AEDs in Renal Failure / Hemodialysis


How does renal disease affect AED levels?

  • Renal insufficiency alters the pharmacokinetics of seizure medications that are metabolized by the kidneyes, leading to increased half-lives and accumulation of the drug.
  • Albuminuria and acidosis that frequently occur in renal failure also decreases drug binding, increasing the free levels of AEDs and volume of distribution.
  • Gastroparesis delays maximum serum levels of AEDs, intestinal edema diminishes absorption of AEDs.

Take home message:  It is difficult to predict drug levels based on the creatinine clearance.

AEDs that are extensively eliminated by kidneys:

  • hydrosoluble
  • low molecular weight
  • low Vd
  • little protein-bound
  • Examples:  gapabentin, topiramate, ethosuxamide, vigabatrin, levetiracetam
  • accumulate in renal disease
  • easily removed by hemodialysis and requires post-HD administration

AEDs that are not extensively eliminated by kidneys:

  • lipophylic
  • high protein-bound
  • Examples:  carbamazepine, phenytoin, lamotrigine, benzodiazepines, valproate
  • little affected by renal disease
  • HD has little impact on carbamazepine, phenytoin and valproate levels
  • HD has unpredictable effects on benzodiazepines or oxcarbazepine monohidroxi derivative
  • 4-hour HD decreases lamotrigine levels by ~20%

Peritoneal dialysis has variable effects on AED serum levels, check free levels for drug adjustment


  • CrCl >80 mL/minute/1.73 m2: 500 to 1,500 mg every 12 hours
  • CrCl 50 to 80 mL/minute/1.73 m2: 500 to 1,000 mg every 12 hours
  • CrCl 30 to 50 mL/minute/1.73 m2: 250 to 750 mg every 12 hours
  • CrCl <30 mL/minute/1.73 m2: 250 to 500 mg every 12 hours
  • End-stage renal disease (ESRD) requiring hemodialysis: Dialyzable (50%); 500 to 1,000 mg every 24 hours; supplemental dose of 250 to 500 mg is recommended posthemodialysis
  • Peritoneal dialysis (PD): 500 to 1,000 mg every 24 hours (Aronoff 2007)
  • Continuous renal replacement therapy (CRRT): 250 to 750 mg every 12 hours (Aronoff 2007)


  • There are no dosage adjustments provided in the manufacturer’s labeling; <5% excreted as unchanged drug. Serum concentration may be difficult to interpret in renal failure. Monitoring of free (unbound) concentrations or adjustment to allow interpretation is recommended.
  • Fosphenytoin:  There are no dosage adjustments provided in the manufacturer’s labeling. Free (unbound) phenytoin levels should be monitored closely in patients with renal disease or in those with hypoalbuminemia; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in these patients leading to increase frequency and severity of adverse events.


  • Dosage adjustments are not required or recommended in the manufacturer’s labeling; however, the following guidelines have been used by some clinicians:
  • Children and Adults:
    • GFR <10 mL/minute: Administer 75% of dose
    • Hemodialysis, peritoneal dialysis: Administer 75% of dose (postdialysis)
  • Continuous renal replacement therapy (CRRT):
    • Adults: No dosage adjustment recommended
    • Children: Administer 75% of dose


  • There are no specific dosage adjustments provided in the manufacturer’s labeling; reduced doses are recommended.
  • The following guidelines have been used by some clinicians:
    • CrCl ≥10 mL/minute: No dosage adjustment necessary.
    • CrCl <10 mL/minute: Administer every 12 to 16 hours.
    • HD (moderately dialyzable [20% to 50%]): Administer dose before dialysis and 50% of dose after dialysis.
    • PD:  Administer 50% of normal dose.
    • CRRT: Administer normal dose and monitor levels.


  • Mild to severe impairment: No dosage adjustment necessary (including patients on hemodialysis); however, due to decreased protein binding in renal impairment, monitoring only total valproate concentrations may be misleading.



  • Dosing: Renal Impairment
  • Oral: No dosage adjustment necessary
  • IM, IV: Risk of propylene glycol toxicity. Monitor closely if using for prolonged periods of time or at high doses.
    • Mild-to-moderate disease: Use with caution.
    • Severe disease or failure: Use is not recommended.


