Last Day at NTUH

It is hard to believe that my NTUH APPE is coming to an end!  During my time here, I have met with many great preceptors, physicians, and students, who have all been a part of my educational experience here in Taiwan.  In my opinion, the greatest benefit I got was seeing the difference between Taiwan and U.S. pharmacy practice.  

Generally speaking, the treatment approaches at NTUH are highly dependent on the personnel in charge of that particular medical team.  In both Family Medicine and PSICU, I noticed that the treatment decisions were based on a combination of evidence based medicine as well as experience based medicine.  Just as in the U.S., they referred to IDSA guidelines for infections, CHEST guidelines for antithrombotic therapy, and ATPIII guidelines for high cholesterol treatment.  As for experience, they referred to their attending physicians.  The main difference that I found was that, often times, experience trumped evidence.  Guidelines are there as a reference, however, they were not always followed.  In contrast, I felt that in my rotations at UCDMC, guidelines were followed much more closely.  This is an example in which the culture of Taiwan has a profound effect on the overall treatment approach of patients.  The difference in culture was especially apparent towards the beginning of my time at NTUH, during the Ghost Month or 鬼月.  During this month, it is believed that ghosts and spirits of the deceased return.  Many of the locals, including my family, make trips to pay homage to deceased loved ones.  Since this period of time is associated with death, many people tend to postpone medical procedures as well.  As a result, the patient load for many of the services was much lighter than other times of the year.     

In a hospital setting, Taiwan pharmacy personnel is estimated to be 1/8 ~ 1/16 that of the U.S.  The number of patients each pharmacist manages is much greater, and therefore, it is impossible to devote as much time to each individual patient.  For this reason, not all clinical pharmacists attend daily rounds with the medical team.  On the Family Medicine service, the pharmacists do not ever round and interventions are made primarily via telephone.  On ICU services, including PSICU, the pharmacists round with the teams on a daily basis.  The type of team dynamic I observed in the ICU was more similar to my experience at UCDMC, where pharmacy support is not only appreciated, but sought after.  In order to have an established pharmacy department, rapport between the pharmacy personnel and other members of the healthcare team must be established.  This simply cannot be done without working together on a consistent basis.  Clinical pharmacy is a much younger field in Taiwan, and many aspects of pharmacy are still in the process of becoming established.  

Photo of some of the pharmacists at PSICU on my last day.

Commonly Used Medications on the PSICU Service

Being on the PSICU service has introduced me into a completely new realm of pharmacy.  This was my first pediatrics rotation, my first ICU rotation, and my first surgical rotation.  As my three weeks on PSICU nears its end, I've had the opportunity to see and learn a lot.  In this post, I will attempt to break down what I've learned and specifically tailor it in terms of pharmacy.  

The main role of the physicians, pharmacists, nurses, and respiratory therapists is to manage the patients postoperatively.   The pharmacist's job is to ensure the appropriate medication management of these patients.  Once the patients are stable, they are transferred to the floors and, if all goes well, they are discharged home. 

What I have found is that the medications used on this service all come down to the following classes: 

1) Antibiotics

2) Inotropic agents

3) Sedation/pain relief

4) Stress Ulcer prophylaxis

5) TPN

Antibiotics 

The antimicrobial regimens used on the service are primarily for surgical prophylaxis.  With any surgery, there is an increased chance of infection, and the risk is even higher in pediatric patients.  For the most part, they followed the Antimicrobial Prophylaxis for Surgery guidelines from The Medical Letter, Inc.  However, after listening to discussions on rounds and speaking with my preceptor, I realized that the antibiotic selection largely depends on how the surgeon felt about the surgery ie how long the surgery took, if there were any complications.  From a pharmacy standpoint, my pharmacist was not as involved in the antibiotic selection, but more in the dosage adjustment for the individual patients.  As the patients clinically improve after surgery, the antibiotics are peeled off gradually.  Some of the considerations the physicians take into account to see if patients are improving are the number of lines and drainages remaining, whether an extracorporeal membrane oxygenation (ECMO) is required, and lab values returning to normal limits.  There was not official antibiotic algorithm at NTUH, however, the basic progression of antibiotic selection consisted of the following:

no complications in surgery---------->severe complications
cefazolin-->ampicillin/sulbactam-->piperacillin/tazobactam-->vancomycin + ceftazidime-->ADD fluconazole

Inotropes
Every single patient is started on dopamine and milrinone to start.  If another agent is indicated, epinephrine is added on.  My assessment of these agents is mentioned in a previous post.  As the patient clinically improves, the inotropic agents are gradually tapered off, and eventually, discontinued.  In general, the epinephrine is tapered off first, followed by the dopamine.

