Utility of CRP in Emergency Departments

C-reactive protein (CRP) is an acute phase protein synthesized in the liver. It is commonly used in Emergency Departments, especially in febrile and possibly infectious patients. It is also used as a measure of tissue inflammation, a biomarker of disease activity and a prognostic tool of many acute and chronic diseases. CRP functions as a bacterial opsonin, promoting phagocytosis, accelerating chemotaxis, and activating platelets. Normal levels increase with aging. Other possible reasons for higher levels could be:

• Pregnancy
• Coronary Artery Disease
• Viral Infections (10–40 mg/L)
• Bacterial infection (>40mg/dL)
• Malignancy, Obstructive Sleep Apnea, Connective Tissue Disorders

Serial CRP measurements may be helpful to monitor a patient’s response to medical intervention. Although CRP rises with tissue injury or ischemia, in septic patients with fulminant hepatic failure, it is more to be a marker of severe liver dysfunction rather than be used as a marker of infection.

Utility of CRP

1. ACS and Aortic Dissection - For ACS and Dissection, the higher CRP levels, the worse prognosis. It is not used to diagnose ACS/Dissection. Increased CRP levels were independently associated with mortality. 

2. Meningitis - For meningitis, CRP plays a role of distinguishing bacteria from non-bacteria etiology infection.

3. CRP in Acute Abdomen pain
CRP cannot play a suitable role in the diagnosis of cholecystitis but can be a factor indicating the severity of cholecystitis and response to therapy. A normal CRP along with a normal WBC count and a normal neutrophil count is unlikely to be a case of appendicitis. Although early in the course of appendicitis, the white blood cell (WBC) count has shown the best diagnostic sensitivity among laboratory tests, there are 21% of appendicitis is normal levels of WBC count before appendectomy. 

An elevated serum CRP concentration is not accurate in localizing the site of a urinary tract infection in girls who do not have clinical signs of acute pyelonephritis. 

There is no substitute for serial and prudent clinical examinations during an observation period for abdominal pain, especially the initial epigastric pain or peri-umbilical pain.

4. Pnemonia

For pneumonia, CRP plays the roles of prognosis prediction and therapy reflector rather than making diagnosis. CRP is an independent biomarker of severity in community-acquired pneumonia. 

5. Sepsis
Sepsis is a clinical diagnosis and CRP should never used be rule out infection. Procalcitonin has emerged as the most studied and promising sepsis biomarker. For diagnostic and prognostic purposes in critical care, PCT is superior to CRP and other traditional markers of sepsis.


Take Home

In the ED, CRP should not be used to make a diagnosis but to assist evaluation and support your clinical suspicion. In clinically unwell patients, a normal CRP level should never delay antibiotic coverage in ED.  Like other biomarkers, it does not stand alone. In admitted patinets or those on thepary for chronic inflammatory states, CRP can be used for treatment monitoring and severity. 

References

1. Su YJ. The value of C-reactive protein in emergency medicine. Journal of Acute Disease. 2014 Jan 1;3(1):1-5.
2. Rossi E. C-reactive protein and progressive atherosclerosis.Lancet 2002; 360(9344): 1436-1437.
3. Schillinger M, Domanovits H, Bayegan K, Hölzenbein T, Grabenwöger M, Thoenissen J, et al. C-reactive protein and mortality in patients with acute aortic disease. Intensive Care Med2002; 28(6): 740-745.

Posted by:

              

     Lakshay Chanana

     

     ST4 Trainee

     Royal Infirmary of Edinburgh

     Department of Emergency Medicine

     Edinburgh

     Scotland

     @EMDidactic

Febrile Neutropenia

Neutropenia in oncology patients often results due to chemotherapy. The lowest neutrophil count is generally seen 5 -10 days after the last chemotherapeutic dose and the risk of developing an infection primarily depends on the severity and duration of neutropenia, comorbidities, use of in-dwelling catheters. 

The absolute neutrophil count (ANC) normal range is 1500 to 8000/mm3 (1.5 to 8.0 × 109/L).  Fever is defined as a temperature of 38.3°C on one occasion or 38.0°C persisting >1 hour.


Definitions
Neutropenia is defined as an absolute neutrophil count <1000/mm3(<1.0 × 109/L)
Severe neutropenia is defined as an absolute neutrophil count <500/mm3 (<0.5 × 109/L) Profound neutropenia is defined as an absolute neutrophil count <100/mm3 (<0.1 × 109/L).

