive protein are necessary to rule out serious infection. White blood cell indicators are less valuable than inflammatory markers for ruling in serious infection (positive likelihood ratio 0.87-2.43), and have no value for ruling out serious infection (negative likelihood ratio 0.61-1.14). The best performing clinical decision rule (recently validated in an independent dataset) combines testing for C reactive protein, procalcitonin, and urinalysis and has a positive likelihood ratio of 4.92 (3.26 to 7.43) and a negative likelihood ratio of 0.07 (0.02 to 0.27).

CONCLUSION: Measuring inflammatory markers in an emergency department setting can be diagnostically useful, but clinicians should apply different cut-off values depending on whether they are trying to rule in or rule out serious infection. Measuring white blood cell count is less useful for ruling in serious infection and not useful for ruling out serious infection. More rigorous studies are needed, including studies in primary care, to assess the value of laboratory tests alongside clinical diagnostic measurements, including vital signs.

1. Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review
BMJ. 2011 Jun 8;342:d3082
2. How useful are laboratory tests in diagnosing serious infections in febrile children?
BMJ. 2011 Jun 8;342:d2782

Normal heart and respiratory rates in children

A large review has established normal ranges of heart rate and respiratory rate in children from birth to 18 years of age. Some of the results differed markedly from some existing ranges quoted, such as in the Advanced Paediatric Life Support Course.

BACKGROUND: Although heart rate and respiratory rate in children are measured routinely in acute settings, current reference ranges are not based on evidence. We aimed to derive new centile charts for these vital signs and to compare these centiles with existing international ranges.

METHODS: We searched Medline, Embase, CINAHL, and reference lists for studies that reported heart rate or respiratory rate of healthy children between birth and 18 years of age. We used non-parametric kernel regression to create centile charts for heart rate and respiratory rate in relation to age. We compared existing reference ranges with those derived from our centile charts.

FINDINGS: We identified 69 studies with heart rate data for 143,346 children and respiratory rate data for 3881 children. Our centile charts show decline in respiratory rate from birth to early adolescence, with the steepest fall apparent in infants under 2 years of age; decreasing from a median of 44 breaths per min at birth to 26 breaths per min at 2 years. Heart rate shows a small peak at age 1 month. Median heart rate increases from 127 beats per min at birth to a maximum of 145 beats per min at about 1 month, before decreasing to 113 beats per min by 2 years of age. Comparison of our centile charts with existing published reference ranges for heart rate and respiratory rate show striking disagreement, with limits from published ranges frequently exceeding the 99th and 1st centiles, or crossing the median.

INTERPRETATION: Our evidence-based centile charts for children from birth to 18 years should help clinicians to update clinical and resuscitation guidelines.

Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies
Lancet. 2011 Mar 19;377(9770):1011-8

How about pre-hospital tranexamic acid?

The CRASH 2 trial showed improved outcomes in trauma from the administration of the antifibrinolytic drug tranexamic acid. A further analysis of the data has shown that benefit was only seen in CRASH-2 when tranexamic acid was administered within 3 hours of injury1.
An accompanying editorial2 makes the following interesting points:

  • Acute traumatic coagulopathy is a hyperacute process in which systemic fibrinolysis releases D-dimers that are detectable within 30 min of injury.
  • Those severely injured patients who develop acute coagulopathy are much more likely to die and to die early.
  • Once fully activated, fibrinolysis has been shown to continue unabated until endogenous antifibrinolytic elements are restored.
  • The earlier that tranexamic acid is administered, the more likely it might be to prevent full activation of fibrinolysis.
  • Hospital massive transfusion protocols incorporate fresh frozen plasma that contains all the endogenous antifibrinolytic elements in plasma and so the place for tranexamic acid in high income countries with such protocols is unclear.
  • The best place for tranexamic acid in developed trauma systems might actually be in the prehospital environment, where trauma bypass policies have extended prehospital times and the administration of plasma is uncommon and often impractical.

BACKGROUND: The aim of the CRASH-2 trial was to assess the effects of early administration of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage. Tranexamic acid significantly reduced all-cause mortality. Because tranexamic acid is thought to exert its effect through inhibition of fibrinolysis, we undertook exploratory analyses of its effect on death due to bleeding.

