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!

Adverse drug reaction, a ghost of yesterday past…

I was involved in the care of a pleasant, elderly patient with a high number of comorbidities, admitted post-fall with CHF, liver disease with abdominal ascites and hepatic encephalopathy, Afib, leg chronic leg ulcers secondary to venous insufficiency with a historical ADR to furosemide (list incomplete!). She was being treated with an increased dose of metolazone and spironolactone in hospital for ++ abdominal ascites that would not drain mechanically. Her renal function declined below CrClIBW of 30mL/min and spironolactone use was no longer safe in this patient.

Rather that presenting the problem alone (spironolactone was unsafe at CrClIBW < 30mL/min). I was able to investigate the ADR to furosemide in more detail to determine if it was “off the table” as an option for symptom management. The family had expressed the wish to avoid furosemide if alternatives are available but what if there were not? The reported ADR was hearing loss. By talking with the family I discovered she had previously been stabilized on furosemide for 10 years with no adverse reaction. Following an incident of ++ edema three years previously, she was reportedly instructed to increase the dose of furosemide to 4 times her regular amount. In the days following the dose increase, she experienced reversible hearing loss in her left ear. She was admitted to hospital and treated with corticosteroids. Reversible and non-reversible hearing loss/deafness is a side effect of furosemide when administered by IV push or IM. Her husband believes she was taking furosemide 40mg PO daily and her dose increase would have been 160mg (unverified by pharmanet).

Conclusion? It appears that the sudden furosemide dose increase was responsible for the ADR rather than the medication alone. Given that spironolactone is not a safe medication to use with her current renal function, low dose furosemide could be a suitable alternative given it was titrated very slowly with close monitoring of her hearing (in addition to other monitoring parameters). In the end, the acute on chronic kidney injury which related temporally with increased diuretic use improved by decreasing the diuretics to pre-hospital doses. Her journey is not over and there may be a time in the future that furosemide use could be considered.

Take home for my learning: Diagnosis and treatment is often a moving target with co-morbidities complicating drug treatment. This sometimes requires re-evaluation of past therapies.

The Dreaded Penicillin Allergy

On arrival to CCU, the knowledgeable medical resident assessed a patient at high-risk of infection post emergency bowel resection and the decision to continue a short course of antibiotics post-op was made. Unfortunately, the patient had a documented penicillin allergy and there was some debate as to which antibiotics to use. A suggestion put forward was to switch the medication order from metronidazole/cefazolin to metronidazole/ciprofloxacin. The coverage of ciprofloxacin for common skin pathogens such as the Streptococcus spp. and Staphylococcus aureus could have been suboptimal. This was true for some of the common Enterobacteriaceae ssp. associated with post procedure infection. Given the recommended alternatives form Bugs and Drugs for severe penicillin allergies (gentamicin/ metronidazole or gentamicin/clindamycin) and the patient’s eGFR of 36ml/min, some investigation was warranted. After reviewing the chart history, it was discovered the patient received:

Ceftriaxone 1g IV and metronidazole 500mg IV at 08:30 March 16, 2106

Cefazolin 1g IV and metronidazole 500mg IV at 02:00 March 17, 2016

The patient had also tolerate imipenem in hospital on a previous visit.

During the patient interview, she described the allergy as a rash to her arms, chest and abdomen that had emerged within 24hrs of penicillin use in 2006.

On exam, the patient had no signs of rash on her chest, abdomen, back or legs. Given the alternatives, if antibiotic therapy were to continue, the suggested was made that cefazolin 1g IV and metronidazole 500mg IV be continued tid as ordered with careful monitoring for signs of an allergic reaction. The probability of cross reactivity between penicillins and cephalosporins was communicated to the residents, nurses and dispensary pharmacist. Needless to say, I was diligent to monitor closely for signs of an allergic reaction!

This served as a good lesson of where reviewing the patient medication history and a careful allergy assessment was beneficial in ensuring the patient received the most effective and safe medication. It was also an opportunity to demonstrate the utility of a pharmacist as part of the patient care team. A medical resident and a pharmacy resident may have a different approaches to the same problem however by working as a team we were able to determine the most viable option for the patient.

Start with the Patient, End with the Patient

In one of my patient interviews physical/visual assessment of the patient was particularly useful. The patient was experiencing a muscle jerking reaction that began in hospital. It appeared to be either an ADR or a reaction to her uncontrolled pain. She had not been receiving any doses of metoclopramide prn, a medication known to cause EPS in some patients, and the reaction appeared to be either pain related or potentially an opioid induced myoclonus. After speaking with the physician, we decided that her pain needed to be controlled but with a different drug. The hydromorphone CR was switched to a fentanyl patch with break through hydromorphone doses to be reassessed. I look forward to following up with this patient to assess the efficacy and safety of my recommendations.

Through this experience, I was able to work with the physician to tailor drug therapy for this patient and provide valuable information as a clinical pharmacist. I further realized that as part of an interdisciplinary team, my assessments and recommendation are valued and expected by other members of the team.

Update: Patient is doing well and was up for physio. Pain is under control (4-5/10 was her tolerable pain level) and the myoclonus, drowsiness and sedation have resolved.