Fever is the most common finding seen with bacterial infections in the neutropenic patient. Common symptoms and signs are often absent in the neutropenic patient because impaired inflammatory response. 



Examination (Head to toe to look of any signs of infection)

Lungs
Skin
Urine
Abdomen
CNS

Oral cavity
Perianal area
Intravascular catheters (Thrombophlebitis, Infective Endocarditis)

Avoid doing a Digital Rectal Examination in neutropenic patients. Id necessary, do only after antibiotic administration. 

Work up

• Blood cultures
• Urinalysis, Urine culture,
• CXR
• Sputum, stool, and wound drainage Gram stains and culture 
• FBC, Renal and Liver function  

Treatment 

Known source - Guided Antibiotics
Unknown source and ill patient - Empiric Broad Spectrum Antibiotics

Gram-positive bacteria currently account for more than half of microbiologically confirmed infections in febrile neutropenic patients. Monotherapy with an appropriate broad-spectrum agent is as effective as dual-agent treatment in most circumstances. Consider adding vancomycin if:

• Hemodynamic instability
• Radiographic pneumonia
• Catheter-related infection
• Skin or soft tissue infection
• Known colonization with a resistant gram-positive organism
• Severe mucositis (recent use of fluoroquinolone prophylaxis)

Discussion with patient's treating oncologist should happen simultaneously about the choice of Antibiotics (unless there are agreed existing protocols) and plan for admission v/s discharge since hospitalization may lead to drug-resistant infections. 

A subgroup of patients with febrile neutropenia may appear well with no signs of infection. They are expected to settle their neutropenia within a week have a low risk of severe infection and can be considered for outpatient care in liaison with the Oncologist.        Ensure early follow up for them prior to discharge. 

Decision Rules to risk stratify Neutropenic Patients

Clinical Index of Stable Febrile Neutropenia 

MASCC Risk Index for Febrile Neutropenia 

Clinical evidence supports the benefits of empiric antibiotics only with ANC ≤500/mm. There is little evidence for empiric antibiotics when the ANC >1000/mm. Abx are continued until the infection has clinically resolved and/or the ANC is >500/mm3 (>0.5 × 109/L).

Posted by:

              

     Lakshay Chanana

     

     ST4 Trainee

     Royal Infirmary of Edinburgh

     Department of Emergency Medicine

     Edinburgh

     Scotland

     @EMDidactic

Febrile Seizures

Simple Febrile Seizures 

Generalized tonic-clonic seizure that last <15 minutes with fever 38°C in a child 6 months to 5 years of age that occurs only once in a 24-hour period. Simple febrile seizures tend to occur within the rst 24 hours of a febrileillness. If the seizure occurs > 24 hrs after the onset of fever as in this case, the index of suspicion for a serious bacterial illness should be heightened. Anticonvulsant therapy is not recommended for simple febrile seizures since side effects outweigh the minor risks of seizure recurrence. No dedicated seizure workup is required for simple febrile seizures. The workup should focus on looking for the source of the fever, and the approach should be the same as if the child had only the fever with no seizure. However, lumbar puncture should be strongly considered in children who presnet with signs or symptoms suggestive of intracranial infection or those who are unimmunized. 

The height of fever does

not correlate with seizures; however, the rapidity of the rise in temperature is thought to correlate with the occurrence of seizures.

Complex febrile seizures 

Seizures with fever that last >15 minutes, that recur within a 24-hour period, are focal or generalised, or occur in children <6 months or >5 years of age without any signs of serious infection. The distinction between simple versus complex febrile seizures is important, as complex febrile seizures may indicate a more serious underlying disease process and warrant a workup. Meningitis should always be on thedi erential diagnosis in a child with complex febrile seizures. 

Having a febrile seizure does not mean that a child will develop epilepsy. Risk of epilepsy is approximately 2% after a simple febrile seizure and 5% after a complex febrile seizure (compared with 1% in the general population)

When working up, routine tests include FBC, CRP, Blood Cultures, Urine Analysis, Electrolytes and LP should be considered if:

• Post-ictal >1 hr
• Signs of meningitis
• Irritable
• ALready on Antibiotics
• Unvaccinated
• Complex Partial Seizures

Although antipyretics are indicated in children with fever, there is no evidence that antipyretics can prevent subsequent febrile seizures.

