Clinical trial NCT04812028
Conditions: Postoperative Pain
Sponsor: University of Minnesota
Start date: 2021-03-01; Completion date: 2023-08-10
Enrollment: 66 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To use magnesium sulfate as adjuvant analgesia by implementing a treatment protocol in order to determine whether can benefit pediatric pain in post-operative transplanted patients and decrease overall opioid consumption.

Detailed description:
The post-operative ICU course for children receiving liver transplants and TPIAT (total pancreatectomy with islet cell autotransplantation) includes a number of different challenges, one of which includes pain. Pain is treated with both medications and approaches without medications (such as music and other distraction techniques). Opioids are one such effective pain medication which is universally used, however like all medications has risks of certain side effects (such as nausea, constipation, itching, and others). Modern research has searched for other medications and methods to treat pain in both children and adults. In this study, the investigators aim to apply one of these methods that has been shown to be effective in certain operative populations through a medicine called Magnesium-Sulfate, which may be a safe way to decrease the use of other pain medications (specifically opioids). Magnesium is already a physiologic electrolyte the body uses, which are consumed from certain foods. Used as an IV medication to reach higher levels of magnesium can work to decrease pain via its action on specific nerve receptors. Magnesium-Sulfate will be given at the beginning of transplant surgery for consented liver and TPIAT transplant patients, and continue an infusion for 48 hours into their ICU course. The investigators will monitor side effects and treat pain the same way otherwise the care team would without magnesium to determine whether there is any beneficial effect that can be applied to children in the future.

Arms: arm 1: Participants in this group will prospectively receive the intervention. arm 2: Participants in this group will have their medical records retrospectively reviewed.
Interventions: intervention 1: Magnesium sulfate
Intervention descriptions: intervention 1: Magnesium sulfate (MgSO4) will be administered intravenously at induction of anesthesia as a 30-minute bolus dose of 50 mg/kg (maximum 2 grams) in the OR, followed by a 15 mg/kg/hr IV infusion for 48 hours or once the patient has transferred out of the PICU, whichever comes first.

Protocol documents:
Prot_SAP_000.pdf: 
MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 1 of 49 
Template Revised On: 09/01/2019 
INSTRUCTIONS: 
 
ANCILLARY REVIEWS 
 
Which ancillary reviews do I need and when do I need them? 
Refer to HRP-309 for more information about these ancillary reviews. 
Select yes or 
no 
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Include Gillette resources, staff 
or locations 
Gillette Scientific review and Gillette 
Research Administration approval is 
required.  Contact: 
research@gillettechildrens.com   
Required 
prior to IRB 
submission 
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Involve Epic, or Fairview 
patients, staff, locations, or 
resources? 
The Fairview ancillary review will be 
assigned to your study by IRB staff 
Contact: ancillaryreview@Fairview.org 
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must be 
received 
prior to IRB 
committee/ 
designated 
review.   
 
Consider 
seeking 
approval 
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submission. 
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screening/prevention, or 
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Complete the CPRC application process.  
Contact: ccprc@umn.edu  


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 2 of 49 
Template Revised On: 09/01/2019 
☐ Yes 
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(x-ray imaging, 
radiopharmaceuticals, external 
beam or brachytherapy) 
Complete the AURPC Human Use 
Application and follow instructions on 
the form for submission to the AURPC 
committee. 
Contact: barmstro@umn.edu  
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from these 
committees 
must be 
received 
prior to IRB 
approval;  
 
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groups each 
have their 
own 
application 
process.  
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Resonance Research (CMRR) as 
a study location? 
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review  
Contact: ande2445@umn.edu  
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or synthetic nucleic acids, 
toxins, or infectious agents? 
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eprotocol.umn.edu 
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embryonic stem cells? 
Contact OBAO for submission 
instructions and guidance 
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requesting a HIPAA waiver? 
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approval. 
 
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MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 3 of 49 
Template Revised On: 09/01/2019 
☐ Yes 
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clinicaltrials.gov? 
If you select “No” in ETHOS, the 
clinicaltrials.gov ancillary review will be 
assigned to your study by IRB staff 
Contact: kmmccorm@umn.edu  
information 
from the 
study team 
may be 
required. 
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☐ No 
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ETHOS, the OnCore ancillary review will 
be assigned to your study by IRB staff 
Contact: oncore@umn.edu  
Does not 
affect IRB 
approval. 
 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 4 of 49 
Template Revised On: 09/01/2019 
Protocol Title 
Magnesium sulfate as adjuvant analgesia and its effect on 
opiate use of post-operative transplant patients in the pediatric 
ICU. 
Principal 
Investigator/Faculty 
Advisor 
Name: Dr. Gwenyth Fischer 
Department: Pediatric Critical Care 
Telephone Number: 612-625-9950 
Email Address: fisch662@umn.edu 
Co-investigator 
Name: Joseph Resch 
Current Academic Status: Assistant Professor 
  
Department: Pediatric Critical Care 
Telephone Number: 702-575-4648 
Institutional Email Address: resch066@umn.edu 
Scientific 
Assessment 
HRPP facilitated scientific assessment. 
IND/IDE # (if 
applicable) 
144569 
IND/IDE Holder 
Gwenyth Fischer 
Investigational Drug 
Services # (if 
applicable) 
5570 
Version 
Number/Date: 
Version1.06-06/09/2022 
PROTOCOL COVER PAGE 
 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 5 of 49 
Template Revised On: 09/01/2019 
 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1 
2/15/2020 
Clarify blood draw spacing if 
infusion turned off, clarify COVID 
influence on patient enrollment and 
consent procedure, minor 
adjustments to data build 
No 
2 
12/15/2021 
Updated co-investigaor status and 
IDS#, updated timing of MgSO4 
initiation in liver transplants (4.1), 
eliminated need for dose conversion 
calculations – pump library was 
fixed (13.1), deleted method for 
MME calculation with 
identification of relevant literature 
(15.1) 
No 
3 
04/12/2021 
Updated version date, minor 
formatting corrections (8.1,8.2), 
added new exclusion criteria (8.2), 
added new withdrawal criteria 
clarifier (12.1), increased language 
regarding potential for less patient 
enrollment (10.1), added risk of 
protocol deviation (13.1), added 
additional monitoring element to 
prevent protocol deviation (18.1) 
No 
4 
6/9/2021 
Provided additional wording 
responding to stipulation letter for 
continued magnesium approval 
(18.1) 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
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Template Revised On: 09/01/2019 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 7 of 49 
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Table of Contents 
 
1.0 
Objectives 
8 
2.0 
Background 
8 
3.0 
Study Endpoints/Events/Outcomes 
8 
4.0 
Study Intervention(s)/Investigational Agent(s) 
8 
5.0 
Procedures Involved 
9 
6.0 
Data and Specimen Banking 
10 
7.0 
Sharing of Results with Participants 
10 
8.0 
Study Population 
12 
10.0 Local Number of Participants 
15 
11.0 Local Recruitment Methods 
15 
12.0 Withdrawal of Participants 
16 
13.0 Risks to Participants 
17 
14.0 Potential Benefits to Participants 
17 
15.0 Statistical Considerations 
17 
16.0 Health Information and Privacy Compliance 
17 
17.0 Confidentiality 
21 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
21 
19.0 Provisions to Protect the Privacy Interests of Participants 
22 
20.0 Compensation for Research-Related Injury 
23 
21.0 Consent Process 
23 
22.0 Setting 
26 
23.0 Multi-Site Research 
27 
24.0 Coordinating Center Research 
28 
25.0 Resources Available 
28 
26.0 References 
29 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 8 of 49 
Template Revised On: 09/01/2019 
ABBREVIATIONS/DEFINITIONS 
Include any abbreviations or definitions for key or technical terms you use in your 
protocol. 
● PICU: pediatric intensive care unit 
● TPIAT: total pancreatectomy and islet cell autotransplantation 
● CTSI: Clinical and Translational Science Institute 
● BPIC: Best Practices Integrated Informatics Core 
● IDS: investigational drug service 
● IND: investigational drug 
● FDA: Food and Drug Administration 
● UMN: University of Minnesota 
● PI: principal investigator 
● EMR: electronic medical record 
● MgSO4: magnesium sulfate 
● PCA: patient-controlled analgesia (machines where patient can press button to 
have medicine delivered, giving them more personalized control of their care) 
● POD#0: post-operative day # 
● OR: operating room 
● T&A: tonsillectomy and adenoidectomy 
● IV: intravenous 
● pt: patient 
● PO: per os (latin for ‘by mouth’) 
● PRN: pro re nata (latin for ‘as needed’) 
● mg: milligram 
● kg: kilogram 
● hr: hour 
● AE: adverse event 
● SAE: serious adverse event 
● CRF: case report form 
● PACCT: Pediatric Pain and Advanced/Complex Care Team 
● CRNA: certified registered nurse anesthetist  


