General dosing guidelines in hemodialysis patients make dosing straightforward right?

I am certain you know where this is going…let’s take the treatment of confirmed influenza as an example. Oseltamivir 75mg PO post-HD for five days is recommended for treatment of influenza onset within the past 48h. Since oseltamivir is removed by high-flux HD, this can mean post-HD x 2 or 3 doses depending on the number of days between sessions. To simplify this, I have been recommending 3 doses (in cases where a clinical pharmacist is not readily available). This avoids under dosing however may result in a longer treatment time. The consequences of a prolonged influenza infection in this population include nausea, vomiting, diarrhea, missed HD sessions, increased risk of complications and acute hospital admission. Consequences of extended treatment include an increase in medication cost for the hospital (one capsule per incidence) and increased side effects such as headache (2-17%), nausea (8-10%) and vomiting (2-16%). With the knowledge that simplicity can reduce under dosing for a medication not routinely ordered, this generalized recommendation seems justifiable although an assessment of treatment days would be ideal.

Gentamicin pharmacokinetic assessment

A 45 year old female hemodialysis patient I had been following was febrile during her nocturnal dialysis session. That night an order for gentamicin 80mg IV post-HD had been ordered. She has polycystic kidney disease and the concern was infection from a ruptured cyst could quickly turn fatal. I completed an assessment of the order the following day and the empiric dosing had not taken into consideration the patient’s dry weight of 110kg at a height of 5’4. She did recover quickly following a gentamicin dose of ~1mg/kg and the cause was likely not bacterial. After speaking with the nephrologist, I documented the assessment in her chart including her adjusted body weight (ABW), calculations to reassess if her weight changes significantly and suggestions to consider for dosing. She is considered at high risk of a cyst rupture requiring timely and effective antibiotic dosing. Given a long list of drug allergies which include antibiotics, gentamicin would likely be employed if this occurred. Her antibiotic allergies are cephalexin (hives/vomiting), ciprofloxacin (hives/anaphylaxis), sulfa drugs (anaphylaxis), vancomycin (hives/anaphylaxis). So I wanted to share this if only to solidify it in my own head. Just to be clear, I am not in anyway implying that the nephrologist need the equations written in the chart. It’s just that as long as she remains on nocturnal dialysis, there is the possibility of a 2 am call and no matter how brilliant you are, EVERYONE deserves an equation sheet at 2 am.

Given her weight and height, an adjusted weight of 76.8kg was calculated. Firstly a loading dose (LD) of 2-3mg/kg for an infection of this etiology was recommended. A LD would more quickly approach steady state concentrations (not steady state!). Gentamicin exhibits concentration dependent killing whereas adverse drug reactions are generally time dependent. Gentamicin 160mg IV post-HD as a LD was suggested rather than 200mg IV on the higher end of the spectrum. This was in part in an effort to protect any residual kidney function and in part because it seems like a very high dose (very scientific, I know). When determining an appropriate maintenance dose, the most likely pathogens from a burst cyst are reportedly E. coli (75%) or another gram negative rod (UptoDate). The suggested dosing for this was gentamicin 1.5-2mg/kg. This gives a maintenance dose of 120mg IV post-HD or alternately 100mg IV post-HD (1.3mg/kg) which is a safer dose in the absence of gentamicin level and close to the reference range. Optimally, the maintenance dose is guided by a pre-HD trough (target 2.5-5mg/L in HD patients).

Quinine no more!

This presentation focused on de-prescribing quinine in hemodialysis patients. It is difficult to see the de-prescribing flow chart I created to outline of my approach when de-prescribing quinine in this patient population and so I have added it as well. The time frames are guidelines and may be adjusted as appropriate for a given patient. One way this approach differs from others is that I do not recommend restarting quinine at the lowest effective dose if cramping occurs. Rather, I would consider another treatment first. Re-initiating quinine at the lowest effective dose may be employed if necessary before introducing additional therapy however I believe this needs to be done mindfully with a de-prescribing strategy in mind. My concern is a patient may inadvertently be continued on two therapies for muscle cramps both with side effects (such as concurrent quinine and gabapentin).

Another question was regarding discontinuing prn quinine on hemodialysis as a last step. It was rightly noted that the pharmacokinetics of quinine suggest that prn dosing for muscle cramps may not be very effective clinically. However this is in patient already using prn doses at differing times during the hemodialysis session. Quinine prn dosing may be effective if taken at hemodialysis initiation in anticipation of muscle cramps in the last half-hour. This may be done if a large fluid volume is removed. In situations where it is truly a prn dose in response to muscle cramps, my justification is building patient trust. Discontinuing a medication that may have been effective at a time during the course of dialysis can require a step wise approach. In my experience, discontinuing the dose during hemodialysis last has been the most acceptable to patients. Possibly because during hemodialysis is where the patient is most likely to experience cramps (or associate with muscle cramps). This is just one possible approach and I welcome any feedback.