Admission and discharge depends on parental comfort, well/sick looking child but consider admission for the following groups: 

• Complex febrile seizures 
• A child with a febrile fit who is less than 18 months of age 
• The child with no serious clinical findings but who is recently/currently taking antibiotics 
• Children who do not have a clear focus of infection 

References:

• Provisional Committee on Quality Improvement, Subcommittee on Febrile Seizures:practice parameter: the neurodiagnostic evaluation of the child with a first simple febrile seizure. Pediatrics 97: 769, 1996.
• Subcommitte on Febrile Seizures, American Academy of Pediatrics: Neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics 127: 389, 2011.
• Kimia AA, Capraro AJ, Hummel D, et al: Utility of lumbar puncture for first simple febrile seizure among children 6 to 18 months of age. Pediatrics 123: 6, 2009. [PMID: 19117854]
• SteeringCommitteeonQualityImprovementandManagement,SubcommitteeonFebrile Seizures: Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. Pediatrics 121: 1281, 2008.
• https://cks.nice.org.uk/febrile-seizure#!scenario

Posted by:

              

     Lakshay Chanana

     

     Speciality Doctor

     Northwick Park Hospital

     Department of Emergency Medicine

     England

     @EMDidactic

Postpartum Endometritis

Any postpartum women presenting with persistent fever of >38.0C should be assumed to have a genital tract infection until proven otherwise. Other common sources of fever include respiratory tract infection, UTIs, mastitis, and thrombophlebitis. However, Pelvic infection is the most common serious complication of the puerperium.

Risk factors of Postpartum Endometritis

• Cesarean Section
• Multiple Gestation
• Younger maternal age
• Prolonged labour and PROM
• Internal fetal monitoring
• Digital examination 
• Immunocompromised state

Common Bugs (reside in the bowel and colonize the perineum, vagina, and cervix) 

• Gram-positive and gram-negative aerobes, anaerobes
• Chlamydia trachomatis, and Neisseria gonorrhoea
• Gardnerella vaginalis is isolated more often in younger women. 
• MRSA

Many infections are polymicrobial

Clinical Presentation

• Fever 38.0C 
• Foul-smelling loch
• Leukocytosis
• Tachycardia
• Uterine tenderness

ED Management

• ABC
• General Sepsis Care (Fluids, Antibiotics, Cultures, Septic Screen). Combination of Ampicillin or Clindamycin plus gentamicin is sufficient for 90% of patients
• Drainage of abscesses and purulent material or debridement of necrotic tissue 
• OBGYN Consultation 

Complications of endometritis include parametrical spread of infection, pelvic abscesses; infected hematomas; septic pelvic thrombophlebitis; necrotizing fasciitis; and peritonitis. 

Posted by:

              

     Lakshay Chanana

     

     Speciality Doctor

     Northwick Park Hospital

     Department of Emergency Medicine

     England

     @EMDidactic

  

Hyperlactatemia and Lactic Acidosis

I recently came across a young patient with unexplained hyperlactatemia. He came in with severe abdominal pain and was found to have a normal CT Abdomen with a background of ethanol related chronic pancreatitis . He was eventually admitted for pain relief and unexplained hyperlactatemia. So I went back and did a bit of reading on LACTATE...

What is Lactate?

Lactate is the normal endpoint of the anaerobic breakdown of glucose. Most of the lactate production occurs in skeletal muscle, bowel, brain, and RBCs. The lactate generated can be taken up by the liver and converted to glucose (via gluconeogenesis) or can be used as a primary oxidative fuel. In the setting of decreased tissue oxygenation, lactic acid is produced as the anaerobic cycle is utilized for energy production.

Evidence suggests increased morbidity and mortality for patients with  increasing lactate levels or a decreased rate of lactate clearance.

How is lactate cleared from our body?

Lactate is cleared from blood by thru liver, kidneys (10-20%) and skeletal muscles. The ability of the liver to consume lactate is concentration-dependent and progressively decreases as the level of blood lactate increases. 

Lactate producers: skeletal muscle, the brain, the gut, and the erythrocytes. 

Lactate metabolizers: Liver, the kidneys, and the heart.

Lactate v/s Lactic Acid and Hyperlactatemia v/s Lactic Acidosis.

Lactate is not synonymous with lactic acid, and hyperlactatemia is not synonymous with lactic acidosis.