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 9 of 49 
Template Revised On: 09/01/2019 
 
1. 
Objectives 
1.1. Purpose: To use magnesium sulfate as adjuvant analgesia by implementing a 
treatment protocol in order to determine whether can benefit pediatric pain in 
post-operative transplanted patients and decrease overall opioid consumption. 
2. 
Background 
2.1. Significance of Research Question/Purpose: Our study’s purpose would be to 
improve analgesia in TPIAT (total pancreatectomy and islet cell autotransplant) 
and liver transplant recipients in the PICU, and to expand growing literature 
regarding magnesium as an analgesic, including in a yet-studied population. There 
is currently some promising data that MgSO4 can be beneficial as an analgesic in 
certain operative and post-operative pediatric patients, though data remains 
mixed depending on the method of magnesium delivery, as well as the dosing 
used and study design.  Pain remains a significant source for morbidity in post-
transplant pediatric patients, and to our knowledge use of magnesium for 
analgesia has not been studied in these populations.  Opioid-sparing medication 
and targeting new analgesic options is an important and growing research topic in 
medicine. 
2.2. Preliminary Data: To our knowledge there is no data regarding magnesium use for 
pain control in post-operative transplant patients, despite growing literature of 
effective use of magnesium as an analgesic (both adults and pediatrics).  There is 
data in MgSO4 pediatric analgesia studies, extrapolated data from continuous 
MgSO4 infusions in asthmatics, and numerous adult studies, the combination of 
which support safety for our intended infusion dosing in our study. 
2.3. Existing Literature: Early data regarding MgSO4 use as adjuvant analgesia dates 
back to the late 90’s in adult literature (2), and has since been studied in a wide 
variety of those populations, with some meta-analysis data now showing efficacy 
as well (3-13).  Pediatric literature often lags behind, however now also has 
growing data over the past two decades.  Much of the pediatric analgesic-specific 
data is in tonsillectomy populations, which has mixed but promising results on 
efficacy depending on the method of delivery as well as outcome measure 
studied (14,15,22-25,28-29).  Potentially more comparable pediatric populations 
to our proposed study population include osteotomies in cerebral palsy and 
scoliosis repairs, which both tend to have more analgesic requirement than T&A.  
Both of these populations have been studied and shown to have decreased opioid 
needs and/or pain scores with magnesium analgesia (17,18).  Most statistically 
significant beneficial data of MgSO4 use cites a bolus IV dose in the OR, followed 
by a continuous infusion during the procedure.  Adult studies have shown 
potential benefit in extending this infusion beyond the OR as well (40,41).  Given 
the increased and prolonged opioid needs in the PICU course of both liver 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 10 of 49 
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transplant and particularly TPIAT patients, we intend to implement a combination 
of intra-operative and post-operative magnesium protocol.  To our knowledge 
there is no definitive therapeutic window for magnesium’s analgesic effect, and 
studies vary as to what supra-physiologic levels are obtained based on their 
derived infusion protocol.  Comparable intra-operative infusion doses in pediatric 
analgesic studies range from as low as 30 mg/kg + 10 mg/kg/hr (25) and 50 mg/kg 
+ 8 mg/kg/hr (17) to as high as 50 mg/kg + 15 mg/kg/hr (18).  The study at our 
proposed dosing had levels of 3.2 mg/dL immediately post-op (18).  Infusions of 
higher doses have been used safely in pediatric asthma studies, including doses of 
50-75 mg/kg + 40 mg/kg/hr for 4 hours, reaching interquartile levels of high 3’s to 
mid 4’s mg/dL (37).  In adult studies prolonged infusions have been used for 
subarachnoid hemorrhage targeting higher ranges of 4-6 mg/dL for up to 10 days 
duration (38,39).  Adult studies have also demonstrated efficacy in infusion 
protocols beyond the operative period (40,41).  One protocol of 30 mg/kg + 10 
mg/kg/hr was used for 48 hours in thoracotomy patients with levels of 2.8 +/- 0.3 
mg/dL at conclusion (41).  Prolonged infusions in pediatrics beyond 24 hrs in the 
literature to our knowledge exist only in asthma studies, including one with 
average duration of ~4 days (42).  None of the above studies encountered any 
clinically significant magnesium side effects, and only transient diplopia and 
muscle weakness was reported in the adult subarachnoid hemorrhagic study 
when levels reached 6 mg/dL (symptoms resolved with lowering dose).   
According to DynaMED and Micromedex searches on magnesium, normal levels 
may range 1.5 - 2.5 mEq/L (equivalent to 1.8-3.1 mg/dL), and toxic 
hypermagnesemic levels are typically not seen until >4 mEq/L (4.86 mg/dL), which 
does not yet include many of the hemodynamic and EKG changes (typically at >5 
mEq/L or 6.08 mg/dL).  Most background data in our referenced sources cite 
~4.5-5 mg/dL as potential sources of clinically relevant magnesium toxicity.  We 
intend to target levels well below this and will avoid adverse effects by checking 
serial magnesium levels and titrating our infusion dose down if needed.  Level 
checks and titration plan is determined from existing 
pharmacokinetic/pharmacodynamic data, discussions with our pharmacy team, 
which is standardly involved with safety modifications of all admitted PICU 
patients, and recommendations from the FDA during the IND process.  The 
significance and rationale for this study has been alluded to above, namely due to 
the extensive pain that post-operative transplant children endure, and our clinical 
duty to treat this medical problem (benevolence).  Our post-operative patients 
are scheduled on a number of analgesic modalities simultaneously, including 
acetaminophen, NSAIDs, opioids, ketamine, non-pharmacologic intervention 
(child life, music therapy, etc), and even procedural (paravertebral block in TPIAT 
patients) - stressing both the difficulty of their pain control as well as the need for 
safe alternatives.  Additionally, the growing threat of the opioid crisis and 
shortage has emphasized the need for adjuvant analgesic options in a multitude 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 11 of 49 
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of patient populations to better distribute what opioids are available (justice).  
Magnesium is one of the potential adjuvants that we hope to expand existing 
literature on by investigating a yet-studied population.  Secondary benefit from 
the use of MgSO4 is the optimization of hypomagnesemia, which is especially 
common in ICU populations, including post-transplant patients who are often on 
tacrolimus for immunosuppression (43-45).  Hypomagnesemia in itself is 
associated with hypokalemia, hypocalcemia, hypoalbuminemia, metabolic 
alkalosis, and prolonged PICU stays (45).  Based on its safety profile outlined 
above, promising literature search, and optimal patient population (high analgesic 
requirement), we feel that this study has tremendous potential for scientific 
significance in pediatric patients. 
3. 
Study Endpoints/Events/Outcomes 
3.1. Primary Endpoint/Event/Outcome: Primary outcome focuses on the total opioid 
requirement (morphine equivalent per body weight) over the operative and post-
operative PICU course (which may range upwards of 7 days in some transplant 
cohorts).  The hypothesis is that magnesium sulfate use will decrease this dosage 
compared to controls, however measurements will be used to determine 
whether the intervention does not have any statistical difference as well (or even 
increases doses, which would be otherwise unexpected in the literature).  We 
intend to pilot 30 prospective transplant patients (liver, TPIAT).  Retrospective 
control data will consist of the last 60 transplants (30 liver, 30 TPIAT), which was 
determined based on original power analysis targets for a larger-based study 
anticipated in the future.  The study will be stopped prematurely if during 
obligated data reviews it is determined that opioid needs are increasing.  The 
study will also be halted if 2 patients develop clinically significant adverse 
reactions secondary to magnesium, at minimum until able to further review 
dosing and protocols.  If arrhythmia (other than transient bradycardia), 
respiratory failure, or coma are encountered once (also deemed secondary to 
magnesium), the study will be halted immediately with that patient.  Per above, if 
encountering more frequent anemia than typical post-transplant, the study will 
be halted to evaluate lab frequency’s effect. The study will also be halted for 
further review if there is a dosing error.  A list of data measures is provided in a 
secondary attachment with this protocol. 
3.2. Secondary Endpoint(s)/Event(s)/Outcome(s): Secondary outcome data will 
evaluate total opioid use by post-operative day (i.e. POD#1, POD#2, POD#3, etc) 
to help determine any variance in effect based on proximity to the surgery as 
well. Secondary outcomes will also focus on other opioid variables, including 
amount of ‘requested’ (PRN) opioids versus what is scheduled.  Secondary 
outcomes will also include opioid side effect data, since these would 
hypothetically be less if MgSO4 does indeed lessen opioid needs.  We will collect 