METHODS: The CRASH-2 trial was undertaken in 274 hospitals in 40 countries. 20,211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min followed by infusion of 1 g over 8 h) or placebo. Patients were randomly assigned by selection of the lowest numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Both participants and study staff (site investigators and trial coordinating centre staff ) were masked to treatment allocation. We examined the effect of tranexamic acid on death due to bleeding according to time to treatment, severity of haemorrhage as assessed by systolic blood pressure, Glasgow coma score (GCS), and type of injury. All analyses were by intention to treat. The trial is registered as ISRCTN86750102, NCT00375258, and South African Clinical Trial Register/Department of Health DOH-27-0607-1919.

FINDINGS: 10,096 patients were allocated to tranexamic acid and 10,115 to placebo, of whom 10,060 and 10,067, respectively, were analysed. 1063 deaths (35%) were due to bleeding. We recorded strong evidence that the effect of tranexamic acid on death due to bleeding varied according to the time from injury to treatment (test for interaction p<0.0001). Early treatment (≤1 h from injury) significantly reduced the risk of death due to bleeding (198/3747 [5.3%] events in tranexamic acid group vs 286/3704 [7.7%] in placebo group; relative risk [RR] 0.68, 95% CI 0.57-0.82; p<0.0001). Treatment given between 1 and 3 h also reduced the risk of death due to bleeding (147/3037 [4.8%] vs 184/2996 [6.1%]; RR 0.79, 0.64-0.97; p=0.03). Treatment given after 3 h seemed to increase the risk of death due to bleeding (144/3272 [4.4%] vs 103/3362 [3.1%]; RR 1.44, 1.12-1.84; p=0.004). We recorded no evidence that the effect of tranexamic acid on death due to bleeding varied by systolic blood pressure, Glasgow coma score, or type of injury.

INTERPRETATION: Tranexamic acid should be given as early as possible to bleeding trauma patients. For trauma patients admitted late after injury, tranexamic acid is less effective and could be harmful.

1. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial
Lancet. 2011 Mar 26;377(9771):1096-101
2. Tranexamic acid for trauma
Lancet. 2011 Mar 26;377(9771):1052-4

Dexamethasone for community acquired pneumonia

Another Dutch study has examined steroids for community acquired pneumonia, this time with the primary outcome measure being hospital length of stay, which was reduced by one day on the steroid group. Compare this study with a previous negative study of prednisolone for pneumonia.

BACKGROUND: Whether addition of corticosteroids to antibiotic treatment benefits patients with community-acquired pneumonia who are not in intensive care units is unclear. We aimed to assess effect of addition of dexamethasone on length of stay in this group, which might result in earlier resolution of pneumonia through dampening of systemic inflammation.

METHODS: In our double-blind, placebo-controlled trial, we randomly assigned adults aged 18 years or older with confirmed community-acquired pneumonia who presented to emergency departments of two teaching hospitals in the Netherlands to receive intravenous dexamethasone (5 mg once a day) or placebo for 4 days from admission. Patients were ineligible if they were immunocompromised, needed immediate transfer to an intensive-care unit, or were already receiving corticosteroids or immunosuppressive drugs. We randomly allocated patients on a one-to-one basis to treatment groups with a computerised randomisation allocation sequence in blocks of 20. The primary outcome was length of hospital stay in all enrolled patients. This study is registered with, number NCT00471640.

FINDINGS: Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4-5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6·5 days (IQR 5·0-9·0) in the dexamethasone group compared with 7·5 days (5·3-11·5) in the placebo group (95% CI of difference in medians 0-2 days; p=0·0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemia compared with 35 (23%) of 153 controls (p<0·0001).

INTERPRETATION: Dexamethasone can reduce length of hospital stay when added to antibiotic treatment in non-immunocompromised patients with community-acquired pneumonia.

Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial
Lancet. 2011 Jun 11;377(9782):2023-30

Central lines in coagulopathic patients

If a patient needs a central line, he/she needs one. Often low platelets or a deranged coagulation profile are cited as reasons for omitting or delaying the procedure, but this is not based on evidence of increased complications. A recent Best Evidence Topic Review concludes:

…insertion of CVC lines do not require correction of haemostatic abnormalities prior to intervention. Rates of haemorrhage are low in patients with elevated PT, APTT or low thrombocyte count and appear to be closely related to the level of experience of the physician … rather than the defects of haemostasis.

Links to the abstracts of a couple of relevant articles reviewed are included below.
Central line insertion in deranged clotting
Emerg Med J. 2011 Jun;28(6):536-7 Full text
Low levels of prothrombin time (INR) and platelets do not increase the risk of significant bleeding when placing central venous catheters.
Med Klin (Munich). 2009 May 15;104(5):331-5
US-guided placement of central vein catheters in patients with disorders of hemostasis
Eur J Radiol. 2008 Feb;65(2):253-6

Tympanic monitoring for targeted temperature management

As the authors of this study point out, the reliability of tympanic temperature monitoring is still under debate. Since invasive measures of core temperature employed in the ICU may not be practicable in the pre-hospital setting, it would be helpful to employ a simpler method in the field, particular if we are implementing targeted temperature management post-cardiac arrest. In this small study of ten patients (with 558 temperature measurements) there was a high degree of correlation between tympanic and oesophageal temperature (r=0.95, p<0.0001, 95% CI 0.93 to 0.96) and also between tympanic and bladder temperature (r=0.96, p<0.0001, 95% CI 0.95 to 0.97). This finding is apparently in keeping with results obtained from patients undergoing cardiac surgery.

Objective Prehospital induction of therapeutic hypothermia after cardiac arrest may require temperature monitoring in the field. Tympanic temperature is non-invasive and frequently used in clinical practice. Nevertheless, it has not yet been evaluated in patients undergoing mild therapeutic hypothermia (MTH). Therefore, a prospective observational study was conducted comparing three different sites of temperature monitoring during therapeutic hypothermia.
Methods Ten consecutive patients admitted to our medical intensive care unit after out-of-hospital cardiac arrest were included in this study. During MTH, tympanic temperature was measured using a digital thermometer. Simultaneously, oesophageal and bladder temperatures were recorded in a total of 558 single measurements.
Results Compared with oesophageal temperature, bladder temperature had a bias of 0.019°C (limits of agreement ±0.61°C (2SD)), and tympanic measurement had a bias of 0.021°C (±0.80°C). Correlation analysis revealed a high relationship for tympanic versus oesophageal temperature (r=0.95, p<0.0001) and also for tympanic versus bladder temperature (r=0.96, p<0.0001).
Conclusions That tympanic temperature accurately indicates both oesophageal and bladder temperatures with a very small discrepancy in patients undergoing MTH after cardiac arrest is demonstrated in this study. Although our results were obtained in the hospital setting, these findings may be relevant for the prehospital application of therapeutic hypothermia as well. In this case, tympanic temperature may provide an easy and non-invasive method for temperature monitoring.

Tympanic temperature during therapeutic hypothermia
Emerg Med J. 2011 Jun;28(6):483-5

UK Radiology guidelines for trauma

The Royal College of Radiologists in the UK has published a guideline document to set standards related to diagnostic and interventional radiology for use by major trauma centres (MTCs) and trauma units (TUs). The standards are:

