Vancomycin Dosing

When to use vancomycin

The most common use for vancomycin is in invasive Gram positive infections

You need to consider

  • Infection site
  • Patient weight
  • Kidney function
  • Pathogen susceptibility

Pharmacokinetics

  • Vancomycin has bad oral bioavailability so it’s almost never used as a pill
    • Occasionally it is orally to supplement C. diff infections (because that’s going on in the GI tract)
  • Volume of distribution: IV serum 0.4-1 L / kg
  • Normally vancomycin doesn’t cross the blood brain barrier very well, but in the setting of meningitis the inflamed meninges increases permeability

Adverse effects

  • Redman syndrome: A histamine-like flushing during or immediately after dose. Occurs mostly on the face and neck. This is NOT life threatening
    • Treatment: anti-histamine, pause infusion, then restart at a slower rate
    • If the reaction is severe, stop the infusion, give antihistamines, wait until symptoms resolve before restarting. When you restart, give the infusion reaaaalllllly slooooooowly (over more than 4 hours)
  • Nephrotoxicity

Dosing

This is where vancomycin can get tricky, because you are aiming for a target trough (between dose) serum concentrations.

  • Generally the target is 10 mcg/ml, but this may need to be higher for treating MRSA or osteomyelitis
  • Trough concentrations should be measured 30 minutes before the 4th dose any time a course of vanco is started or the dose is changed
  • Monitor creatinine at least once a week (remember that whole nephrotoxicity bit)

Starting dose should be 15-20 mg/kg (based on actual not ideal body weight) every 12 hours. This usually works out to 1-2 g IV Q12H. If the kidneys are not working well, reduce the dose.

References

  • UpToDate.com “Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults”

Renal replacement therapy (dialysis)

Renal replacement therapy (RRT) is a process of removing waste products and excess free water from the blood during renal failure and critical illness.
Common indications for RRT can be remembered with the mnemonic AEIOU:
  • (Metabolic) Acidosis
  • Electrolyte abnormalities (especially severe hyperkalemia)
  • Ingestions/toxins (aspirin, lithium, methanol, ethylene glycol)
  • (Volume) Overload
  • Uremia

There are many different variations of RRT, but the main principles behind it can be quite simple.

In hemodialysis, diffusion is responsible for removing unwanted solutes and water. The setup involves a semipermeable membrane that can allow water and some water-soluble molecules to pass. Blood will flow on one side of the membrane, under pressure, while the dialysate (contains glucose and some electrolytes) generally flows on the other side in the opposite direction. This creates a suitable concentration gradient for unwanted molecules to pass into the dialysate, while excess water is forced across the membrane based on the amount of pressure is applied by the dialysis circuit.

In hemofiltration, blood is pushed across a semipermeable membrane, under pressure. Most of the plasma water is able to pass through the membrane, while unwanted molecules get stuck in the membrane (convection). A substitution fluid may be added back to the blood, in order to dilute out waste molecules (e.g., urea), replace useful molecules (e.g., bicarbonate), and to avoid losing too much fluid from the patient’s circulation.
Some modes of RRT will involve both hemodialysis and hemofiltration. Others only use one of these mechanisms.

References

  • Butcher BW, Liu KD. 2013. Renal replacement therapy and rhabdomyolysis. In: Critical Care Secrets (Parsons and Wiener-Kronish, Eds.) Mosby, Philadelpia PA.
  • Hoste E, Vanommeslaeghe. 2017. Renal replacement therapy. In: Textbook of Critical Care (Vincent, Abraham, Moore, Kochanek, and Fink, Eds.) Elsevier, Philadelphia PA.
  • Ricci Z, Romagnoli S, Ronco C. 2015. Extracorporeal support therapies. In: Miller’s Anesthesia (Miller, Ed.) Elsevier/Saunders, Philadelphia PA.

Tumescent Solution (for burn surgery and liposuction and other things too)

tumescent_a

Tumescent solution is also called “Klein’s Solution” after the physician who characterized the recipe and the use of it.