‘pain scores’ as well, however literature suggests these are often difficult to 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 12 of 49 
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interpret and do not always correlate well with true comfort measures.  Other 
data collection listed below will be used to help track safety data regarding 
magnesium effects, correlations between magnesium level and opioid variables, 
other analgesic dosing, as well as general statistical comparisons such as sex, type 
of surgery, and age.  A list of data measures is provided in a secondary 
attachment with this protocol. 
4. 
Study Intervention(s)/Investigational Agent(s) 
4.1. Description: MgSO4 is a pharmacological agent which will be administered 
intravenously as a 30-minute bolus dose of 50 mg/kg (maximum 2 grams) in the 
OR, followed by a 15 mg/kg/hr IV infusion for an additional 48 hours or once the 
patient has transferred out of the PICU, whichever comes first.  The bolus will be 
given after anesthesia induction for TPIAT patients, and after reperfusion of the 
transplanted liver for liver transplant patients (this is deemed by surgeon to pose 
less hemodynamic risk). Of note, it is not anticipated that our patient population 
would leave the PICU prior to 48 hours.  Standard bolus dosing of MgSO4 in 
pediatrics is 25-75 mg/kg, so per the above literature search 50 mg/kg seems a 
confirmed safe dosing.  Similar dosing protocols using a bolus and infusion which 
have been studied for analgesia in children without side effect in the literature 
include the following: 50 mg/kg then 15 mg/kg/hr (18,20), 30 mg/kg then 10 
mg/kg/hr (14,25), 50 mg/kg then 8 mg/kg/hr (17).  Our proposed 50 mg/kg + 15 
mg/kg/hr infusion dose has been utilized effectively and safely at the adult level 
as well (5,49).  Dosing as high as 100 mg/kg then 40 mg/kg/hr has been used in 
tetanus.  To our knowledge, MgSO4 for analgesia remains ‘off-label’ use, unless 
discussing for headache pain (used commonly in emergency room medication 
‘cocktails’ for migraines).  It is known however that magnesium acts 
antagonistically on the NMDA receptor, a common nociceptor, one also targeted 
by ketamine (1).  MgSO4 will be delivered at concentration of 100 mg/mL via 
patient’s central line (placed in all transplants regardless of study intervention).  
MgSO4 is also a physiologically vital electrolyte in the human body, and one that 
is replaced frequently in the ICU, including in the post-operative transplant 
population.  To avoid nearing toxic magnesium levels, we will titrate medication 
dosing to be below 3.5 mg/dL.  Total magnesium level will be checked in the OR 
following bolus dose, every 2 hours throughout the transplant procedure, at the 
initial PICU transfer and every 4 hours [expected window +/- 1 hour] for the 
remainder of infusion.  Other electrolytes (including potassium, ionized calcium, 
phosphorus) will be checked at least daily (sometimes more if deemed 
appropriate for other standard of care transplant requirements, which is typically 
every 6 hours).  If any magnesium level is above target, infusion dose will be 
decreased by 5 mg/kg/hr.  These adjustments are based on pharmacokinetic-
pharmacodynamic data and pharmacist expertise at the UMN.  If magnesium 
infusion is at any time decreased to 0 mg/kg/hr based on these levels, it will not 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 13 of 49 
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be restarted.  Should the infusion be discontinued, once magnesium levels 
normalize we will plan to check magnesium levels at discretion of primary team 
rather than study intervals, so as to minimize risk of anemia and excessive 
accessing of central line.  If levels are not able to be drawn due to some other 
unpredicted variable (patient participating in physical therapy, patient escorted 
down to gift shop, patient had emergent surgical intervention for other reasons, 
etc), blood draw will be performed at earliest availability.  This is standard of care 
for any serial blood draw ordered on the unit.  If there is an adverse event that 
there is concern magnesium may be contributing, the infusion will be 
immediately turned off until further investigation deems safe to restart.  Any 
adverse event deemed secondary to magnesium will result in indefinite 
discontinuation of the infusion, notification of safety monitor, and review of 
study protocol as outlined elsewhere.  This is discussed further in risk sections.  
Despite magnesium being an approved elemental agent, based on the above 
protocol and the extended duration of magnesium infusion compared to available 
literature, as well as the absence of previous research in our targeted population, 
this proposed project was submitted to and approved by the FDA under an IND 
application.  Based on the sources discussed above in existing literature section, 
our dosing protocol has been tried intraoperatively in both pediatrics and adults 
without side effect and demonstrated levels below which cause hemodynamically 
relevant side effects.  Further data (asthma in pediatrics, multiple purposes in 
adults) have demonstrated prolonged durations of magnesium infusion at 
comparable doses without adverse effects, including durations longer than our 
proposed 48 hours.  Additionally, some studies mentioned reached higher levels 
than our proposed target and remained free of side effect. 
4.2. Drug/Device Handling: This is an IND research study, in which case the 
Investigational Drug Service at UMN will monitor handling of magnesium 
including ordering, storage, and handling of the medication.  OnCore 
programming will be used for IDS-monitoring and study’s protocol schedule.  
Costs for medication and drug levels will be paid for by grant funding.  Nurses 
perform 2-person checks to confirm all ICU-delivered medications, which will 
include MgSO4.  This includes checking name of medication, dose, and infusion 
rate when starting the medication.  There will be no change-over to a new MgSO4 
bag at transfer from OR to PICU.  The medication is already currently ordered and 
stored at the UMN, so would not otherwise require any new/additional hospital 
design, other than pharmacy and IDS tracking any shortage of supply. 
4.3. 
Biosafety: n/a 
4.4. 
Stem Cells: n/a 
4.5. 
Fetal Tissue: n/a 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 14 of 49 
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5. 
Procedures Involved 
5.1. Study Design: 
Experimental Group: Prospective Cohort of next 30 incoming liver and TPIAT transplant 
children which meet inclusion criteria.  Due to the more difficult predictability of when 
liver transplants occur, and to ensure adequate enrollment of 30 patients occurs within 
the 3-year pilot duration, we have chosen not to have a 50/50 balanced prospective 
cohort. 
Control Group: Control will be via retrospective chart review of the last 60 transplant 
patients from the same population (liver, TPIAT) with same surgeon.  Intervention and 
data collection will be as outlined elsewhere in protocol. 
5.2. Study Procedures: 
Experimental Group: There will be no operative procedures per study parameters 
(though the transplantation procedure itself as well as any secondary procedures from 
complications are otherwise per standard of care).  Patient’s medical record will be 
reviewed for basic eligibility criteria (history of myasthenia gravis or heart block).  If 
female and of reproductive age, patient will have a urine B-hCG, which is routine prior 
to any abdominal surgery.  The only prospective study procedure will be the 
magnesium protocol previously outlined, where IV MgSO4 will be delivered as a 30-
minute bolus dose of 50 mg/kg (maximum 2 grams) in OR followed by a 15 mg/kg/hr 
infusion initiated immediately after (i.e. in OR as well) until conclusion of PICU stay or 
48 hours, whichever comes first.  Magnesium levels will be monitored throughout the 
duration of the infusion per above - every 2 hours in OR starting after bolus dose, then 
every 4 hours [expected window +/- 1 hour].  There are no other baseline visits or 
follow-up visits independent of the PICU stay and initial consent process.  We do not 
anticipate this study intervention impacting workflow significantly, as infusion 
medications are standard interventions in the PICU, and these patients already have 
frequent blood draws.  A study schedule with these interventions will be created via 
OnCore program to ensure compliance with protocol.  Data outcomes will be collected 
from epic EMR at the conclusion of each patient’s ICU admission by co-investigator and 
medical student researcher and stored in REDCap.  All collected data is via EMR, so no 
surveys/scripts/forms are needed for data collection.  Specifically, the EMR will be 
accessed for appropriate transplant patient, followed by selecting the appropriate 
surgical encounter (which would be current), followed by selecting only specific portals 
in Epic EMR where intended data elements are located (for example: Intake/Output 
section, or results review -> magnesium level, etc).  Only specific data collection 
pathways will be targeted while in a patient’s medical chart.  There are no other 
drugs/devices involved in study or that would alter MgSO4 delivery.  Similarly, there 
are no out-of-hospital prescriptions or interference during the ICU admission which 
would alter the study protocol.  Any out-of-hospital contact (i.e. pre-admission consent 
if performed) will include adherence to COVID precautions per hospital guidelines. 