  1. The trauma team leader is in overall charge in acute care
  2. Protocol-driven imaging and intervention must be available and delivered by experienced staff. Acute care for SIPs must be consultant delivered
  3. MDCT should be adjacent to, or in, the emergency room
  4. Digital radiography must be available in the emergency room
  5. If there is an early decision to request MDCT, FAST and DR should not cause any delay
  6. MRI must be available with safe access for the SIP
  7. A CT request in the trauma setting should comply with the Ionising Radiation (Medical Exposure) Regulations 2000 (IR(ME)R) justification regulations like any other request for imaging involving ionising radiation
  8. There should be clear written protocols for MDCT preparation and transfer to the scan room
  9. Whole-body contrast-enhanced MDCT is the default imaging procedure of choice in the SIP. Imaging protocols should be clearly defined and uniform across a regional trauma network
  10. Future planning and design of emergency rooms should concentrate on increasing the numbers of SIPs stable enough for MDCT and intervention
  11. The primary survey report should be issued immediately to the trauma team leader
  12. On-call consultant radiologists should provide the final report on the SIP within one hour of MDCT image acquisition
  13. On-call consultant radiologists must have teleradiology facilities at home that allow accurate reports to be issued within one hour of MDCT image acquisition
  14. IR facilities should be co-located to the emergency department
  15. Angiographic facilities and endovascular theatres in MTCs should be safe environments for SIPs and should be of theatre standard
  16. Agreed written transfer protocols between the emergency department and imaging/interventional facilities internally or externally must be available
  17. IR trauma teams should be in place within 60 minutes of the patient’s admission or 30 minutes of referral
  18. Any deficiency in consumable equipment should be reported at the debriefing and be the subject of an incident report

Some interesting snippets include:
IV access
Right antecubital access is preferred for contrast administration (left-sided injections compromise interpretation of mediastinal vasculature). However, if arm vein access is not possible and a central line is in situ, it should be of a type that can accept 4 ml contrast/ second via a power injector. This might require local negotiation with emergency department doctors beforehand

Pelvic fracture
If a pelvic fracture is suspected, a temporary pelvic stabilisation (wrap, binder and so on) should be applied before MDCT.
Limb fractures
Rapid immobilisation such as air splints. Only immediately limb conserving manipulations/splinting should be performed prior to CT.
Urinary catheter
All significantly injured patients without obvious contraindications should be catheterised unless this would delay transfer to CT. The catheter should be clamped prior to MDCT.
Standards of practice and guidance for trauma radiology in severely injured patients
Royal College of Radiologists – Full Text Link

Hyperkalaemia dogmalysis

One of the things I enjoy most is the dismantling of medical dogma. In his brilliant blog Precious Bodily Fluids, nephrologist Joel Topf reviewed some of the hyperkalaemia literature and offers some of the following pearls:

  • The ECG is insensitive and non-specific as a means of diagnosing (and in particular ruling out) hyperkalaemia (sensitivity of ‘strict’ criteria of symmetrical peaked T waves that resolve on follow up: 18%; sensitivity of any ECG change: 52%).
  • The dangers of calcium treatment for digoxin toxicity-associated hyperkalaemia may be exaggerated and are supported by very weak evidence
  • Sodium bicarbonate does not effectively lower potassium but does lower ionised calcium which can increase the risk of hyperkalaemia-associated dysrhythmia

Read the full blog post here
View Dr Topf’s presentation below:

Targeted temperature management guidelines

Okay – rather than ‘therapeutic hypothermia’, the recommended phrase now is ‘targeted temperature management’. Several critical care authorities got together to produce clinical recommendations on this topic. Here are a few interesting points from the document:
On coagulation:
Hypothermia affects platelet function and prolongs the prothrombin time and partial thromboplastin time. These effects are masked when laboratory analysis is performed at 37°C, suggesting that any risk will be mitigated by rewarming.
Although not mentioned in the abstract, the authors examined the role of TTM in raised intracranial pressure (ICP):
Sufficient evidence exists to conclude that TTM does decrease ICP compared to unstructured temperature management. However, there is no sufficient evidence to make a recommendation regarding the use of targeted hypothermia to control elevated ICP to improve patent-important outcomes in TBI. The jury makes NO RECOMMENDATION regarding the use of TTM as an ICP control strategy to improve outcomes in brain injuries regardless of cause (trauma, hemorrhage, or ischemic stroke).
Regarding acute liver failure with severe cerebral edema:
there are currently no RCTs. There is a case series suggesting a strongly favorable effect. This is a powerful argument for support of an RCT evaluating TTM alone or in combination with hepatic dialysis strategies

OBJECTIVE: Representatives of five international critical care societies convened topic specialists and a nonexpert jury to review, assess, and report on studies of targeted temperature management and to provide clinical recommendations.
DATA SOURCES: Questions were allocated to experts who reviewed their areas, made formal presentations, and responded to questions. Jurors also performed independent searches. Sources used for consensus derived exclusively from peer-reviewed reports of human and animal studies.
STUDY SELECTION: Question-specific studies were selected from literature searches; jurors independently determined the relevance of each study included in the synthesis.