Quinine De-Prescribing

De-prescribing Flow Chart

Fun fact: Can drinking tonic water improve muscle cramps? Drinking 10 cans of tonic water would provide enough quinine to potentially yield therapeutic benefit and harm…not so great for fluid restrictions though! (yes, this was a real question)

 

 

 

Up date: the project name may be changed from QSTOP to Quiditch, brilliant!

Nephrology, two ears to listen and 2 kidneys to filter

 

March 9th was World Kidney Day! After a one month rotation in the hemodialysis unit, I definitely appreciate my kidneys enough to give them a whole day. Filter the blood, regulate potassium, phosphate and calcium, promote red blood cell production, help activate vitamin D (so it can do its thing), indirectly keep calcium in my bones and not in my arteries….I think they deserve a week rather than a day next year. In all seriousness, the World Kidney Day is a global campaign for kidney health awareness and so I do digress. In terms of drug therapy and drug dosing, nephrology can be a whole other world. Nephrology, where uncommon drugs are used commonly and common drugs are used uncommonly. In hemodialysis (HD), vancomycin and gentamicin are relatively common empiric IV antibiotics. The dosing of these renally cleared medications is simplified as the extended half-life allows outpatients to be dosed each HD rather than daily. The target/accepted pre-HD gentamicin trough is also elevated at 2.5-5mg/L with the assumption that at least half of the drug is removed by hemodialysis (giving a post-HD trough of 1-2.5mg/L or less).

Decreasing or de-prescribing medications such as PPIs and H2RAs has required a little more investigation prior to a recommendation. A patient with polycystic kidney disease was taking rabeprazole 20mg PO bid for GERD caused by the pressure of her enlarged kidneys on the stomach (a fairly solid indication). The dose was reduced as her last flare was in the fall however until her kidneys are removed (hopefully during a transplant) she may require the high dose PPI in the future. Cases of severe GERD are not uncommon however re-evaluation and de-escalation of drug therapy is often warranted as conditions change. Terazosin, indicated for BPH, may act as a two-fer for the management of refractory hypertension. Heparin, replavite, alfacalcidol, IV iron, calcium carbonate (Tums), domperidone and quinine are seemingly the rule rather than the exception.

Management of disease states can differ as well. There have been three trials assessing the CV benefit of statins in HD patients. The 4-D, AURORA, and SHARP trials have failed to demonstrate a significant reduction in cardiovascular events despite reduction in LDL cholesterol. This may be secondary to the proposed mechanism of cardiovascular disease in these patients. Rather than atherosclerotic, vascular calcification is thought to be the predominant pathological change resulting in increased cardiovascular risk however, like osteoporosis and bone mineral disease, these two can co-exist. As a general rule, statins are not started in HD patients however they are continued if the statin preceded HD. A cardiology consult may change this when the harm of not treating may be substantial however questionably evidence based.

Stroke prevention in non-valvular atrial fibrillation (not to be confused with vavular atrial fibrillation or VTE treatment) is another good example. Warfarin appears to pose a greater bleed risk than stroke reduction in HD patients. It may even contribute to stroke risk. Warfarin inhibits the synthesis of vitamin K dependent clotting factors and it also inhibits the activation of matrix gla. Matrix gla is a protein which promotes bone calcification (rather than blood vessels). Hence the association of warfarin with calciphylaxis! Interestingly, in rat models, supplementation with vitamin K reduces warfarin associated vascular calcification. Could this benefit HD patients with atrial fibrillation and a mechanical valve??

I have to admit that I will miss the patients in the hemodialysis unit. They are truly inspiring individuals with a unique story and complicated, fascinating medication management needs.

 

 

 

 

For your enjoyment, I will leave you with this. You’re welcome 🙂

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Time for nephrology!

Renal excretion is an important pharmacokinetic parameter for many drugs. Clinical pharmacists carefully monitor patient’s renal function to assess if changes in drug dosing are required to avoid toxicity or maximum efficacy. The kidney do a lot more than excrete drugs, they participate in maintaining fluid and electrolyte balance, acid/base homeostasis, red blood cell production, vitamin production and waste excretion. As kidney function declines into chronic kidney disease (CKD), pharmacotherapy may be employed to partially regulate these homeostatic functions. However, now a patient less able to renally excrete drugs requires a greater number of medications. This is one of the dilemmas that will be addressed during my nephrology rotation. Hemodialysis (HD) may be employed when kidney function declines to a point where medications and life style alone cannot compensate for the loss in filtration. HD also has its limitations and an in-depth understanding of these is required when optimizing drug therapy in these individuals. Something tells me there will be a lot to learn on this rotation.

These are my personal rotation specific goals in addition to those presented on the ROAD document.

  • To gain a thorough understanding of common co-morbidities and treatment options in CKD and dialysis patients including but not limited to heart failure, hepatic disease, atrial fibrillation and infection.
  • To conduct pharmacokinetic assessment in patients with CKD or on dialysis including vancomycin, aminoglycosides and phenytoin if the opportunity presents.
  • To evaluate and form a treatment plan for acid-base disturbances in patients with CKD and on dialysis.
  • To evaluate and form a treatment plan for electrolyte disturbances in patients with CKD and on dialysis.