MEDICAL PROTOCOL (HRP-590) 
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post-operative transplant patients in the pediatric ICU.  
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Control Group: For collection of control data, a MRN list of the most recent 60 
transplant patients under the same surgeon at this institution (30 liver, 30 TPIAT) who 
have not opted out of research will be obtained via UMN’s Best Practices Integrated 
Informatics Core (BPIC), followed by access to EPIC EMR outside of the Information 
Exchange to review patient’s chart and collect for intended outcomes, which are also 
uploaded into RedCap.  This will be done in identical manner as that for prospective 
data collection — the EMR will be accessed for appropriate patient by MRN, followed 
by selecting the appropriate surgical encounter by date, followed by selecting only 
specific portals in epic where intended data elements are located (for example: 
Intake/Output section, or results review -> magnesium level, etc).  Collection of this 
data will be initiated at the start of IRB approval and ongoing to completion.  Full data 
analysis will be completed at conclusion of study followed by construction of 
manuscript.  Of note, hypomagnesemia is corrected per standard ICU care with IV 
MgSO4 regardless of study, and liver transplant patients currently have a pre-designed 
magnesium replacement protocol (also used in our CVICU post-operative cardiac 
patients).  This will still be included in data collection without adjustment to any 
comparison data in statistical analysis.  This replacement protocol will not be used in 
our study as we will already be providing continuous IV MgSO4.  Similarly, magnesium 
blood levels are checked independent of this study, although will be more frequent 
now for safety monitoring.  These blood levels are drawn through a central line that is 
already in place independent of this study, so will not require percutaneous needle 
stick. There are no other drugs/devices involved in study or that would alter MgSO4 
delivery. 
5.3. Study Duration: 
Experimental Group: Enrollment of study participants will be ongoing for entire 
duration of study as transplant becomes available.  The total duration of participant 
participation will be approximately 1 week, however the length of time in the ICU is 
dependent on the overall post-operative transplant course, which can vary between 
patients.  The duration anticipated to enroll all study participants is dependent on how 
long will be required to reach the targeted patient volume of 30, which will likely be 
approximately 3 years.  The circumstances secondary to COVID-19 have made surgical 
schedules more unpredictable, and therefore a more confirmatory timeline is difficult 
to infer.  Institutional scheduling of elective procedures and approval of patient 
enrollment did not occur until July 2020.  Data analysis should not extend the study 
duration by more than 2-3 months.  
Control Group: Control will be via retrospective chart review of same transplant 
population.  Data analysis and manuscript preparation will follow (ideally with the 
project being fully concluded by May-June 2023).  There is no intended long-term data 
follow up needed.  Data analysis will be performed alongside experimental group data, 
and is not expected to extend the study duration by more than ~2-3 months. 


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5.4. Use of radiation: n/a 
5.5. Use of Center for Magnetic Resonance Research: n/a  
6. 
Data and Specimen Banking - n/a 
 
7. 
Sharing of Results with Participants 
7.1. Summary data from all participants will be created to acknowledge study 
participation and inform patients/parents of study conclusions once complete.  
No identifying information will be shared.  Magnesium levels and overall pain 
requirements will be shared on daily family-centered rounds, however this is in 
accordance with standard information sharing with patients/families and is 
independent of research study. 
 
8. 
Study Population 
8.1. Inclusion Criteria:  In order to be eligible to participate in this study, an individual 
must meet all of the following criteria: 
Experimental Group: 
1. Male or female of at least 3 years and <18 years of age at screening. 
2. Written informed consent from participant’s legal representative and assent 
(when applicable) obtained from participant and ability for participant to 
comply with the requirements of the study. 
3. Stated willingness to comply with all study procedures and availability for the 
duration of the study 
4. Be scheduled for and receive a liver transplant or total pancreatectomy and islet 
cell autotransplantation 
 
Control Group: 
1. Male or female of at least 3 years and <18 years of age at transplantation. 
2. Received a liver transplant or total pancreatectomy and islet cell 
autotransplantation. 
8.2. Exclusion Criteria:  An individual who meets any of the following criteria will be 
excluded from participation in this study: 
Experimental Group: 
1. Pregnant or unwilling to abstain from sex if not practicing birth control during 
participation in the study. 
2. Presence of a condition or abnormality that in the opinion of the Investigator 
would compromise the safety of the patient or the quality of the data. 


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3. Known allergic reactions to components of the MgSO4 
4. History of heart block or myasthenia graves in past medical history. 
5. Presence of cardiac pacemaker. 
6. Age less than 3 years or greater than 18 years at screening. 
7. Any patient with preoperative creatinine level > 1.5x upper limit of normal. 
8. If study staff member not available for in-hospital presence on day of procedure. 
 