It’s called “tumescent” because it makes things tumescent, which is a fancy word for swollen. Tumescent is a dilute solution of lidocaine, epinephrine, and sodium bicarbonate that is injected in the subcutaneous tissue (fat). The epinephrine is the most important ingredient as it causes vasoconstriction, this means that the blood loss that could be a big problem for large procedures like burn surgery and liposuction becomes much less of a big deal.

The other interesting thing is that since fat is relatively avascular compared to other tissues, the “safe amount” of tumescent is much higher than what is normally stated for injections of lidocaine or epinephrine.

For example, it was reported by Klein that the toxic dose of lidocaine for tumescent solution is 35 mg/kg of body weight.

There are a few different recipes for tumescent anesthesia, the one presented in the doodle is the one first outlined by Klein, some use more or less lidocaine or epinephrine.

References

  1. Kucera IJ1, Lambert TJ, Klein JA, Watkins RG, Hoover JM, Kaye AD. Liposuction: contemporary issues for the anesthesiologist. J Clin Anesth. 2006, 18(5): 379-87.
  2. Klein JA. The tumescent technique. Anesthesia and modified liposuction technique. Dermatol Clin. 1990, 8(3): 425-37.
  3. Klein JA. Tumescent technique for local anesthesia improves safety in large-volume liposuction. Plast Reconstr Surg. 1993, 92: 1085-100.

Clotting Cascade – NOW WITH NOACs

clotting_cascade_NOAC

The clotting cascade was one of the first doodles posted on Sketchy Medicine, I’ve now updated it to include some of the Novel Oral Anticoagulants (NOACs): Dabigatran, Rivaroxaban and Apixiban.

Dabigatran (Pradaxa)

  • Selective, reversible direct thrombin inhibitor
  • Is actually a prodrug that reaches peak concentration 2-3 h post ingestion
  • Approved (in Canada) for:  Thromboprophylaxis in atrial fib, post-op, and treatment of VTE and VTE recurrence
  • T1/2: 7-17 h
  • CYP independent (not as many drug-drug interactions)
  • Excreted in urine 95% / Feces 5%
  • Reversal: hemodialysis?
  • Big trial = RELY, REMEDY

Rivaroxaban (Xarelto)

  • Selective, reversible direct factor Xa inhibitor
  • Approved (in Canada) for:  Thromboprophylaxis in atrial fib, post-op, and treatment of VTE and VTE recurrence
  • T1/2: 3-9 h (relatively speedy!)
  • CYP3A4
  • Very good oral bioavailability
  • Almost all of it is protein-bound in the serum
  • Urine 70% / Feces 30%
  • Reversal: ???? (not hemodialysis)

Apixaban (Eliquis)

  • Selective, reversible direct factor Xa inhibitor
  • Approved (in Canada) for:  Thromboprophylaxis in atrial fib, post-op, and treatment of VTE and VTE recurrence (only atrial fib in the USA)
  • T1/2: 8-15
  • CYP3A4
  • Almost all (95%) protein-bound in the serum
  • Urine 30% / Feces 70%
  • Reversal: ???? (not hemodialysis)

Reversal agents:

  • Hemodialysis
    • Only good for agents that aren’t highly protein bound (i.e. dabigatran).
    • Warfarin, rivaroxaban and apixaban are all mostly bound to protein in the serum, so dialysis won’t get rid of them
  • PCC
    • Plasma-derived product containing factors II, IX and X (3-factor PCC) or II, VII, IX and X (4-factor PCC) in addition to variable amounts of proteins C and S, and heparin
  • aPCC
    • Plasma-derived product containing activated factors II, VII, IX and X
  • Recombinant factor VIIa
    • Looks good in test tubes, clinical evidence lacking
  • Idarucizumab
    • Humanized monoclonal antibody against dabigatran
  • Andxanet alfa
    • Recombinant factor Xa derivative
    • Could theoretically be used for rivaroxaban and apixaban

