SEPSIS MIMICS

"one can mimic the result,
but can not mimic the creativity"

Sepsis is the clinical syndrome that results from a dysregulated inflammatory response to an infection, often leading to organ dysfunction. It is still associated with high mortality and financial burden.

Sepsis is one of the challenge, that keeps on intriguing critical care physician time and again. Several diseases closely masquerade sepsis, due to similar pathophysiology of immune modulation. 

Sometimes it becomes challenging to differentiate sepsis from these mimics as critically ill patients have multiple confounding factors from hospital acquired infections to drug interactions and toxicity.

●LINEZOLID INDUCED LACTIC ACIDOSIS :
Linezolid is the precious arsenal for VRSA (vancomycin resistant staph. aureus), VRE (vancomycin resistant enterococcus) and MDR tuberculosis.

•Presentation of linezolid induced lactic acidosis is characterized by nausea, pain abdomen, altered mental state, hypotension and high anionic gap metabolic acidosis. Serious consequences such as refractory shock, cardiac dysfunction, multi organ failure and death may result.

There is currently no data available about incidence and risk factors of linezolid induced lactic acidosis.

•Mechanism: Linezolid binds to bacterial ribosomal RNA and inhibits protein synthesis. Due to molecular mimicry between bacterial ribosome and mammalian cytoplasmic ribosome, linezolid binds to mammalian ribosome,  resulting in impaired activity if mitochondrial respiratory chain complexes and enzymes. 

Thus decreased celluar aerobic metabolism results in lactic acidosis. 

Lactic acidosis associated with the use of linezolid, may occur, at any time during the course of therapy. 

In a 2008 report of the results of a survey, conducted by the Infectious Diseases Society of America Emerging Infections Network, 32% of identified 29 cases developed lactic acidosis after a treatment duration less than 15 days.

•Treatment: Discontinuation of linezolid is shown to be sufficient, to resolve lactic acidosis. Dialysis and hemofiltration is not very effective in correcting lactic acidosis (only 3% of lactate is cleared by dialysis), but can be helpful in partial removal of linezolid.

Respiratory chain cofactors, such as thiamine, riboflavin, L-carnitine or coenzyme Q10, has been attempted in a few cases as a strategy to treat lactic acidosis. Evidence to support the systematic use of respiratory chain cofactors is, however, lacking.

●PROPOFOL RELATED INFUSION SYNDROME:
Propofol related infusion syndrome (PRIS) is defined as abrupt onset of profound and refractory bradycardia in the presence of lipemic plasma, hepatomegaly, myoglobinuria, severe metabolic acidosis, rhabdomyolysis, cardiovascular collapse and acute kidney injury.

However numerous case reports have reported tachycardia as common abnormality observed, it has been argued that definition should be revised to state myocardial failure with dysrhythmias instead of profound bradycardia.

True incidence of PRIS is not known probably because of poor reporting. Mortality rate has been 64% in reported cases.

Propofol is highly lipophilic and insoluble in water. It is formulated as lipid emulsion, containing lecithin and soyabean oil, for intravenous use. Therefore it has a high risk of contamination by bacteria and fungi.

•Predisposing factors for PRIS are young age, critical illness (acute neurologic injury, trauma, sepsis, pancreatitis), low carbohydrate and high fat intake, inborn errors in mitochondrial fatty acid oxidation; while triggering factors are propofol dose more than 4 mg/kg/hour, infusion duration more than 48 hours, catecholamine infusion and corticosteroid use.

•Pathophysiology of PRIS has been suggested as, uncoupling of oxidative phosphorylation in mitochondrial electron transport chain, impaired fatty acid oxidation, diversion of carbohydrate metabolism to fat substrate, and or presence of unidentified metabolites. The resulting accumulation of fatty acid intermediates and reduced ATP production, causes tissue hypoxia.

In addition, excessive concentrations of serum fatty acids has proarrhythmic effects. Propofol also impairs binding of catecholamines to adrenergic receptors, thereby potentiating hypotension and increasing dose of vasopressor drugs.