Control Group: 
1. Any patient who had filed as research-exempt (opt-out of research previously). 
2. Age less than 3 years or greater than 18 years at transplantation. 
3. Any patient with preoperative creatinine level > 1.5x upper limit of normal. 
8.3. Screening: No specific screening measures will be used.  Any transplant patient 
will be considered eligible if not pregnant.  All consent/recruitment for the study 
is at same time as transplant procedural consent, which is performed by the 
transplant surgeon (whom is also a Co-Investigator on this study). 
9. 
Vulnerable Populations 
9.1. 
Vulnerable Populations: 
 
Population / Group 
Identify whether any of the 
following populations will be 
targeted, included (not necessarily 
targeted) or excluded from 
participation in the study.  
Children 
Targeted Population 
Pregnant women/fetuses/neonates 
Excluded from Participation 
Prisoners 
Excluded from Participation 
Adults lacking capacity to consent 
and/or adults with diminished 
capacity to consent, including, but 
not limited to, those with acute 
medical conditions, psychiatric 
disorders, neurologic disorders, 
developmental disorders, and 
behavioral disorders 
Excluded from Participation 


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Non-English speakers 
Included/Allowed to Participate 
Those unable to read (illiterate) 
Included/Allowed to Participate 
Employees of the researcher 
Excluded from Participation 
Students of the researcher 
Excluded from Participation 
Undervalued or disenfranchised 
social group 
Included/Allowed to Participate 
Active members of the military 
(service members), DoD personnel 
(including civilian employees) 
Excluded from Participation 
Individual or group that is 
approached for participation in 
research during a stressful situation 
such as emergency room setting, 
childbirth (labor), etc. 
Included/Allowed to Participate 
Individual or group that is 
disadvantaged in the distribution of 
social goods and services such as 
income, housing, or healthcare. 
Included/Allowed to Participate 
Individual or group with a serious 
health condition for which there are 
no satisfactory standard treatments. 
Included/Allowed to Participate 
Individual or group with a fear of 
negative consequences for not 
participating in the research (e.g. 
institutionalization, deportation, 
disclosure of stigmatizing behavior). 
Included/Allowed to Participate 


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Any other circumstance/dynamic 
that could increase vulnerability to 
coercion or exploitation that might 
influence consent to research or 
decision to continue in research. 
Included/Allowed to Participate — 
though coercion will be adamantly 
avoided 
 
 
9.2 Additional Safeguards:  
Children: Entire targeted cohort will be a pediatric population <18 yo cared for in 
the PICU, where medical standards for care of pediatric patients are maintained 
and all attending level staff have degrees in pediatric intensive care or pediatric 
surgery.  If a patient turns 18 while the study is ongoing, we will re-consent using 
an adult consent form.  If a patient turns 18 while the study is ongoing, but is 
unable to consent for themselves (incapacitated), we intend for parental consent 
to stand until that participant became able to consent.  Parental consent is 
described further in section 20.5. 
Non-English Speakers: It is possible that family may be encountered which are 
non-English speaking, given the overall diversity in our area.  Consent standards 
will be maintained in these cases with use of interpreter (in person, by phone, or 
by video), services which are provided by the University of Minnesota.  We will 
include short form consent templates and a 2nd witness.  Interpreters are also 
used for daily medical updates and on medical rounds, which is our current 
standard practice for all patients. 
Illiterate: Consent forms will be read for the patient by research investigator with 
standard ‘teach back’ technique to ensure full understanding is obtained prior to 
informed decision-making.  This aligns with standard of care and that used for 
consent for transplant surgery. 
Military/Employees/Colleagues: While these populations are excluded given their 
age, children of any members of this population would be eligible for 
participation. 
Undervalued or disenfranchised social group:  Intention will be to offer IV MgSO4 
analgesia to all patients of all variety without any discrimination toward wealth, 
race, sexual identity or orientation, politics, social interests or preferences, 
stereotypes, or any other characteristic not mentioned in the exclusion criteria 
above. 
Stressful Situation: Only anticipated situation for this study would be if patient 
develops acute disease exacerbation necessitating organ transplant (i.e. Liver).  In 


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these cases patient and family are still given formal consent process prior to 
surgery.  Consent for this IV MgSO4 use will be done at this time per protocol (i.e. 
no variance from the standard for other patients).  Any unwillingness to discuss 
research protocol/consent due to stress will be immediately honored and patient 
excluded from study. 
Disadvantaged: Intention will be to offer IV MgSO4 analgesia to these patients 
without any discrimination.  Consent per routine protocol will be discussed 
without variance from the standard for other patients. 
Serious Health Condition: Any patient which has developed a condition without 
any satisfactory standard treatments and has thus been offered transplant will 
still be considered eligible for this study.  Consent per routine protocol will be 
discussed without variance from the standard for other patients.  MgSO4 
analgesia is independent of the underlying disease due to secondary pain from 
transplant. 
Fear of negative consequences: Derived consent forms address our intent that 
participating or not participating has no bearing on consequences to patient 
regarding their care in the ICU.  This will be discussed during the consent process 
without variance from the standard for other patients. 
Increased vulnerability/coercion: There are no anticipated dynamics which would 
otherwise alter discussions of post-operative pain, which is a part of the initial 
transplant consent regardless.  As for coercion, research investigators are also 
physicians directly involved in patient care.  Dedication will be paid to patient 
autonomy as is for all patients.  Consent will be obtained without variance from 
the standard for other patients. 
None of the above populations affect the underlying physiology of post-operative 
pain and so seem appropriate to have all analgesic options discussed.  Ongoing 
PICU research studies at the UMMC children’s hospital are shared within the PICU 
physician group, so all are aware of any effects on medical care strategies.  
Emphasis on respect for patient autonomy will be made regarding decision for or 
against MgSO4 therapy in this communication.  Additionally, this study’s IV 
MgSO4 dosing will be built into the post-operative transplant care protocols 
which are shared with the medical team for each transplant patient.  No one 
aside from the necessary treatment team is aware of medical management of 
these patients, so as to protect confidentiality and anonymity.  These 
interventions should help prevent any undue harm to above populations. 
10. 
Local Number of Participants 
10.1. Local Number of Participants to be Consented: Local Number of Participants to be 
Consented: 30 consented for prospective cohort, 60 previous patients for control 
group.  Assuming ~75% consent rate, this will require ~40 patients approached.  


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This number was originally determined based on power analysis performed on 
available literature - see section 15.2 (Power Analysis), however has been 
adjusted based on further stipulations during IND approval. Due to COVID 
alterations and other instigators on decreased procedures at this institution, this 
target may be altered to a lower number, with intentions to prove feasibility. 
11. 
Local Recruitment Methods 
11.1. Recruitment Process: 
Experimental Group: Study team personnel will introduce this study at a patient’s 
routine pre-operative PACCT appointment (pain specialist) for all TPIAT patients.  This 
team is routinely involved in all TPIAT patients and is familiar with the post-operative 
analgesic course, and also presents an un-biased view in regards to this research.  The 
transplant surgeon (Co-Investigator) will introduce this study at all Liver transplant 
patients’ pre-operative visit while discussing analgesic management after surgery.  It is 
possible that liver transplantation may be introduced as an emergent medical situation.  
Regardless, visits/discussions are done in private consultation.  When available the co-
investigator will be present for study introduction and consent as well.  If the patient 
expresses interest, the TPIAT physician, transplant surgeon or co-investigator would 
introduce the details of study.  Formal consent discussion will ensue if participant 
intends to enroll and will be supplemented from created consent/assent documents.  
Any signed documents will be uploaded to patient chart for adequate communication 
to treatment team.  Similar procedure will be performed for liver transplant patients, 
however approach will be at a similar outpatient appointment with liver transplant 
team or while inpatient (if admitted for acute hepatic complications).  Recruitment is 
intended to continue until the intended patient number is reached.  Any patient 
contact, including if pre-admission consent is performed, will include adherence to 
COVID precautions per hospital guidelines. When it is not possible to obtain written 
informed consent for infection control or other justifiable reasons, we will use a waiver 
of documentation of written/signed documentation of consent and obtain phone 
consent from a parent or legal guardian and assent from the patient when deemed 
possible based upon patient age, developmental status and illness severity. Study 
coordinators will generally err on the side of utilizing the phone consenting process for 
infection control, unless the treating team allows for entrance into the patient’s room. 
Study staff will create a consent narrative for each enrolled patient to document the 
consent process in detail.   
Control Group: Participants will be identified from medical records 
11.2. Identification of Potential Participants: 
Experimental Group: Potential participants will be identified by the investigator from 
among patients under their care and that of their colleagues who have legitimate 