Anticoagulation Assays

Effect of oral anticoagulants on coagulation assays (Jackson II & Becker, 2014)

(Adapted from Jackson II & Becker, 2014)

Approach to bleeding

Managing target-specific oral anticoagulant (Siegal, 2015)

(From Siegal, 2015)

References

  • Jackson II LR & Becker RC. (2014). Novel oral anticoagulants: pharmacology, coagulation measures, and considerations for reversal. Journal of Thrombosis and Thrombolysis, 37(3), 380-391.
  • Ufer M. (2010). Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thrombosis and Haemostasis. 103: 572-585.
  • Siegal DM. (2015). Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. Journal of Thrombosis and Thrombolysis, 1-8.

Side Effects of Atypical Antipsychotics

antipsychotics

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Atypical (a.k.a., “second-generation”) antipsychotics are commonly used in the treatment of psychotic disorders, and mood disorders as well. Compared to typical (first-generation) antipsychotics, the atypical antipsychotics have lower affinity for dopamine D2 receptors, and they also act at serotonin (5-HT) receptors (they are antagonists for these receptors). Other neurotransmitter receptors are affected as well, and each atypical antipsychotic preferentially antagonizes different receptors.

When atypical antipsychotics were first introduced, it was hoped that they would be more effective than typical antipsychotics and have fewer extrapyramidal side effects (see below). While these expectations may have been somewhat overblown and atypicals are not markedly superior in decreasing psychosis symptoms, most atypicals certainly have a lower risk of developing extrapyramidal side effects. However, they do come with their own array of side effects.

Extrapyramidal side effects (EPSE): These are movement-related side effects caused by dopamine antagonism. These include acute dystonia (torticollis, an uncomfortable muscular spasm of the neck; as well as spasms of the eyes, tongue, jaw), akathisia (motor restlessness and a need to remain in motion), tardive dyskinesia (repetitive, involuntary movements usually involving facial muscles), parkinsonian symptoms (resting tremor, rigidity, slowed movements), and neuroleptic malignant syndrome (potentially fatal!).
Elevated prolactin (PRL): This can lead to gynecomastia (breast growth) and galactorrhea (milk-production), which can be very distressing for male patients! Can also cause infertility and sexual dysfunction. It also happens with typical antipsychotics.
Weight gain: This can be very a troublesome symptom, and may lead to diabetes in some patients.
Sedation: This may prevent patients from engaging in their usual activities and work.
Orthostatic hypotension: Drop in blood pressure after standing from sitting position.

Some antipsychotics have especially severe side effects. Clozapine, for example, is extremely effective in treating psychosis but can lead to fatal agranulocytosis (drop in white blood cells), as well as tremendous weight gain and sedation. Ziprasidone use can lead to QTc prolongation and increase the risk for serious cardiac arrhythmia.

The above chart shows the relative side effect profiles of eight atypical antipsychotics (aripiprazole, clozapine, lurasidone, olanzepine, paliperidone, quetiapine, risperidone, ziprasidon) versus two typical antipsychotics (chlorpromazine, haloperidone).

  • Haddad PM, Sharma SG. 2007. Adverse effects of atypical antipsychotics: Differential risk and clinical  implications. CNS drugs; 21:911.
  • Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lassig B, Salanti G, Davis JM. 2013. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple treatments meta-analysis. Lancet; 382:951.
  • Meltzer HY. 2013. Update on typical and atypical antipsychotic drugs. Annual Review of Medicine: 64:393.
  • Sadock BJ, Sadock VA (Eds.). 2007. Serotonin-dopamine antagonists: Atypical antipsychotics. In: Kaplan & Sadock’s Synopsis of Psychiatry. Lippincott Williams & Wilkins, Philadelphia PA.