  • Dosing: Renal Impairment
    • There are no dosage adjustments provided in manufacturer’s labeling; however, patients with renal failure receiving a continuous infusion cannot adequately eliminate the active hydroxylated metabolites (eg, 1-hydroxymidazolam) contributing to prolonged sedation sometimes for days after discontinuation
  • Intermittent HD:  Supplemental dose not necessary
  • CVVH: Unconjugated 1-hydroxymidazolam not effectively removed; 1-hydroxymidazolamglucuronide effectively removed; sieving coefficient = 0.45
  • PD: Significant drug removal unlikely


  • There are no dosage adjustments provided in the manufacturer’s labeling. Decreased maintenance dosage may be effective in patients with significant renal impairment; has not been adequately studied; use with caution.


  • No dosage adjustment necessary.



Lacerda, Glenda Corrêa Borges de. “Treating Seizures In Renal And Hepatic Failure”. J. epilepsy clin. neurophysiol. 14 (2008): 46-50.

Uptodate.  Accessed 07/12/2016.


Watershed Infarcts

Patients presenting with severe hypertension are at risk for watershed infarcts if blood pressure is rapidly and dramatically reduced, even without frank hypotension.  Blood pressure should be lowered by no more than 25% to reduce the chance of cerebral, coronary or renal ischemia.

Watershed infarcts comprise ~10% of all ischemic strokes.  These infarcts are localized to borderzones between major vascular territories in the brain, and are classified as internal borderzone (IBZ) or cortical borderzone (CBZ) infarcts.


*CBZ in red, IBZ in blue.

The CBZ are located at the junctions of the distal branches of the ACA, MCA and PCA territories.  CBZ infarcts are associated with small cortical infarcts that are more likely due to thromoembolism.

The IBZ are located at the junctions of the distal branches of the ACA/MCA/PCA with the deep perforating arteries (lenticulostriate, artery of Heubner, anterior choroidal artery).  IBZ infarcts are more often associated with severe stenosis or occlusion in the ICA or MCA.  The IBZ is more vulnerable to decreased perfusion due to the anatomic characteristics of cerebral arterioles within this area – being the most distal branches of the ICA, perfusion pressure is likely to be the lowest.  Also the lenticulostriate arteries have limited collateral blood supply.



Patient admitted for hypertensive emergency, started on nicardipine drip and blood pressure lowered from 200+ to 100 systolic.  Relative hypotension maintained for 2 hours.  Patient became comatose thereafter.  MRI showed IBZ infarcts.


Patient with aortic dissection, BP lowered from 200s with nicardipine drip.  Patient became unarousable at SBP 114 where it remained for ~3 hours.   MRI showed IBZ and corpus callosum infarctions.  Patient never regained consciousness.




Kurowski, Donna, Michael T. Mullen, and Steven R. Messé. “Pearls & Oy-Sters: Iatrogenic Relative Hypotension Leading To Diffuse Internal Borderzone Infarctions And Coma”. Neurology 86.24 (2016): e245-e247.

The AKIKI Trial

Aside from the fact that this trial has a really cool acronym, I thought this trial deserved a blog because the results are practice-changing (or practice-confirming if you’re already practicing the delayed strategy.)  Published ahead of print in NEJM.

Artificial Kidney Initiation in Kidney Injury trial (AKIKI)

Compared two groups:

  • early initiation of renal-replacement therapy (early-strategy group)
  • delayed initiation of renal-replacement therapy (delayed-strategy group)

Primary outcome:

  • overall survival


Secondary outcomes:

  • receipt of renal-replacement therapy at least once with the delayed strategy
  • renal-replacement therapy–free days
  • dialysis catheter–free days
  • mechanical ventilation–free days
  • vasopressor therapy–free days
  • Sepsis-related Organ Failure Assessment (SOFA) score at day 3 and day 7
  • vital status at day 28
  • length of stay in the intensive care unit and in the hospital
  • proportion of patients with treatment limitations (i.e., withholding or withdrawal of treatment)
  • nosocomial infections
  • complications potentially related to acute kidney injury or renal-replacement therapy


Results of the study:

  • 5528 patients eligible
  • 620 patients underwent randomization
    • 312 were assigned to the early-strategy group
    • 308 were assigned to the delayed-strategy group
  • early-strategy group underwent first renal-replacement therapy session within a median of 2 hours after randomization and within a median of 4.3 hours after documentation of stage 3 acute kidney injury and of the fulfillment of other inclusion criteria
  • 157 patients (51%) received renal-replacement therapy in the delayed-strategy group within a median of 57 hours after randomization, median interval between the occurrence of at least one criterion mandating renal-replacement therapy and its initiation was 4.7 hours
    • 49% in delayed-strategy group did not receive RRT
  • rate of catheter-related bloodstream infections was higher in early-strategy group
  • diuresis occurred earlier in the delayed strategy group
  • No difference in mortality, delayed strategy averted the need for RRT in an appreciable number of patients.