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access to their medical records. Potential participants will be asked about their interest 
in the study at the time of the pre-transplant visit.  
All potential participants will be those that have become eligible for transplantation 
with our pediatric transplant surgeons.  No other recruitment strategies will be used.  
The transplant surgeon (also a co-investigator of this study) will make initial contact 
with these patients/families, and will describe the intended treatment plan including 
consent for our study.  The surgeon and PI will be in contact regarding each upcoming 
transplant patient that will be cared for in the PICU, in addition to consent and HIPAA 
authorization forms being added to patient chart so that can be confirmed at admission 
to the PICU. 
Control Group: The records used in the study for the control group are the records of 
the patients in the investigators’ clinical practices.  Any medical records marked with 
the opt-out-research flag will not be viewed.  A list of the past 60 patients based on 
inclusion criteria will be obtained from the BPIC at the UMN. 
11.3. Recruitment Materials: n/a 
11.4. Payment: n/a 
12. 
Withdrawal of Participants 
12.1. Withdrawal Circumstances:  Participants are free to withdraw from participation 
in the study at any time upon request. An investigator may terminate 
participation in the study if: 
1. Any clinical adverse event (AE), such as secondary toxic reaction to 
magnesium sulfate, laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be 
in the best interest of the participant.  Specifics regarding secondary 
reactions: 
▪ regarding the hemodynamic adverse effects of magnesium: the drug will 
be halted for etiologic evaluation in the presence of confirmed 
hypotension or sustained bradycardia; if deemed secondary to magnesium 
that patient’s therapy will be permanently discontinued 
▪ regarding sedative effects: the PICU team addresses sedation goals each 
day with rounds and follow up; preference with over-sedation will be to 
decrease other analgesia/sedative infusions as able given overall goal of 
this study (i.e. lower opioids, benzodiazepines, dexmedetomidine first as 
able).  If deemed unable to decrease other infusions or already at a 
minimum, and over-sedation still present, then magnesium infusion will 
be discontinued. 
▪ regarding frequency of blood draws: blood draws are already frequent in 
this population of patients in initial 2 days post-op (typically every 6 


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hours at minimum already).  If deemed by safety committee (familiar 
with typical transplant PICU course) that this population is suffering 
hemoglobin < 8 g/dL more frequently than is typical, and is not felt to be 
secondary to other complications from the surgery or transplant course, 
the patient’s infusion will be stopped and the study will be halted to 
review the protocol and lab frequency further 
 
2. Patient dosing is serially decreased to 0 mg/kg/hr per protocol 
3. The participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation, including 
if study staff member no longer able to be present in-hospital for OR check-
in throughout procedure 
12.2. Withdrawal Procedures: If a participant wishes to withdraw or we determine that 
the participant should withdraw, all data collected up to that point will be used in 
analysis unless the participant wishes for their data not to be used. We will intend 
for a partial withdrawal, where data will continue to be collected via 
private/protected records. 
12.3. Termination Procedures: This study may be temporarily suspended or 
prematurely terminated if there is sufficient reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to investigator, funding agency, 
the IND sponsor and regulatory authorities. If the study is prematurely 
terminated or suspended, the PI will promptly inform the IRB and will provide the 
reason(s) for the termination or suspension. The study team will notify the 
participants of the study termination.  Specifically, the study will be halted if 2 
patients develop clinically significant adverse reactions secondary to magnesium, 
at minimum until able to further review dosing and protocols.  If arrhythmia 
(other than transient bradycardia), respiratory failure, or coma encountered once 
(also deemed secondary to magnesium), the study will be halted immediately 
with that patient until able to review with IRB and FDA.  Per above, if 
encountering more frequent anemia than typical post-transplant course on 
multiple patients, the study will be halted to evaluate lab frequency’s effect.  The 
study will also be halted for further review if there is a dosing error. 
Circumstances that may warrant termination or suspension include, but are not 
limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to 
participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 


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• 
Determination of futility. 
The study may resume once concerns about safety, protocol compliance, 
and/or data quality procedures are addressed and satisfy IRB and FDA. 
Data collected for the study prior to the study termination will be handled in 
the following manner: 
• 
if the study is terminated due to safety reasons, the data related to AEs 
will be evaluated.  
• 
if the study is terminated for any other reason, the regulatory and 
institutional document/data retention policies will apply. 
13. 
Risks to Participants 
13.1. Foreseeable Risks: This would include the potential for known side effects from 
magnesium toxicity, namely: hypotension, cardiac arrhythmia, hyporeflexia, 
effects on other electrolytes (such as potassium and calcium), muscle weakness, 
respiratory depression (secondary to muscle weakness), and increased sedation 
(including when combined with opioids and benzodiazepines).  These toxic risks 
are cited typically at levels of > 4-4.5 mg/dL.  We will minimize this risk by 
targeting magnesium thresholds below this.  Hypotension is monitored for via 
routine serial blood pressure monitoring in all ICU patients, and can be treated 
with IV fluid resuscitation as needed (standard for hypermagnesemia treatment).  
Cardiac arrhythmia is monitored for via cardiac telemetry in all ICU patients, and 
cardiology specialists and arrhythmia resuscitation techniques are available per 
standard ICU care.  Both of these are risk factors that are present in these 
populations regardless of magnesium use, however if these conditions are felt 
potentially contributed to by hypermagnesemia the infusion will be stopped for 
further evaluation.  Electrolyte abnormalities are also common in ICU populations 
and are monitored routinely per post-transplant protocols.  Respiratory 
depression is monitored routinely in this population as well, however if secondary 
to perceived muscle weakness out of proportion to standard post-operative 
course, the magnesium infusion will be stopped as well.  Sedation and other 
analgesia is routine in post-operative transplant care and is addressed and 
titrated based on daily goals.  Decreasing other sedatives will take precedent over 
magnesium in cases of oversedation given the overall objective of the study.  
Increased blood draws may occur during monitoring, however in 48 hours of 
infusion may result in only 4-8 mL of extra blood specifically from magnesium 
draws alone, which clinically seems insignificant relative to overall course.  There 
is potential for dosing error as is for all PICU delivered medications, however 
correct units for MgSO4 has been updated in UMMCH pump library, and there is 
additionally standard ICU regulations per institutional and leadership for routine 
drip/dose checks.  The only other potential foreseeable risk would be that of 
intravenous line capability.  Post-operative transplant patients require multiple IV 


