Shock is defined as a state where the organs and tissues of the body are not receiving adequate blood perfusion and ultimately, enough oxygen. When this state of hypoperfusion occurs in the context of infection, it is termed “septic shock”.
The mechanism of septic shock becomes problematic due to its widespread nature within the body. When bacteria are degraded, free LPS is released which binds to LPS-binding protein intravascularly. CD14, located on monocytes and macrophages, then binds this LPS-LPS binding protein complex and subsequently recruits and activates monocytes via the Toll-like receptor (TLR). As macrophages become activated, they release interleukin-1 (IL-1) and tumour necrosis factor (TNF). The widespread nature of this reaction causes systemic vasodilation, leading to hypotension and inadequate end organ perfusion, decreased myocardial contractility, diffuse endothelial injury, and disseminated intravascular coagulation.
Kemp, W. L., Burns, D. K., & Brown, T. G. (2008). Pathology: The big picture. New York: McGraw-Hill Medical.
King, E. G., Bauzá, G. J., Mella, J. R., & Remick, D. G. (2013, September 23). Pathophysiologic mechanisms in septic shock. Retrieved from https://www.nature.com/articles/labinvest2013110
Refeeding Syndrome is a set of clinical complications that typically occur in severely malnourished patients as a result of aggressive fluid and electrolyte shifts during oral, enteral, or parenteral nourishment.
What conditions put you at risk for Refeeding Syndrome?
Anything that can cause ongoing electrolyte losses (Diarrhea, vomiting, fistulas)
Any condition that places patients in the ICU
What are the clinical manifestations of Refeeding Syndrome?
Prolonged malnourishment leads to decreased carbohydrate intake which reduces serum glucose and ultimately a decreased insulin secretion. As a result, energy supply to the tissues and organs of the body is maintained through lipolysis and protein catabolism which causes intracellular losses of electrolytes, particularly phosphate.
When glucose is re-introduced into the malnourished patient, insulin secretion goes up, and rapidly drives phosphate into cells (including potassium) causing a decrease in the serum concentration of these electrolytes.
Hypophosphatemia:See mechanism above. Insulin also causes several molecules to utilize phosphate (i.e. ATP and 2-3 DPG) which further exacerbates the hypophastatemia. The decrease in phosphorylated intermediates contributes to tissue hypoxia and subsequent myocardial dysfunction, but also causes an inability of the diaphragm to contract which can cause respiratory failure. Hypophosphatemia can also induce: rhabdomyolysis, seizures, and delirium)
Hypokalemia:See mechanism above.
Vitamin and trace mineral deficiencies: due to decreased nutritional intake
Volume overload: insulin secretion can stimulate renal sodium absorption and retention and ultimately, fluid retention which can push a patient into congestive heart failure.
Fuentebella, J., & Kerner, J. A. (2009). Refeeding Syndrome. Pediatric Clinics of North America,56(5), 1201-1210. doi:10.1016/j.pcl.2009.06.006
Hearing, S. D. (2004). Refeeding syndrome. Bmj,328(7445), 908-909. doi:10.1136/bmj.328.7445.908
The Frank-Starling mechanism is a relationship characterizing stroke volume with pre-load. Stroke volume is dependent on the following:
Pre-load: changes in pre-load affect the end-diastolic volume/pressure which in turn alter stroke volume
Contractility: can be influenced by sympathetic/parasympathetic nervous system changes and electrolytes. Increases in contractility cause decreases in end-systolic volume while decreases in contractility result in increased end-systolic volumes.
Afterload: can be altered by changes in vascular resistance or damage to semi-lunar valves of the heart
In a normal heart, increasing pre-load or venous return will result in increased contractility leading to increased stroke volume and ultimately leading to increased cardiac output (CO= Heart Rate x Stroke Volume).