Sedation/pain relief
The two mainstays of sedation and pain relief on the service were fentanyl and pancuronium.  The fentanyl is an analgesic and pancuronium is on mainly as a muscle relaxant.  Most patients are tapered to midazolam,which has both sedative and analgesic effects.

Stress Ulcers
Surgery is putting stress on the body.  With high stress, patients are at risk of stress ulcers.  Famotidine is the medication used for prophylaxis.  If, however, the patient experiences bloody stools, they transition them to a proton pump inhibitor.

Other medications that are commonly seen are antiplatelets such as heparin and aspirin, to prevent shunts from clotting.  Coumadin is common for older patients, especially those with shunts and mechanical valves.

Everyday on rounds, I learned something new.  I feel that six weeks (ore more) could easily have been devoted to a rotation like this.

The front of the Children's Hospital.

Photo with my pharmacist (left), nurses on our team (middle), attending physician(second from the right).

Neonatal TPN

Earlier in the week, I presented a patient case on a neonate who had undergone cardiac surgery to repair his transposition of the great arteries.  In his postoperative management, the patient developed a chylothorax, at which point the patient was placed on NPO until the fluid drainage from her chest tubes resolve.  To provide adequate nutrients to this growing baby during this time, TPN was administered.  

Since I was following this patient, I attached an addendum to my case presentation that included a SOAP of the TPN regimen given.  As my references, I looked at both NTUH's guidelines as well as Neonatal and Pediatric Parenteral Nutrition Support Guidelines from the University of Illinois at Chicago Medical Center.  

Neonatal TPN
S/O	1.      Patient is NPO due to a chlyothorax.
A	1.      Patient is NPO, and therefore, requires TPN to supply essential nutrients crucial to promote normal growth and development. 2.      Current TPN regimen: Concentration Rate Dextrose 17% 48.96 gm Aminosteril Infant 2.20% 2.64 gm/kg/day Na 30 mEq/L 3.60 mEq/kg/day K 30 mEq/L 3.60 mEq/kg/day Cl 30 mEq/L 3.60 mEq/kg/day Ca 25 mEq/L 3 mEq/kg/day P 10 mmol/L 1.2 mEq/kg/day Mg 5 mEq/L 0.6 mEq/kg/day Infuvita 5 mL Zn 188 ug Trace Element 50 uL Rate=340 mL @ 0.2 mL/min 3.      Calculations 　 Calculation Assessment Dextrose 48.96 gm/day x 1/2.4 kg x 1 day/24h x 1h/60 min x 1000 mg/g = 14.2 mg/kg/min Goal:  11-14 mg/kg/min; patient's dextrose rate is approximately the within the normal range Amino Acid 2.2%=2.2 gm/100 mL/day x 288 ml x 1/2.4 kg=2.64 gm/kg/day Goal:  ~3 gm/kg/day for preterm infant; patient's rate is appropriate Lipids 5 mL of 20% emulsion-->20gm/100mL x 5mL/2.4 kg=0.42 mg/kg/day Goal: start at 1gm/kg/day, max: 3gm/kg/day; slightly below goal Total Calories dextrose:  48.96 gm x 3.4 kcal/gm = 166.5 kcal; AA:  6.336 gm x 4 kcal/gm = 25.3444 kcal; lipid:  1 gm x 9kcal/gm = 9 kcal; Total=83.69 kcal/kg/day Goal:  40-50% of total caloric intake; dextrose consists of 83%; dextrose is above normal range Total Fluid 12 mL/h x 24 H = 288 mL; 288 mL/2.4 kg = 120 mL/kg/day Max:  140-150 mL/kg/day; total fluid is appropriate
P	Goal	·         Provide adequate nutrition while the patient is NPO ·         Fluid ·         Sodium ·         Protein ·         Carbohydrates ·         Fat ·         Electrolytes ·         Caloric intake ·         Increase lipids to at least 1gm/kg/day ·         Increase amino acids to ~ 3 gm/kg/day ·         Increase concentration of dextrose, may go up to 20-25% ·         Decrease percentage of dextrose to goal of 40-50%
	Monitoring	·      Ca, Cl, Mg, P, K, Na ·      Fluid overload ie edema, renal function ·      Total caloric intake ·      Dextrose ·      Amino Acids ·      Lipid