Warning signs of PRIS are unexplained, new onset lactic acidosis, increased creatinine phosphokinase, myoglobinuria, arrhythmias and hypotension and cardiac dysfunction.

Development of Brugada like EKG abnormality (RBBB with coved ST elevation in V1-3 leads) has been reported as early sign of PRIS.

Appearance of or worsening metabolic acidosis, in patient on propofol infusion, should raise the suspicion of PRIS.

•Prevention of PRIS is limiting the propofol dose to less than 4 mg/kg/hour and duration less than 48 hours, in patients with risk factors for PRIS.

Adequate carbohydrate intake may be protective against PRIS, by preventing switch to fat metabolism.

•Management: early recognition, discontinuation of propofol and switching over to alternate sedative agent. Cardiovascular support and pacing if required. Hemodialysis or hemofiltration for elimination of propofol and other toxic metabolites. 

However PRIS is often fatal and patient are unresponsive to vasoactive medication.

●HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS:
Hemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive, life-threatening syndrome of excessive immune activation. Trigger for immune activation may be genetic defect or secondary to infection, rheumatologic, neoplastic or metabolic diseases.
If left untreated, patients die in a few months, due to progressive multiorgan failure.

•Presentation is characterized by fever of unknown origin, organomegaly, skin rashes, jaundice, hypotension, respiratory failure, bleeding, encephalopathy, seizures and metabolic acidosis.

Laboratory findings are bicytopenia or pancytopenia, coagulopathy, hypofibrinogenemia, hyperferritinemia, transaminitis, hyperbilirubinemia, hypoalbuminemia, hyperlipidemia and hyponatremia.

•Pathophysiology- exact pathogenesis is not well understood. Hyperactivation of CD8+T lymphocytes and macrophages, proliferation, ectopic migration, and infiltration of these cells into various organs; hypercytokinemia with persistently elevated levels of proinflammatory cytokines, result in progressive organ dysfunction and death.

•Diagnosis is often delayed or missed because clinical presentation masquerades with sepsis and lack of laboratory investigations to confirm the diagnosis.

The initial evaluation includes a complete blood count with differential, coagulation studies, serum ferritin, liver function tests, triglycerides, blood cultures, and viral testing.

The bone marrow should be examined for the cause of cytopenias, infectious organisms, hemophagocytosis, and macrophage infiltration; and sent for cultures.

All patients should have cerebrospinal fluid analysis and magnetic resonance imaging of the brain. Computed tomography scans of the neck, chest, abdomen and pelvis should be done to evaluate for possible malignancy.

•Diagnostic criteria:
The diagnosis of HLH can be established if one of either 1 or 2 below is fulfilled:

1. A molecular diagnosis consistent with HLH is made.

2. Diagnostic criteria for HLH are fulfilled (5 of the 8 criteria below):
●Fever ≥38.5°C
●Splenomegaly
●Peripheral blood cytopenia, with at least two of the following: hemoglobin <9 g/dL (for infants <4 weeks, hemoglobin <10 g/dL); platelets<100,000/microL; absolute neutrophil count <1000/microL
●Hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenemia (fibrinogen <150 mg/dL)
●Hemophagocytosis in bone marrow, spleen, lymph node, or liver
●Low or absent NK cell activity
●Ferritin >500 ng/mL (the author prefers to consider a ferritin >3000 ng/mL as more indicative of HLH [68])
●Elevated soluble CD25 (soluble IL-2 receptor alpha) two standard deviations above age-adjusted laboratory-specific norms.

•Treatment:
Patients should be urgently referred to a hematology or oncology specialist.

Treatment of underlying trigger like infection, rheumatologic disease, maglignancy.

Immunosuppressive drugs and chemotherapy and hematopoetic stem cell transplantation (HCT) are cornerstone of therapy.

Median survival for patients with HLH is approximately 50 percent. Poor prognostic factors include younger age, CNS involvement, and failure of therapy to induce a remission prior to HCT.

●FAT EMBOLISM SYNDROME:
FES is characterized by triad of hypoxemic respiratory failure, neurologic abnormality and typical petechial rash, developing 24 to 72 hours after long bones or pelvic fractures.