Monitoring Neuromuscular Blockade

nmb

As mentioned in a previous post, neuromuscular blocking drugs are used in anesthesia to ensure paralysis during surgery. The degree of neuromuscular block is assessed using nerve stimulation, where two electrodes impose a pulse of current on a peripheral nerve (e.g., ulnar n., facial n., posterior tibial n.) and induce muscle twitches which can then be monitored through the surgery. There are a few different ways to do nerve stimulation :

Tetany: A sustained stimulation (5 s)
Train-of-four (TOF): Four pulses in rapid succession
Double-burst stimulation (DBS): A series of 3 pulses followed after a pause by 2 or 3 pulses.
Post-tetanic potentiation: When a pulse is sent after a tetanic stimulation, it will bring on a stronger twitch than at first.

With non-depolarizing muscle blockers, there is a fade phenomenon where twitch amplitude decreases from the first stimulation. For instance, in a TOF each twitch is weaker than the last; the last twitch is the first to disappear with non-depolarizing blockade, while the first twitch is the last to disappear. This non-depolarizing fade is also seen in DBS and tetany, though there is still post-tetanic potentiation.

With a depolarizing muscle blockade, no fade will be seen. Instead, all twitches in response to stimulation will be uniformly decreased, and there is no post-tetanic potentiation. This pattern is known as a Phase I block. But, if there is a ton of succinylcholine or the blockade is of a long duration, the pattern of response will look like a non-depolarizing block. This would be a Phase II block.

Recovery of neuromuscular function
Throughout a surgery, the TOF ratio is often mentioned as a means of assessing neuromuscular blockade on an ongoing basis. This means dividing the amplitude of the fourth (and most influenced  by neuromuscular blockers) twitch in a TOF by the amplitude of the first (which is the least affected). In normal people, the 4:1 amplitude is the same, for a TOF ratio of 1. In a Phase I depolarizing block, the TOF ratio is also 1. The TOF ratio will be less than 1 in a non-depolarizing block (remember the fade?). It is commonly mentioned that a TOF ratio of 0.7 represents an full recovery of neuromuscular function, but these days it is thought that a TOF ratio of at least 0.9 is needed before extubation.

It is very hard to tell what the TOF ratio is by sight or feel alone! DBS ratio is more sensitive than TOF ratio for assessing neuromuscular block, and it’s easier to gauge by tactile evaluation than the TOF ratio. So, quantitative monitoring by electomyography (EMG), mechanomyography (MMG), or accelerometry is ideal!

  • Fuchs-Buder T. 2010. Neuromuscular monitoring in clinical practice and research. Springer.
  • McGrath CD, Hunter JM. 2006. Monitoring of neuromuscular block. Continuing Education in Anesthesia, Critical Care & Pain; 6:7.
  • Neuromuscular blocking agents. 2006. In: Clinical Anesthesiology (Eds: Morgan GE, Mikhail MS, Murray MJ). Lange.
  • Viby-Mogensen J. 2005. Neuromuscular monitoring. In: Miller’s Anesthesia (Eds: Miller RD, Erikkson LI, Fleisher LA, Wiener-Kronish JP, Young WL). Elsevier.

Induction Agents in Anesthesia

General anesthesia has a bunch of different steps:

  1. Pre-oxygenation/Pre-induction (some people don’t count this as a step)
  2. Induction (putting them “to sleep”)
  3. Maintenance (keeping them asleep)
  4. Emergence (waking them up)

In North America, many physicians like to use a combination of an analgesic and a sedative followed by the induction agent propofol. Sometimes other agents are used for induction such as etomidate or ketamine, particularly if there is a worry about hemodynamic instability as propofol not uncommonly can cause bradycardia and/or hypotension.

If the patient is going to be intubated, a paralytic (muscle relaxant) is also used to relax the vocal cords to prevent unnecessary trauma as the tube is passed through them. Competitive acetyl choline (ACh) receptor antagonists such as rocuronium or succinylcholine are used for this. The main difference between the two is that succinylcholine is a depolarizing agent – meaning that when it first binds to the ACh receptor, it causes a contraction, whereas rocuronium is non-depolarizing – so when it binds nothing happens. So with this pesky contraction thing why would any one choose succinylcholine? The nice thing is that the half-life is much much shorter than rocuronium, so if things don’t work out quite the way you want them to, or you just want something fast, you don’t need to continue to help the patient breath.