Similar to medication dosing for the pediatric population, the estimated energy needs, dextrose, protein, lipid, electrolyte and maintenance fluid requirements are based on patient weight.  The normal and goal ranges for each of the components are listed in my assessment above.  

In our schooling, we did not extensively go over TPN, let alone neonatal TPN.  We spent one lecture going over a case with Dr. Ferrone, and that was the end of it.  At NTU, the students are well trained in TPN and seem to have a relatively solid grasp on management of TPN components.  This may be because TPN is considered a very specialized sector of pharmacy in the US.  At NTUH, the TPN orders are done by different individuals, depending on which department of the hospital they are in.  On the PSICU service, the nurses did the TPN orders.  Once the orders are processed on their computer system, the TPN pharmacy verifies the order.  In certain departments, the TPN pharmacy does the order as well as the verification.  At UCDMC, the TPN pharmacy is a consult service, and thus, only the services that call for a consultation have the orders done by the TPN pharmacist.

Pediatric Compounding

Today, I spent the day with Dr. Dong, the only compounding pharmacist at the Pediatric Inpatient Pharmacy.  Before beginning the process of compounding, Dr. Dong stressed the importance of consistency.  What it all boiled down to was the fact that uniform medication doses leads to appropriate drug levels in the blood, which leads to efficacy while minimizing toxicity.  The second point of emphasis was sterile technique.  In 1676, Leeuwenhoek discovered the existence of bacteria, which as we know now, is invisible to the naked eye.  In 1881, the concept that bacteria can lead to illness was born and, in 1905, the concept that isolated bacteria can infect differet hosts and cause the same illness was born (Koch's postulates).  All of these microbiological advancements lead to sterile technique, which is the standard of practice for compounding at NTUH.

When compounding, Dr. Dong follows three rules:  1) The drug cannot be wrong 2) the dose cannot be wrong 3) amount of drug dispensed cannot be wrong.  At the same time, he understands that "to err is human."  The attitude that mistakes are embarrassing and should be swept under the rug is the exact attitude that will lead to more errors in the future.  Rather, mistakes should be brought to the forefront and corrected to prevent future errors of the same nature. 

We started out by thoroughly washing our hands with soap and scrubbing every fold/nail/crease.  We then sprayed our hands with 75% alcohol, a concentration that has been shown to effectively penetrate the bacterial cell membrane and cause cells the shrivel.  Once our hands were dry, we put on gloves, hair nets, and carbon face masks.  Dr. Dong explained that the carbon masks are designed to prevent dust inhalation, whereas the surgical masks used elsewhere in the hospital are designed to protect against disease transmission.  The medication we were compounding was Aldactone 3.1 mg/dose.  The standard tablet comes in 25 mg, and therefore, our job was to take 1/8 of each tablet and package them into unit doses packages in powder form.  Since the medication would be administered to children, flavoring would need to be added as well.  For liquid formulations, flavoring agents consist of syrups.  For powder formulations, flavoring is done by adding lactose monohydrate for two reasons:  1) When the disaccharide is broken down to a monosaccharide, it tastes sweet 2) The lactose increases the volume so it is easier to ingest.  The first step was to weigh the appropriate amount of lactose.  Next, we ground up the Aldactone tablets using an automatic grinder, shown below.