Take-home points:

  • do not interpret study as “wait and see” approach is safe for all patients
  • careful surveillance is mandatory when deciding to delay RRT in patients with severe AKI



Gaudry, Stéphane et al. “Initiation Strategies For Renal-Replacement Therapy In The Intensive Care Unit”. New England Journal of Medicine (2016): n. pag. Web. 19 May 2016.



RIFLE Criteria for Acute Kidney Injury

The table below shows the RIFLE (Risk Injury Failure Loss End stage) classification scheme for acute kidney injury.


This system has a separate criteria for creatinine and urine output.  If the patient’s condition falls under two different levels, then the worse classification should be used.

RIFLE-FC = denotes ‘acute-on-chronic’ disease.

RIFLE-FO = when RIFLE-F classification is reached by urine output criteria only


Checklist:  AKI work-up

  • Urinary sediment
  • Urinalysis
  • exclude obstruction
  • review of meds
  • rhabdomyolysis: creatine kinas, free myoglobin
  • vasculitis: CXR, blood smear, measurement of nonspecific inflammatory markers, specific antibodies (anti-GBM, ANCA, anti-DNA, anti-smooth muscle)
  • TTP: LDH, haptoglobin, unconjugated bilirubin, free hemoglobin
  • Cryoglobulins
  • Bence-Jones proteins
  • Renal biopsy



Bersten, Andrew D, and Neil Soni. Oh’s Intensive Care Manual. London: Elsevier Health Sciences UK, 2013. Print.

Drug Dosage During Dialysis

Drug Dosage During Dialysis



*These values represent approximations and should be used as a general guide only. Critically ill patients have markedly abnormal volumes of distribution for these agents, which affects dosage. CRRT is conducted at variable levels of intensity in different units, also requiring adjustment. The values reported here relate to continuous venovenous hemofiltration at 2 L/h of ultrafiltration. Vancomycin is variably removed during continuous venovenous therapies, and constant evaluation of serum levels is recommended. IHD also may differ from unit to unit. The values reported here relate to standard IHD with low-flux membranes for 3 to 4 hours every second day.




Vincent, J. L. Textbook Of Critical Care. Philadelphia, PA: Elsevier/Saunders, 2011. Print.



How much hypertonic solution?

To determine how much hypertonic solution to give a patient with hyponatremia:

  1.  calculate sodium deficit (mEq) = weight (kg) x 0.6 x (desired Na – actual Na)
    1. use 0.5 for females
    2. desired sodium in mEq/L
  2. calculate the safe rate of sodium correction for the patient in mEq/hr (0.5-1 mEq/L/hr) = weight (Kg) x 0.6 x 1.0 (rate of correction desired)
  3. 3% hypertonic saline contains 513 mEq/L; 2% contains 342 mEq/L; 1.5% contains 256 mEq/L and 0.9% contains 154 mEq/L
  4. desired rate = (safe rate of correction / 513) x 1000
  5. infusion time (hrs) = sodium deficit (mEq) / safe rate of correction (mEq/hr)


Marino: estimate initial infusion rate of 3% NaCl by multiplying patient’s KgBW by the desired rate of increase in plasma Na. Example: 70Kg male, desired rise in plasma is 0.5 mEq/L per hour, then infusion rate = 70×0.5 = 35 ml/Hr

References,. “Sodium Chloride 3% –  Intravenous (IV) Dilution”. N.p., 2016. Web. 30 Jan. 2016.

Marino, 2014. The ICU Book.