When heart failure occurs, increases in pre-load do not result in a stroke volume sufficient to meet the demands of the body’s peripheral tissues. As a result of the decreasing effective circulating volume of blood, the body responds with multiple ways in an effort to increase tissue perfusion. These include:
Activation of renin-angiotensin-aldosterone system
Activation of sympathetic nervous system
The systemic vasoconstriction that results from the above mentioned mechanisms can sustain cardiac output in a heart failure patient for a limited time. As the disease progresses, the cardiac output does not increase appropriately despite increased pre-load. Eventually, the increased in left ventricle end diastolic volume/pressure transmits pressure back to the pulmonary veins leading to the symptoms of pulmonary congestion (dyspnea, orthopnea, PND, etc).
QT interval is the length between the beginning of the QRS complex (ventricular depolarization) and end of the T wave (ventricular re-polarization).
QTc is prolonged if > 440ms in men or > 460ms in women
QTc >500ms is associated with increased risk of torsades de pointes
QTc is abnormally short if < 350ms
A useful rule of thumb is that a normal QT is less than half the preceding RR interval
QTc prolongation can be caused by the following:
Goldstein, J. N., Dudzinski, D. M., Erickson, T. B., & Linder, G. (2018). Case 12-2018: A 30-Year-Old Woman with Cardiac Arrest. New England Journal of Medicine,378(16), 1538-1549. doi:10.1056/nejmcpc1800322
QT Interval. Edward Burns, Last updated November 21, 2017.https://lifeinthefastlane.com/ecg-library/basics/qt_interval/
Classical findings of Normal Pressure Hydrocephalus (NPH) include:
Ataxia (typically the initial and most prominent symptom of NPH)
Urinary Incontinence (typically appears late in the illness)
Abnormal accumulation of cerebrospinal fluid (CSF) gradually dilates the lateral ventricles of the brain. The gradual nature of ventriculomegaly allows for the CSF pressure to adapt and remain normal, hence normal pressure hydrocephalus.
CSF accumulation in the lateral ventricles puts pressure on adjacent cortical tissue and results in the triad listed above.
Verrees M, Selman WR. Management of normal pressure hydrocephalus [summary for patients in Am Fam Physician. 2004;70(6):1085-1086]. Am Fam Physician. 2004;70(6):1071-1078.
McGirt MJ, Woodworth G, Coon AL, et al. Diagnosis, treatment, and analysis of long-term outcomes in idiopathic normal-pressure hydrocephalus. Neurosurgery. 2005;57(4):699-705; discussion 699-705.
Metformin belongs to the Biguanide class of medications used to treat Type 2 Diabetes. Metformin works by decreasing the amount of glucose produced by the liver, improving insulin sensitivity, and by increasing cellular uptake of glucose.
In patients who develop acute or chronic renal failure, the clearance of metformin is decreased resulting in an increased risk of lactic acidosis, which may have a mortality rate up to 50%. Patients who receive IV contrast fluid are at risk for contrast-induced nephropathy and if they are concurrently on metformin, they may experience potentially fatal lactic acidosis. To avoid this issue, most patients scheduled to receive IV contrast have their metformin medication stopped at the time of contrast administration for at least 48 hours after the procedure.
In some patients who have preserved renal function and are receiving small amounts of contrast (< 100 mL), stopping the metformin may not be necessary because the risk of contrast-induced nephropathy is very low in these patients.
1. Baerlocher, M. O., Asch, M., & Myers, A. (2012). Metformin and intravenous contrast. Canadian Medical Association Journal,185(1). doi:10.1503/cmaj.090550
2. BenkoA, Fraser-HillM, MagnerP, et al.Canadian Association of Radiologists.Canadian Association of Radiologists: consensus guidelines for the prevention of contrast-induced nephropathy. Can Assoc Radiol J 2007;58:79–87.
Avascular necrosis of the femoral head (ANFH) occurs when the blood supply to the femoral head is interrupted resulting in ischemia, death of the bone cells, and bone collapse.
Non-traumatic ANFH is a serious and common problem that can occur when patients are on glucocorticoid (GC) therapy; between 5-40% of patients treated with long-term glucocorticoid therapy will develop ANFH.
Although, the exact and complete mechanism of ANFH due to GC therapy is still under determination, a few mechanisms have been proposed.
1. Hypercoagulable Conditions
It is thought that GCs can alter endothelial function by modulation of the Alpha-2-
Macroglobulin (A2M)* gene and also by exerting effects on thrombosis formation. It is believed that through A2M and thromobosis formation alterations, GCs cause ischemia which ultimately results in ANFH.