Before combining the two powders, we put the Aldactone powder through a sift to ensure all of the particles were of uniform size.  To minimize wasting, we ground the large particles remaining with a mortar and pestle and sifted those particles once again.  At this point, we were ready to combine the lactose and Aldactone.  We first ground up the Aldactone with 1/2 of the preweighed lactose using the mortar and pestle.  The second 1/2 was added subsequently to ensure consistency.  Now that the medication and lactose were combined, the final step was the separate them into 3.1 mg unit packages.  Luckily, NTUH has a Japanese made autmoatic package divider, which, in addition to separating the powder and packaging them, also prints the label so that the product is in its final form.  

 As with any pharmacy practice, the final check had to be done.  Dr. Dong does a "recheck" with every order, meaning he checks his own work.  Afterwards, he has another pharmacist do a "double check" to verify his work.  At NTUH, the standard considered adequate for patients to take is a variance in weight of <6%.  In industry, where everything is automated, the standard is 3-5%.  Our batch of Aldactone 3.1 mg ended up having a variance of <5%!

Patient Presentation--Transposition of the Great Arteries

Patient Profile:

Name:	Age: 13 days	Sex: F	Bed: 06PE-13-01	MRN: 5882682
Height: 46.5 cm (BBL: 47 cm, 25-50th percentile)		Weight: 2.4 gm (BBW: 2374 gm, 10-25th percentile)
BHC: 32.3 cm, 50th percentile		NKDA	Vaccinations: BCG (-), HBV (-), HBIG (-)

Chief complaint: prenatal congenital heart disease, cyanosis, respiratory distress after birth

Maternal history:

(1) Maternal disease:	arrhythmia without medication treatment, HBsAg(-), HBeAg(-), VDRL(-), GBS(not done), hyperthyroidism(-), hypothyroidism(-), DM(-), SLE(-), APS(-), hypertension(-), Rh-(-), pre-eclampsia(-), PIH(-), GDM(-), APH(-), placenta abruptio(-), infection(-)
(2) Prenatal exam:	congenital heart disease (suspect TGA) noted since GA 20wk, IUGR(-), oligohydramnios(-), polyhydramnios(-), thalassemia(-), chromosome anomaly(-), other inherited disease(-)
(3) Drug exposure:	MgSO4(-), ritodrine(-), steroid(-), antibiotics(-), others(-)
(4) Radiation exposure:	(-)

History of present illness:

2012/9/4	Female baby was born to her mother, G2P2, GA 26+2 weeks (preterm), and delivered via NSD/CS.  Congenital heart disease, TGA was suspected on prenatal examination since GA 20 weeks.  Baby was delivered without complications and cyanosis and heart murmur were noted after birth (SpO2 80% on room air, 85% under free flow O2).  PGE1 started and tapered down gradually.
2012/9/6	CVS specialist consulted.  Total correction performed (arterial switch operation, PDA division, ASD closure, VSD patch repair) and the patient was transferred to ICU for post op care.  Vancomycin and ceftazidime were started for infection prophylaxis.  Dopamine and milrinone started for hemodynamic support.
2012/9/9	Sternum closure performed.
2012/9/11	Phototherapy started for neonatal jaundice.
2012/9/12	Chylothorax discovered, patient NPO and TPN administered.

Systemic disease and Past medical history:

1.  Chylothorax
S/O	1.      Milky fluid in chest tube drainage 2.      Consolidation in right lung noted on several CXR’s
A	1.      Chylothorax occurs when lymph fluid accumulates in the pleural space due to disruption or obstruction of the thoracic duct. 2.      Traumatic vs nontraumatic; surgical procedures (traumatic) are commonly associated with chylothoraces 3.      Diagnosis:  ·         Chest radiograph ·         Milky fluid from thoracentesis or chest tube drainage ·         Pleural fluid analysis—predominance of lymphocytes, elevated TG (>110 mg/dL) 4.      Postsurgical chylothorax:  ·         Pleural drainage to control symptoms—monitor electrolytes, lymphocyte counts, albumin, total protein, weight ·         Fasting or reduced fat diet—decrease flow of chyle through thoracic duct allows spontaneous closure of a thoracic duct leak ·         Pleurodesis—not responding to thoracentesis, dietary control measures ·         Thoracic duct ligation—high volume chylothorax 5.     Current tx: ·        Chest tube drainage—drainage has become more clear, volume drained is trending down, mediastinal chest tube pulled last night 　 LP RP M 2012/9/11 150 160 10 2012/9/12 40 40 -- 2012/9/13 50 50 pulled ·        Patient NPO on 9/12 ·        May start dextrose and taper down TPN today (9/14)
P	Goal	·         Resolve chylothorax ·         Prevent infection ·         Restart oral intake
	Monitoring	·      Drainage volume, clarity ·      Signs and symptoms of infection:  leukocytosis, fever ·      Clinical signs of improvement ·      Electrolytes, CBC, protein, body weight