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medications (both bolus and drips), which sometimes require placement of 
additional IV catheters.  Given that magnesium is already periodically replaced in 
these populations for hypomagnesemia, we think the risk for impacting line 
availability is rather low, but in theory could increase potential of line 
complications.  IV catheter complications are anticipated/potential risks of any 
patient in the ICU independent of this study.  Per the above protocol, there will 
be both peripheral and central line magnesium concentrations in case there are 
compatibility issues where magnesium cannot be administered in the same IV line 
as another medication (amphotericin and calcium infusions being the two rare 
instances that could occur).  Risk for administering the wrong concentration into 
its intended IV line (peripheral or central) will be avoided via separate Epic orders 
(‘PERIPHERAL’ and ‘CENTRAL’ built into the research medication entry), 
appropriate labeling and delivery by the IDS, pharmacy checks (routine on all ICU 
administered medications), and nursing checks (also routine standard of care).  All 
efforts will be made to protect participants’ confidentiality following Good Clinical 
Practice, the policies of the Committee on Clinical Investigations (IRB), and 
Federal and State laws as they apply. There is risk of protocol deviation. This will 
be mitigated by routine IRB evaluations, study staff check-in communication with 
PICU providing teams and study staff presence in OR on day of procedure. 
13.2. Reproduction Risks: n/a 
13.3. Risks to Others: no perceived risk to others 
14. 
Potential Benefits to Participants 
14.1. Potential Benefits: The most notable potential benefit to study participants is for 
a more comfortable ICU stay with less opioid requirement.  This would hopefully 
correlate with less overall opioid side effects, which otherwise may further 
contribute to morbidity (most notably constipation, ileus, itching, nausea).  It is 
difficult to predict the likelihood of this impact given lack of data in this 
population, however the potential for beneficial effect of an otherwise 
physiologically required electrolyte compared to minimal chance of side effect 
seem an optimal opportunity for study.  If proven beneficial, the magnitude may 
be quite significant, with the potential to alter protocols in these populations, and 
further fuel studies regarding magnesium's analgesic effect and dosing 
optimization.  While we anticipate that our impact on these children will mostly 
be in the ICU, adult patients have more notable long-term opioid requirement 
(something not as replicated in kids according to TPIAT studies), and may be an 
interesting new cohort to study as well given overall opioid burden nationwide. 
15. 
Statistical Considerations 
15.1. Data Analysis Plan: EPIC will be the source document used for collection of all 
data, which will be transferred to REDCap for clinical database.  The following will 


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be the data collected from epic for statistical analysis.  No data is associated with 
any specimens or printed material.  These measures are also provided as a list in 
an attachment for ease of use. 
PRIMARY OUTCOMES 
Total opioid usage 
1. Morphine Equivalents for OR, PICU, and overall course (total dose/kg/day) 
- use MAR to determine which opioid using: morphine, hydromorphone, fentanyl, 
oxycodone, or methadone 
- use summary -> index -> pain monitoring tab to evaluate 24 hr infusion requirements; 
days are considered 7am-7am; this tab will be used for other data collection below 
- confirm infusion dosing adjustments in MAR (hover over green time bars) 
- we will use guidance from our PACCT team (pain specialist) and available literature for 
equianalgesic dosing conversions (i.e. fentanyl to morphine, hydromorphone to 
morphine, etc) 
- divide by weight (kg) for morphine equivalent per kg 
 
     SECONDARY OUTCOMES 
 
opioid variables 
1. Morphine Equivalent daily variance (daily dose/kg on each post-op day) 
2. Total days on IV opioids 
- will use post-operative day when IV opioid discontinued (i.e. POD#6) 
3. Total days on any opioid 
4. PCA variables 
- # of demands, # of deliveries (daily and total values) 
- # of escalations in infusion dose 
5. Scheduled vs PRN dosing 
- scheduled dosing includes PCA infusion dose and scheduled IV or PO opioids 
- PRN includes PCA delivered doses and PRN opioids delivered 
 
Opioid side effect variables 
1. Constipation 
- # of ileus events — search ileus in epic search tool 
- days until first stool — will use first post-operative day which stool documented (i.e. 
POD#3) 
- total stools, stools/day 
- enema use 
2. Nausea 
- # emesis (daily and total per day) 
- # anti-emetic doses (including Zofran, Compazine, granisetron, Benadryl, lorazepam, 
cyproheptadine, scopalamine; daily and total per day) 
3. Itching 
- # days naloxone infusion required 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 27 of 49 
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4. Respiratory Variables 
- # escalations required 
- Peak respiratory requirement each day 
- # Days intubated 
 
Other pain/comfort variables 
1. FLACC, Pain Score (self-reported), comfort B scores - daily and total/day 
2. PICU duration — post-operative day when transfer order placed (i.e. POD#7) 
3. Intubation 
- # of days intubated — will track as earliest post-operative day extubated (i.e. POD#1) 
- # of re-intubations 
4. Paravertebral Block — whether used (yes or no), # of times dose increased 
5. Ketamine use — total mg/kg, mg/kg/d 
6. Total doses and doses/day: Acetaminophen, Ketorolac, ibuprofen, celecoxib, gabapentin, 
amitriptyline 
7. Dexmedetomidine — total mg/kg, mg/kg/day, peak dose 
8. Midazolam – whether infusion required each day 
9. PT involvement (# successful visits, POD# at initiation) 
10. Feeding Advancement (day at initation, day at goal feeds) 
 
SIDE EFFECTS AND MISCELLANEOUS 
 
Magnesium variables 
1. Magnesium levels 
- average daily level (for each post-operative day), average total level 
- peak level during admission 
2. Dosing 
- # of magnesium infusion dosing changes (i.e. # times decreased) 
- total days on magnesium (POD# at discontinuation 
- # times held due to adverse event concern 
- # of adverse events deemed secondary to magnesium 
- type of adverse event 
3. OR Effect 
- Time spent bradycardic (value and %) 
- Overall OR time 
- Fluid requirement 
- Blood product requirement 
- Pressor variables (# required, peak doses) 
4. Other effects 
- ionized calcium levels — average daily level (for each post-operative day) and average 
total level 
- potassium levels — average daily level (for each post-operative day) and average total 
level 
- phosphorous levels - average daily level (for each post-operative day) and average total 
level 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
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- PTH level (for renal patients where relevant) 
- creatinine levels (average daily and average total; part of routine monitoring of all 
transplant patients) 
 
Standard Reporting 
2. type of transplant received 
3. age 
4. weight 
5. height 
6. gender 
15.2. Power Analysis: Power analysis was performed based on pediatric studies by 
Hutchins et al and Jabbour et al (see references section 24), indicating 90 patients 
in order to see a detectable difference of 20% between study groups with 80% 
power.  This would detect a decrease of nearly 3.5 mg/kg over a 7 day PICU 
course, and seemed a reasonable target for our hypothesis.  Given the 
progression of IND review, this number will be reduced to 60 for the retrospective 
cohort (renal transplants removed from study), and 30 for prospective cohort 
(typical target for pilot-based study), to simulate a pilot study rather than fully 
correlational study.  Regardless, original power analysis is shown below: 
 
 
15.3. Statistical Analysis: The primary analysis will compare the total morphine 
equivalent dose per kg during the PICU stay between experimental and historical 
control groups.  Total dose will be compared in both unadjusted analyses and 
adjusted analyses using linear models, with a covariate for study group and 
adjusting covariates for transplant type, age, and gender, to account for potential 
variation due to these factors. Distributional assumptions will be examined and 
data transformations will be used as appropriate.  Secondary outcomes will be 
compared using similar approaches using generalized linear models for count 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
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outcomes (total days on IV opioids, number of PCA demands and deliveries, 
number of infusion dose escalations, number of ileus events, days until first stool, 
emesis counts, number of days naloxone infusion required, PICU duration, 
number of days intubated, paravertebral block dose increases), categorical 
outcomes (ketamine use, presence of side effects), and continuous outcomes 
(FLACC, Pain Score).  Longitudinal measurements of magnesium, other analgesics, 
ionized calcium, PTH, and creatinine levels will be analyzed using mixed effects 
models.  Group summaries including means, standard deviations, and rates will 
be reported and group differences will be summarized as incidence rate ratios, 
odds ratios, or mean differences with 95% confidence intervals.  Analyses will be 
conducted using the intent-to-treat principle; control group participants who 
underwent magnesium replacement (for hypomagnesemia or pre-designed post-
transplant protocol) will be included in the control group, and experimental group 
participants with discontinuation of magnesium, if any, will be included in the 
experimental group.  A two-sided 5% level result will be regarded as significant. 
Statistical analysis will be per statistician’s updated STATISTICAL ANALYSIS 
SOFTWARE (also used in a previous pain study with TPIAT cohort).  
15.4. Data Integrity: 
Data collection is the responsibility of the clinical study staff at the site under the 
supervision of the site PI. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported.  
Source data are all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation 
of the study.  All paper data (which would include only consent/assent forms) will 
be kept in a dedicated, locked, research space, in co-investigator’s office at UMN 
Children’s Hospital.  Other source data will be stored in EPIC.  Consent and assent 
forms will be transitioned to the patient chart upon completion.  Paper copies of 
these forms will be stored in a locked storage bin in co-investigator’s office at UMN 
Children’s Hospital. 
Protocol with study schedule and patient enrollment will be tracked with OnCore 
programming.  Electronic data collected from the PICU admission will be stored on 
REDCap program as a clinical database, a secure environment delivered by the 
Center of Excellence for HIPAA Data intended for storing, sharing and accessing 
sensitive and private highly restricted files. 
Data access will be limited to research assistant, research coordinator, statistician 
support, and key study personnel (PI and co-investigators). 
Upon completion of project, the master data matrix and patient identification key 
will be destroyed. 
16. 
Health Information and Privacy Compliance 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 30 of 49 
Template Revised On: 09/01/2019 
 