  1. The jury opines that the term “targeted temperature management” replace “therapeutic hypothermia.”
  2. The jury opines that descriptors (e.g., “mild”) be replaced with explicit targeted temperature management profiles.
  3. The jury opines that each report of a targeted temperature management trial enumerate the physiologic effects anticipated by the investigators and actually observed and/or measured in subjects in each arm of the trial as a strategy for increasing knowledge of the dose/duration/response characteristics of temperature management. This enumeration should be kept separate from the body of the report, be organized by body systems, and be made without assertions about the impact of any specific effect on the clinical outcome.
  4. The jury STRONGLY RECOMMENDS targeted temperature management to a target of 32°C-34°C as the preferred treatment (vs. unstructured temperature management) of out-of-hospital adult cardiac arrest victims with a first registered electrocardiography rhythm of ventricular fibrillation or pulseless ventricular tachycardia and still unconscious after restoration of spontaneous circulation (strong recommendation, moderate quality of evidence).
  5. The jury WEAKLY RECOMMENDS the use of targeted temperature management to 33°C-35.5°C (vs. less structured management) in the treatment of term newborns who sustained asphyxia and exhibit acidosis and/or encephalopathy (weak recommendation, moderate quality of evidence).

Targeted temperature management in critical care: A report and recommendations from five professional societies
Crit Care Med. 2011 May;39(5):1113-1125

Steroids for sepsis in kids

A small retrospective study suggests adrenal insufficiency is common in kids with septic shock, and that steroid administration in these children was associated with a decrease in vasoactive drug requirements.

INTRODUCTION: Adrenal insufficiency may be common in adults and children with vasopressor-resistant shock. We developed a protocolized approach to low-dose adrenocorticotropin testing and empirical low-dose glucocorticoid/mineralocorticoid supplementation in children with systemic inflammatory response syndrome and persistent hypotension following fluid resuscitation and vasopressor infusion.
HYPOTHESIS: We hypothesized that absolute and relative adrenal insufficiency was common in children with systemic inflammatory response syndrome requiring vasopressor support and that steroid administration would be associated with decreased vasopressor need.
METHODS: Retrospective review of pediatric patients with systemic inflammatory response syndrome and vasopressor-dependent shock receiving protocol-based adrenocorticotropin testing and low-dose steroid supplementation. The incidence of absolute and relative adrenal insufficiency was determined using several definitions. Vasopressor dose requirements were evaluated before, and following, initiation of corticosteroids.
RESULTS: Seventy-eight patients met inclusion criteria for systemic inflammatory response syndrome and shock; 40 had septic shock. Median age was 84 months (range, 0.5-295). By adrenocorticotropin testing, 44 (56%) had absolute adrenal insufficiency, 39 (50%) had relative adrenal insufficiency, and 69 (88%) had either form of adrenal insufficiency. Adrenal insufficiency incidence was significantly higher in children >2 yrs (p = .0209). Therapeutic interventions included median 80-mL/kg fluid resuscitation; 65% of patients required dopamine, 58% norepinephrine, and 49% dopamine plus norepinephrine. With steroid supplementation, median dopamine dose decreased from 10 to 4 μg/kg/min at 4 hrs (p = .0001), and median dose of norepinephrine decreased from 0.175 μg/kg/min to 0.05 μg/kg/min at 4 hrs (p = .039).
CONCLUSIONS: Absolute and relative adrenal insufficiency was prevalent in this cohort of children with systemic inflammatory response syndrome and vasopressor-dependent shock and increased with age. Introduction of steroids produced a significant reduction in vasopressor duration and dosage. Use of low-dose adrenocorticotropin testing may help further delineate populations who require steroid supplementation.

Incidence of adrenal insufficiency and impact of corticosteroid supplementation in critically ill children with systemic inflammatory syndrome and vasopressor-dependent shock
Crit Care Med. 2011 May;39(5):1145-50