2.  Cardiovascular management
S/O	1.     UOP (4.15 mL/kg/hr on 9/12, 5.29 mL/kg/hr on 9/13) 2.     SCr elevated (0.8 on 9/12); should be <0.6 3.     HR (190’s on 9/7, trending down, 130-150 now) 4.     BP (70-80/50’s on 9/14)
A	1.     Pediatric patients are at high risk of being in a low cardiac output state post CV surgery. ·      Hypovolemia from operative/postoperative bleeding ·      Inflammatory cascade ·      Stunning of myocardium 2.     In the ICU: ·      Closely monitor heart ie HR, rhythm, perfusion to other organs ·      Pharmacological support—vasoactive agents are initiated post-op and tapered down gradually as cardiac output, perfusion improves ·      Mechanical support if needed 3.     Currently treating with: ·      Dopamine—preferred:  depressed CO, normal, moderately elevated PL, mod to severe hypotension; MOA:  dose-dependent positive inotropic and chronotropic effects on the myocardium o   Dose:  conc:  80 mg/100 mL D5W, initial rate: 0.9 ml/h 80 mg/100 ml x 0.9 ml/hr x 1hr/60 min x 1/2.7 kg x 1000 ug/1mg = 4.44 ug/kg/min reference range:  2-4 ug/kg/min, 4-8 ug/kg/min o   4-8 ug/kg/min:  stimulation of b1, b2 receptors; increased renal blood flow, heart rate, cardiac contractility, cardiac output α1 smooth muscle contraction α2 smooth muscle, cardiac muscle relaxation β1 heart muscle contraction β2 smooth muscle relaxation ·      Milrinone—inhibiting PDE III, increases CO, lowers filling pressures, reduces pulmonary artery pressures o   Dose:  conc: 10 mg/50mL D5W, initial rate: 0.4 ml/hr 10 mg/50 ml x 0.4 ml/hr x 1hr/60 min x 1/2.7 kg x 1000 ug/1mg=0.493 ug/kg/min reference range: 0.25—1 ug/kg/min o   0.25—1 ug/kg/min:  systemic and pulmonary vasodilator
P	Goal	·          Prevent cardiovascular collapse ·          Hemodynamic stability ·          Optimize preload ·          Control HR, rhythm and synchrony, perfusion ·          Prevent acidosis
	Monitoring	·       HR ·       BP ·       UO ·       End organ function ie Scr, LFT’s ·       Temperature ·       Blood pH

3. Neonatal jaundice
S/O	1.  Jaundice ie yellow color of skin 2.  T. Bili levels (12.41 on 9/12, trending down, 10.27 9/14)
A	1.     Nonpathologic jaundice is caused by ·      Increased bilirubin production—more RBC’s than adults, increased turnover ·      Decreased bilirubin clearance—deficiency of enzyme UGT1A1 til week 14 ·      Increased enterohepatic circulation 2.     Normally resolves within 1-2 weeks after birth 3.     Hyperbilirubinemia with T. Bili >25 to 30 mg/dL is associated with increased risk of neurologic dysfunction 4.     Risk factors:  GA <37 weeks, Asian race 5.     Guidelines from the AAP are not available for infants less than 35 weeks GA due to variability in clinical manifestations, spectrum, and lack of reliable and predive measures of bilirubin neurotoxicity. 6.     The guideline to initiate phototherapy from Norway is based on the BW and postnatal age of the preterm infant. In general, for infants > 4 days of age, the following thresholds of TB are used based on BW: BW >2500 g, but GA between 34 and 37 weeks: 17.5 mg/dL (300 micromol/L) BW between 1500 and 2500 g: 14.6 mg/dL (250 micromol/L) BW between 1000 and 1499 g: 11.7 (200 micromol/L) BW between <1000 g: 8.8 mg/dL (150 micromol/L) 7.     Treatment ·      Phototherapy—conversion of bilirubin to lumirubin, bilirubin isomer, polar molecules ·      Exchange transfusion—if phototherapy failes
P	Goal	·         T. Bili levels within normal limits ·         Resolve jaundice ·         Prevent neurological dysfunction, auditory
	Monitoring	·      T. Bili levels ·      Skin discoloration