Hyperlactatemia is defined as a persistent, mild to moderate (upto 4-5 mmol/L) increase in blood lactate concentration without metabolic acidosis. It can occur in the setting of adequate tissue perfusion, intact buffering systems, and adequate tissue oxygenation.

Lactic acidosis is characterized by persistently increased blood lactate levels (usually >5 mmol/L) in association with metabolic acidosis. Also, lactic acidosis may not necessarily produce acidemia in a patient. The development of lactic acidosis depends on the magnitude of hyperlactatemia, the buffering capacity of the body, and the coexistence of other conditions that produce tachypnea and alkalosis (eg, liver disease, sepsis). Thus, hyperlactatemia or lactic acidosis may be associated with acidemia, a normal pH, or alkalemia.

D-Lactate and L-lactate

L-lactate and D-lactate are the two isomeric forms of lactate.

L-lactate is the most commonly measured level, as it is the only form produced in human metabolism.

D-lactate is a byproduct of bacterial metabolism and may accumulate in patients with short-gut syndrome or in those with a history of gastric bypass or small-bowel resection

What causes an elevated lactate?

1.   Tissue Hypoxia and Anaerobic Metabolism (Traditional school of thought)
2.   Due to decreased clearance rather than increased production in sepsis
3.   Secondary to down-regulating of pyruvate dehydrogenase in skeletal muscles by inflammatory mediators (Cytokines) and Catecholamines.

Is it possible to have hypoperfusion but a normal lactate level?

Short Answer- YES

For significant increase in blood lactate to occur, lactate must be released into the systemic circulation and the rate of production must exceed hepatic, renal, and skeletal muscle uptake. Therefore, regional hypoperfusion of tissues may be present despite normal blood lactate concentrations.

Types of Lactic Acidosis

• Type A – Poor tissue perfusion or oxygenation of blood (eg, hypotension, cyanosis, cool and mottled extremities). It can be caused by the overproduction of lactate or the underutilization of lactate. For instance, muscular activity, seizures, ischemia, shock, hypoxemia, anemia, CO poisoning.

• Type B - no clinical evidence of poor tissue perfusion or oxygenation exists.

1. Type B1 occurs in association with systemic disease, such as renal and hepatic failure, diabetes and malignancy, thiamine deficiency, infection, pancreatitis, short bowel syndrome. 
2. Type B2 is caused by several classes of drugs and toxins, including biguanides, alcohols, iron, isoniazid, zidovudine, and salicylates.
3. Type B3 is due to inborn errors of metabolism.

List of Possible Causes

•       Sepsis related Hypoperfusion and Mitochondrial Dysfunction
•       Bowel ischemia
•       Severe iron-deficiency anemia, Diabetes mellitus
•       Liver disease, Kidney Disease
•       Alcoholic Ketoacidosis, Pancreatitis
•       Malignancy (leukemia, lymphoma, lung cancer)
•       Seizures
•       Heat stroke, Pheochromocytoma
•       Thiamine deficiency (Remember this one during ICU rounds!)
•       Inborn errors of metabolism - von Gierke disease, fructose-1,6-diphosphatase  deficiency, pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, oxidative phosphorylation deficiency, and methylmalonic aciduria.
•       MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke like episodes) - Characterized by migraine like headaches, dementia, hearing loss, ataxia, and episodic vomiting

What drugs can cause an elevated lactate?

•   Acetaminophen

•   Alcohols and glycols (ethanol, ethylene glycol, methanol, propylene glycol)

•   Antiretroviral nucleoside analogs (zidovudine, didanosine, lamivudine)

•   Beta-adrenergic agents (epinephrine, ritodrine, terbutaline, salbutamol)

•   Biguanides (phenformin, metformin)

•   Cocaine

•   Cyanogenic compounds (cyanide, nitroprusside)

•   5-FU

•   Iron, Isoniazid

•   Propofol

•   Salicylates

•   Sulfasalazine

•   Valproic acid

Click here to listen to Scott Weingart talking about Lactate

Take Home:

• Get familiar with Type B causes of an elevated lactate
• See the medication list and co-morbities while evaluating elevated lactate

Other Resources:
EMCrit/Pulmcrit on Lactate
Resus.me 

Author:

              

     Lakshay Chanana
     
     Speciality Doctor
     Northwick Park Hospital
     Department of Emergency Medicine
     England

     @EMDidactic