Shock

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Shock is “a syndrome resulting from failure of the cardiovascular system to maintain adequate tissue perfusion.”

Weil-Shubin Classification of Shock

  1. Cardiogenic –  Poor cardiac function reduces forward blood flow.
  2. Hypovolemic – Loss of intravascular volume caused by: hemorrhage, dehydration, third space loss, vomiting, diarrhea.
  3. Obstructive – Impair cardiac filling due to external restriction. Caused by cardiac tamponade, tension pneumothorax, pulmonary embolus.
  4. Distributive – Primarily characterized by loss of peripheral vascular tone. Caused by septic, anaphylactic, adrenal insufficiency, neurogenic, liver failure.

Adrenergic Receptors

  • α1: Vasoconstriction
  • α2: Inhibits norepinephrine release, decreases BP, sedative effects
  • β1: Positive inoptrope (increases cardiac contractility and stroke volume)
  • β2: Vasodilation, broncodilation

Vasoactive Drugs

Epinephrine

  • Effects: Causes vasoconstriction and increases cardiac output. Inotrope effect predominates at low doses (< 4.0 mcg/min).
  • Disadvantages: Associated with lactic acidosis, hyperglycemia, pulmonary hypertension, tachyarrythmias, and compromised hepatosplanchnic perfusion.
  • Use: First-line agent for cardiac arrest and anaphylaxis. Second-line agent for vasopressor and inotrope effects, when other agents have failed.

Norepinephrine

  • Effects: Potent vasoconstrictor. Causes a minor increase in stroke volume and cardiac output.
  • Disadvantages: May decrease renal blood flow and increase myocardial oxygen demand. Extravasation at site of intravenous administration may lead to tissue necrosis.
  • Use: First line therapy for maintenance of blood pressure.

Ephedrine

  • Effects: Increases heart rate, cardiac output. Bronchodilator. Some anti-emetic effects. Longer duration than epinephrine. Has indirect actions on adrenergic system.
  • Disadvantages: Epedrine losses effect with subsequent doses since part of its effect is indirect, by icreasing NE release, which becomes depleted
  • Use: Common vasopressor during anesthesia, but only a temporizing agent in acute shock.

Dopamine

  • Effects are dose-dependent:
    • < 5 mcg/kg/min – Acts at dopamine receptors only, with mild inotrope effect. Vasodilatory effects purported to improve perfusion through renal and mesenteric vessels; however, there is no clear clinical benefit of dopamine on organ function.
    • 5-10 mcg/kg/min – Predominantly β1 adrenergic effects. Increases cardiac contractility and heart rate.
    • >10 mcg/kg/min – Predominately α1 effects, causing arterial vasoconstriction and increased blood pressure. Overall decrease in renal and splanchnic blood flow at this dose.
  • Disadvantages: Has a high propensity for tachycardia and dysrythmias. Potential for prolactin suppression and immunosuppression.
  • Use: First line vasopressor for shock, but may be associated with more adverse outcomes than norepinephrine.

Dobutamine

  • Effects: Racemic mixture. where the L-isomer acts at α1/β1 receptors and D-isomer acts at β1/β2 receptors. Increases cardiac output and decreases systemic/pulmonary cascular resistance. Can increase splanchnic blood flow and decrease endogenous glucose production.
  • Disadvantages: May cause mismatch in myocardial oxygen delivery and requirement. Vasodilation undesirable in septic patients.
  • Use: A ‘gold standard‘ inotropic agent in cardiogenic shock with low output and increased afterload. In sepsis, vasodilatory effects should be counteracted by co-administration with norepinephrine.

Dopexamine

  • Effects: Acts at β2 and dopamine receptors. Causes vasodilation and decreased afterload. Has some positive inotrope effect. Bronchodilatory. Unlike dopamine, dopexamine is not associated with pituitary suppression.
  • Disadvantages: Not widely accepted in practice.
  • Use: Like dobutamine, useful for cardiogenic shock with decreased output and high afterload.