4. Infection
S/O	1.     WBC elevated 2.     afebrile 3.     peripheral blood cx (-) 9/4 4.     surgical wound site cx (-) 9/10 5.     sputum cx (-) 9/13 6.     CRP decreased since 9/11
A	1.     Patient has persistent leukocytosis despite treatment with antibiotics throughout course 2.     Patient has been afebrile throughout 3.     No cx’s have grown 4.     Currently being treated with Ceftazidime, Vancomycin (9 days) 5.     Ceftaz dose is appropriate 6.     Vanco dose is low, trough on 9/11 was 6.75 7.     Physician changed CVP line on 9/11, opted to stay with current doses of antibiotics 8.     Patient is at risk with many lines
P	Goal	·         Resolve infection ·         Reduce WBC count to normal ·         Next step: consider increase dose of antibiotics ·         Consider adding antifungal agent
	Monitoring	·      WBC ·      Temperature ·      S/sx’s of sepsis ie vital signs

Discussion

One of the most important things I have learned on rotations is to look at patients as a whole and individualize their treatment.  This concept is even more critical in pediatrics.  In adults, slightly overestimating a dose, in most cases, will not have fatal consequences.  In children, it very well can.  Children cannot be treated as miniature adults.  When I was working up patients on the PSICU, there were many things that I had to take into account in addition to the normal parameters, lab values, etc in an adult workup.  The most basic was the patient's size ie weight, height, and head circumference and the percentiles they fit into compared with others of their age.  Secondly, it was important to collect an extensive maternal history, given that the patient him/herself does not a considerable past medical history.  Thirdly, the normal ranges for many lab values (ie potassium, T. bili, albumin, serum creatinine) and vital signs (ie blood pressure, heart rate) changes with age.   Lastly, there was a bigger emphasis on documentation of urine output, especially in neonates where serum creatinine within the first few days of birth is actually indicative of the mother's serum creatinine rather than the child's.  

In this patient, the my concern during the workup was her antibiotic regimen.  Following the patient's cardiac surgery, she was started on ceftazidime and vancomycin for surgical prophylaxis.  Based on the patient's weight and age, she should have been started on q12 dosing of vancomycin at least.  She was treated with daily dosing of vancomycin for a period of 4 days before obtaining a trough that turned out to be 6.75.  After discussing this with my pharmacist, she made the recommendation to the attending physician.  However, he opted to stay with the underdosed vancomycin.  In class and on my ID rotation, I have always learned to "go big or go home" with antibiotics.  Underdosing is merely breeding a resistant strain of the organism.  In addition to the dosing error, the choice of antibiotics was also peculiar to me.  Based on the Antimicrobial Prophylaxis for Surgery guidelines from The Medical Letter, Inc., the common pathogens for a cardiac surgery include Staphylococcus aureus and Staphylococcus epidermidis.  Therefore, the recommended antimicrobials are ONE of the following:  cefazolin, cefuroxime, or vancomycin.  The patient was being treated with two drugs that have similar activity towards the likely pathogens.  

After talking to my preceptor, I found that it comes down to the difference in culture.  Even in the U.S., there are cases when older attendings are set in their ways and are more likely to follow their own experience based medicine rather than the evidence that is out there.  I feel that there is a greater degree of reverence in Taiwan for older generations, that medical residents, etc. do not feel it is their place to disagree with an attending physician.  Although NTUH as an institution preaches evidence based medicine, in some cases, this experience may outweigh evidence.  This is not to say one way better than the other; it merely places the spotlight on a difference in culture.  

Photo of the right and left pleural drainages.

 IV medications for this patient.

Crash cart, present in every patient room.