•Pathophysiology involves fat globules entering the bloodstream through tissue (usually bone marrow or adipose tissue) causing mechanical obstruction in pulmonary and systemic circulation, and production of the toxic intermediaries of plasma-derived fat leading to activation of inflammatory cascade.

•Clinical presentation include petechial rash neck and upper part to chest, altered level of consciousness, hypotension, acute hypoxic respiratory failure, acute kidney injury and DIC.

•Diagnosis: FES is a clinical diagnosis that can be made when the pathognomonic petechial rash occurs in an appropriate clinical setting.

However, since the rash occurs in fewer than half of cases, the diagnosis is more commonly made when characteristic signs (ie, hypoxemia, respiratory insufficiency, neurologic impairment) occur in the appropriate clinical setting and no alternative explanation exists.

It is a common misconception that finding fat globules in sputum, urine, or blood drawn from a wedged PA catheter is necessary to confirm the diagnosis of FES.
In fact, the recovery of fat globules is of uncertain significance. In one study, the presence of fat was demonstrated in the serum of more than 50 percent of fracture patients without symptoms suggestive of FES.

Demonstration of fat globule in alveolar macrophages in BAL may be supportive in diagnosis.

Many diagnostic criteria are proposed to help in diagnosis like Gurd’s criteria, fat embolism index.

▪Gurd’s Criteria for FES diagnosis:
Major Criteria-
· Axillary or subconjunctival petechiae
· Hypoxaemia (PaO2<60)
· Depressed consciousness disproportionate to hypoxaemia
· Pulmonary odema
Minor criteria-
· Tachycardia >110
· Fever >38.5 C
· Retinal emboli on fundoscopy
· Sudden drop in hematocrit or platelet
· Increasing ESR
· Fat globules in sputum

•Treatment:
Supportive care is the mainstay of therapy for clinically apparent fat embolism syndrome.

Mortality is estimated to be 5-15% overall, but most patients will recover fully.

Early immobilization of fractures reduces the incidence of fat embolism syndrome and the risk is further reduced by operative correction rather than conservative management.

Another strategy to prevent fat embolism syndrome is to limit the elevation in intraosseous pressure during orthopaedic procedures, in order to reduce the intravasation of intramedullary fat and other debris.

Although there are published reports suggesting that corticosteroids may be beneficial in preventing FES, the evidence is insufficient to recommend them routinely for patients with confirmed FES. However, for those patients with life-threatening cases of FES, a limited trial of systemic corticosteroids could be considered, but there is little in the literature to guide either the dosing or timing of the medication.

●AMNIOTIC FLUID EMBOLISM SYNDROME:
Amniotic fluid embolism syndrome (AFES) is characterized by abrupt and fulminant onset of altered mentation or seizures, hypotension, hypoxic respiratory failure and DIC, manifesting during labour or immediate postpartum.
Rarely, it has been reported as late as 48 hours after cesarean delivery or postpartum, as well as following a first or second trimester abortion, amniocentesis, or abdominal/ uterine trauma.

•Diagnoses: AFES is a clinical diagnosis, based on constellation of clinical symptoms and signs during labour and immediate postpartum.

Amniotic fluid debris (squamous cells, trophoblastic cells, mucin, and lanugo) can be detected in blood samples drawn from pulmonary circulation by a pulmonary artery catheter.

However, finding amniotic fluid debris should not be considered diagnostic of AFES since such debris is common in the maternal circulation of women without AFES.

Serological assays that detect a fetal antigen, TKH-2 or insulin-like growth factor binding protein-1, appear to have a high sensitivity for detecting AFES.

•Treatment: There is no specific treatment for AFES.
The goal of therapy is to rapidly correct hypoxemia and hypotension, so that ischemic consequences (hypoxic brain injury, acute kidney injury, and myocardial injury) in the mother are prevented and adequate oxygen delivery to the fetus is ensured.

The maternal mortality rate due to AFES has been reported from 10 to 90 percent, however recent data has suggested that overall mortality rates may be closer to 20 percent. But patient who survive generally have a poor outcome, with as many as 85 percent suffering significant neurologic injury due to cerebral hypoxia.