  • vasopressin analogue
    • does not have vasoconstriction / antidiuretic effects of vasopressin
  • DDAVP = deamino-arginine vasopressin


Mechanism of Action:

  • Increases cAMP in renal tubular cells –> increases water permeability –> decreased urine volume
  • Increases plasma vWF, F8 and t-PA –> shortened aPTT and bleeding time



1. Uremic bleeding (off-label): 0.4 mcg/kg IV over 10 minutes

  • corrects bleeding time in 75% of patients with renal failure
  • renal failure with significant bleeding: 1 dose given empirically; 2nd dose 8-12h later
  • recommended dose: 0.3 ug/kg IV, SQ or 30 ug/Kg intranasally
  • effect lasts 6-8h, repeated dosing leads to tachyphylaxis; responsiveness restored if drug withheld x 3-4d

2. Prevention of surgical bleeding in uremia (off-label): 0.3 mcg/kg IV over 30 minutes

3. Diabetes insipidus:

  • IV, SubQ: 2 to 4 mcg daily (0.5-1 mL) in 2 DD or 1/10 of maintenance intranasal dose
  • Oral: 0.05 mg BID, titrate total daily dose to adequate antidiuresis (0.1 to 1.2 mg in 2-3 DD)
  • Intranasal (100 mcg/mL nasal solution): 10-40 mcg OD (0.1 to 0.4 mL) or in 2-3 DD

4. Hemophilia A and von Willebrand disease (type 1):

  • IV: 0.3 mcg/kg by slow infusion; may repeat dose if needed; if used preoperatively, administer 30 minutes before procedure
  • Intranasal (using high concentration spray [1.5 mg/mL] [eg, Stimate]): <50 kg: 150 mcg (1 spray in a single nostril); ≥50 kg: 300 mcg (1 spray each nostril); repeat use is determined by the patient’s clinical condition and laboratory work. If using preoperatively, administer 2 hours before surgery.


5. Reversal of Aspirin in ICH:  0.4 ug/Kg x 1 dose (max dose 20 ug) 






DDAVP (From NCS Guidelines)

  1. Mechanism of Action (reversal of aspirin)
    1. vasopressin analog, little vasopressor activity
    2. increases endothelial release of large factor VII: vWF multimers
    3. may increase platelet membrane glycoprotein expression, promoting platelet adhesion to endothelium
  2. Data
    1. shown to reduce bleeding time, normalize hemostasis in uremic patients undergoing surgery; improved platelet function in uremic patients exposed to aspirin
    2. improved platelet function demonstrated in healthy populations on ASA / COX-1 inhibitors or ADPr inhibitors.
    3. shown to significantly reduce blood loss and improve thrombus formation in cardiac surgery patients exposed to ASA pre-op
  3. Reported side-effects:
    1. facial flushing, peripheral edema, hypervolemia, increased UO, hyponatremia;
    2. rare reports of cerebrovascular thrombosis

“Because of the low risk of serious side effects, the relatively low cost, and the suggestion of benefit in the aforementioned studies, we suggest consideration of a single dose of DDAVP (0.4 mcg/kg) in intracranial hemorrhage patients exposed to antiplatelet agents. In patients deemed appropriate (e.g., those undergoing a neurosurgical procedure), DDAVP can be used in addition to platelet transfusion.” NSC Guidelines



Marino, Paul L, and Kenneth M Sutin. The ICU Book. Philadelphia: Lippincott Williams & Wilkins, 2007. Print.


Frontera, J., Lewin, J., Rabinstein, A., Aisiku, I., Alexandrov, A., & Cook, A. et al. (2016). Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage. Critical Care Medicine44(12), 2251-2257. doi: 10.1097/ccm.0000000000002057


Phenytoin has significant protein binding, so hypoalbuminemia will lead to increased free phenytoin.
Adjust for hypoalbuminemia using the following formula = Total Phenytoin Level / [(0.2*albumin)+0.1]
*0.2 is a correction factor

In renal failure, aside from hypoalbuminia leading to increased free phenytoin, phenytoin binding is further reduced, and this formula will tend to underestimate the free phenytoin levels.  To correct for this, use 0.1 as correction factor if GFR is <10 ml/min.


Drug monitoring: (

  • loading doses should be checked 1 hour after IV load and 24 hours after oral loading
  • long term phenytoin therapy generally do not need to be monitored at intervals <3-12 months after steady state reached unless clinically indicated
  • reference range is 10-20 ug/mL – although half of patients’ seizures are controlled at values lower and higher than therapeutic range
  • adverse effects related to serum levels
    • nystagmus if >20 ug/mL
    • slurreg speech, movement disorders (tremor, choreoathetosis, orofacial dyskinesia) if >30 ug/mL
    • lethargy, stupor, confusion if >40 ug/mL