Phenylephrine

  • Effects: Classic selective α1 agonist, causing vasoconstriction. Rapid onset and short duration.
  • Disadvantages: Can reduce hepatosplanchnic perfusion. May cause significant reflex bradycardia.
  • Use: Generally considered a temporary vasopressor until more definitive therapy is begun. Useful for vasdilated patients with adequate cardiac output, for whom other vasopressors present risk of tachyarrhythmias.

Dexmedetomidine/Clonidine

  • Effects: Arousable sedation with preserved respiratory drive. Improved tissue perfusion and renal function. General sympathetic inhibition.
  • Disadvantages: Bradycardia and hypotension.
  • Use: Not used in acute shock setting, but may be useful in later critical care setting.

Vasopressin (not actually an adrenergic drug)

  • Effects: Acts on V1 receptors to cause vasoconstriction. Increases vasculature response to catecholamines.
  • Disadvantages: May cause tachycardia and tachyarrythmias. Excessive vasoconstriction can impair oxygen delivery and and cause limb ischemia.
  • Use: May be used to augment norepinephrine or other agents. Not typically used alone.

Local Anesthetics and Freezing Fingers

Local anesthetics work by blocking afferent pain sensation. This is great because it means that the patient can be wide awake and not able to feel you reduce their fracture, sew up their gaping laceration or release their carpal tunnel.

Most local anesthetics fall into two broad categories, the esters and the amides. To remember which is which, think about amIdes having an I in the prefix and esters not.

Amides Esters
Lidocaine (Xylocaine)
Mepivacaine
Bupivacaine
Ropivacaine
Procaine (Novocaine)
Chloroprocaine
Cocaine
Benzocaine

Epinephrine can be added to local anesthetics to induce vasoconstriction. This reduces blood loss and prevents excess systemic spread of the anesthetic. As a result, the maximum dose and the duration of action are less without epi than with.

Duration Maximum Dose
Lidocaine without 0.5-1h 5mg/kg (35mL of 1% for a 70kg adult)
Lidocaine with epi 2-6h 7mg/kg (49mL of 1% for 70kg adult)

Signs of local anesthetic overdose

  • Early signs: Perioral numbness/tingling, tinnitus
  • Severe toxicity: grand mal seizures
    * Some people are sensitive to the metabolite PABA that the ester class produces, however amides do not have this metabolite.

How to Freeze a finger

Ring blocks (aiming for the digital nerves on either side of the finger) ARE NOT necessary, you just increase the likelihood that you’re going to injure one with the needle. Instead do a single poke on the volar aspect of the MCP joint, perpendicular to the skin and inject 2-3 cc.  The freezing should go in without much resistance, too much means that the needle is either in the dermis or in the flexor tendon sheath. This should freeze the entire volar aspect of the finger and roughly to from the tip to the DIP joint on the dorsum. If you need the entire finger frozen (e.g. for a reduction), you can also inject 1-2 cc on the dorsal MCP.

The smaller the needle, the less pain is caused by the freezing (which is acidic and stings more than you’d think). Adding 1 cc of bicarb for every 10cc of lidocaine also helps reduce pain, making you a nice person.

Cephalosporins (generations and spectrum of activity)

Cephalosporins work much like penicillins, inhibiting peptidoglycan cell wall synthesis in bacteria (remember those sites of action and mechanisms?)

Of course the issue is that they just keep making new cephalosporins and each generation is a little bit different in terms of its spectrum and whether it’s better at fighting Gram positive or Gram negative bacteria. Generally the newer the generation, the more broad spectrum and less Gram positive coverage. To add another layer to the confusion, there are separate oral and IV cephalosporins for each generation and all of the cephalosporins are usually recognizable by starting with “CEF-” or “KEF-” (except for Suprax and Ancef, who ever came up with those brand names didn’t get the memo)