A2M: a protein that plays a role in thrombosis by influencing inflammation, cell shedding, inhibiting fibrinolysis, and hemostatic plug formation.
2. Angiogenesis Suppression
It is hypothesized that angiogenesis is interrupted in patients with ANFH, however, the complete mechanism is not well understood.
Studies have shown that there is a relationship between ANFH and expression of VEGF. VEGF plays a key role in stimulating angiogenesis, but is also important in bone formation and repair. It has also been shown that when bone tissue undergoes VEGF gene transfection, the processes of angiogenesis and bone repair in necrotic bone are stimulated. These studies suggest that there is a correlation between use of GCs and angiogenesis suppression, however it remains to be more completely elucidated.
3. Increased Adipogenesis
Although, the link between increased adipogenesis and long-term use of GCs is not completely understood, studies have shown the presence of an association.
Kim et al. (2008) looked at the association between sterol regulatory element binding factor (SREBP-2) gene polymorphisms and the risk of ANFH in the Korean population. SREBPs play a role lipogenesis, cholesterol homeostasis, and adipocyte development. In 2009, a study by Lee et al. showed that a polymorphism in intron 7 of the SREBP-1 gene was associated with increased likelihood of ANFH. Although, the relationship is still unclear, these studies do suggest the possibility of alterations in adipogenesis by GC therapy.
4. Bone Remodelling Shifting to Bone Resorption
Bone morphogenetic proteins (BMPs) are proteins that are important in maintaining bone density through remodelling and repair processes. BMPs act as signals, or differentiating factors, which help convert mesenchymal cells into cells involved in forming bone and cartilage. Studies have shown that transfecting bone marrow stem cells with the human BMP-2 gene can repair early-stage ANFH. The results of these studies suggest that in ANFH, bone remodelling and repair may be altered by the use of GCs.
Pouya, Farzaneh, and Mohammed Amin Kerachian. “Avascular Necrosis of the Femoral Head: Are Any Genes Involved?” The Archives of Bone and Joint Surgery 3.3 (2015): 149-55.
Chim SM, Tickner J, Chow ST, Kuek V, Guo B, Zhang G, et al. Angiogenic factors in bone local environment. Cytokine Growth Factor Rev. 2013;24(3):297–310.
Peng H, Wright V, Usas A, Gearhart B, Shen HC, Cummins J, et al. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest. 2002;110(6):751–9.
Samara S, Dailiana Z, Varitimidis S, Chassanidis C, Koromila T, Malizos KN, et al. Bone morphogenetic proteins (BMPs) expression in the femoral heads of patients with avascular necrosis. Mol Biol Rep. 2013;40(7):4465–72.
Kim TH, Baek JI, Hong JM, Choi SJ, Lee HJ, Cho HJ, et al. Significant association of SREBP-2 genetic polymorphisms with avascular necrosis in the Korean population. BMC Med Genet. 2008;9:94.
Lee HJ, Choi SJ, Hong JM, Lee WK, Baek JI, Kim SY, et al. Association of a polymorphism in the intron 7 of the SREBF1 gene with osteonecrosis of the femoral head in Koreans. Ann Hum Genet. 2009;73(1):34–41.
Cao K, Huang W, An H, Jiang DM, Shu Y, Han ZM. Deproteinized bone with VEGF gene transfer to facilitate the repair of early avascular necrosis of femoral head of rabbit. Chin J Traumatol. 2009;12(5):269–74.
Tumour lysis syndrome (TLS) is an oncologic emergency that most often occurs following initiation of cytotoxic therapy, especially in patients with acute lymphoblastic leukemia (ALL). Lysis of tumour cells results in the release of large amounts of potassium, phosphate, and nucleic acids. Nucleic acids are catabolized into uric acid, which leads to hyperuricemia. Excess uric acid excretion can precipitate in the renal tubules and lead to acute kidney injury (AKI) through decreased renal blood blow and inflammation. Excess phosphate can also lead to AKI through calcium phosphate deposition in the renal tubules.