16.1. Select which of the following is applicable to your research:  
 
☐ I am requesting that all research participants sign a HIPCO approved HIPAA 
Disclosure Authorization to participate in the research (either the standalone 
form or the combined consent and HIPAA Authorization). 
Appropriate Use for Research: Per language in the consent at initial 
procedural discussions with the surgeon, unless consenting to enroll for 
magnesium analgesia, patients will not be involved in any research protocol.  
MRN’s will not be forwarded to IDS or protocol team to initiate any form of 
data collection or medication administration. 
 
16.2. Identify the source of Private Health Information you will be using for your 
research (Check all that apply)   
☐ I will pull records directly from EPIC. 
 
16.3. Explain how you will ensure that only records of patients who have agreed to 
have their information used for research will be reviewed:  Patients who have 
consented for the study will have their information shared with the research 
team.  Patient information is updated in RedCap.  Only patients enrolled in 
study will have RedCap entries, which will be the only patients whose Epic 
charts will be accessed for further data collection. 
 
16.4. Approximate number of records required for review:  60 retrospective records 
(30 liver transplant, 30 TPIAT), 30 prospective.  Informatics consulting service will be 
utilized, however certain data may require more thorough progress note analysis and 
therefore direct epic access from data reviewer. 
16.5. Please describe how you will communicate with research participants during 
the course of this research.  Check all applicable boxes 
☐ Communication with research participants will take place in the course of 
treatment, through MyChart, or other similar forms of communication used 
with patients receiving treatment. Specifically, communication will happen 
throughout their PICU course regarding their overall care, which will include 
discussions on analgesia and sedation to ensure these are optimized (this 
happens during family-centered rounds on all patients admitted to the PICU). 
16.6. Explain how the research team has legitimate access to patients/potential 
participants: 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 31 of 49 
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Members of the research team are also part of the PICU team involved in 
patient care, and therefore will have access to medical records independent 
of this project (PI is a PICU attending physician, co-investigators are 
transplant surgeon and PICU fellow physician).  A medical student will also be 
assisting in data collection as part of their research experience.  All members 
have been confirmed to have completed appropriate HIPAA and research 
training through UMN standards.  Access to patient charts is discussed during 
the consent process with patients.  A number of data points require manual 
searching in epic.  None of these data points require demographic or 
personalized information outside of sex, age, and strictly medical information 
(name and contact information are ignored for example). 
16.7. Location(s) of storage, sharing and analysis of research data, including any links to 
research data (check all that apply).   
☐ In the data shelter of the Information Exchange (IE)  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In the Bone Marrow Transplant (BMT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) Database  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In REDCap (recap.ahc.umn.edu)  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In Qualtrics (qualtrics.umn.edu) 
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In OnCore (oncore.umn.edu)  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In the University’s Box Secure Storage (box.umn.edu) 
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In an AHC-IS supported server. Provide folder path, location of server and IT 
Support Contact: 
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In an AHC-IS supported desktop or laptop.  
Provide UMN device numbers of all devices:  
 ☐ Store 
☐ Analyze 
☐ Share 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
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☐ Other. Describe:  
Indicate if  data will be collected, downloaded, accessed, shared or stored using a 
server, desktop, laptop, external drive or mobile device (including a tablet 
computer such as an iPad or a smartform (iPhone or Android devices) that you 
have not already identified in the preceding questions 
☐I will use a server not previously listed to collect/download research data 
☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) not 
previously listed  
☐I will use a mobile device such as an tablet or smartphone not previously listed 
 
16.8. Consultants. Vendors. Third Parties.  N/A 
16.9. Links to identifiable data: MRN’s will be uploaded securely into RedCap, there will 
be no other links or substitute identifiers required. 
16.10. Sharing of Data with Research Team Members. Data will be stored via RedCap 
and OnCore programming only. 
16.11. Storage and Disposal of Paper Documents:  There are no anticipated paper 
products other than signed consent/assent forms, which will be stored in a 
secure, locked storage box in co-investigator’s fellow office on UMN Children’s 
Hospital grounds. 
17. 
Confidentiality 
17.1. Data Security: All members of the investigation team will complete and maintain 
university standard training programs regarding patient information protection, 
including all modules provided at initiation of fellowship.  As stated, this will be 
extended to medical student researcher involved with assistance in chart 
review.  Protocol, study schedule, and patient enrollment will be tracked via 
OnCore.  Various outcome measures collected from the Epic EMR will be 
transferred to REDCap storage system.  Both of these are HIPAA compliant.  This 
system is password-protected and encrypted for security.  Consent forms will be 
stored in patients' medical chart, with the purpose of easy retrieval and access for 
PICU medical staff to initiate the intervention following transfer from operating 
room.  This will be reflected in the confidentiality section of the consent form.  
Paper copies of consent/assent forms will be stored in a secure, locked storage 
box in co-investigator’s fellow office on UMN Children’s Hospital grounds. 
18. 
Provisions to Monitor the Data to Ensure the Safety of Participants 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 33 of 49 
Template Revised On: 09/01/2019 
18.1. Data Integrity Monitoring: The PI and co-investigators will be in direct day-to-day 
contact (specifics below) throughout the study intervention and with any of the 
following that arise.  The PI and/or co-investigator will have direct notifications 
any time a transplantation surgery is planned and will confirm that study 
intervention has been ordered correctly in medical chart on day of PICU 
admission.  Surgery, anesthesia, ICU, and safety monitoring teams will be notified 
prior to interventions when a patient is confirmed as a study participant.  Medical 
staff will be instructed to page PI and/or co-investigators as well as research 
coordinator in case of any intervention side effect for further direction.  The PI 
and co-investigators are the most appropriate direct monitors, as both have full 
understanding of research protocol, and are also frequently in PICU with direct 
care of these patients.  In cases where the PI or co-investigators are not present, 
deferral will be made to the medical team, which is already adept and required to 
be following lab results and ensuring nurse orders are carried out.  A co-
investigator will also otherwise make routine daily lab surveillance for added layer 
of monitoring.  This level of monitoring appears appropriate as once the 
intervention is ordered in our EMS, nurses carry out the order throughout 
duration of study.  There is no blinding required in this study as all participants 
will be intended to receive intervention, so there appears no opportunity for bias 
introduced by the PI or co-investigators while caring for these patients.  As 
patients complete their ICU and conclude their involvement in study, chart 
reviewer will be notified to update data into REDCap.  This will be further 
overseen by PI and co-investigators.  All data collected through chart review will 
be collected with a standardized data collection form to ensure uniformity. 
 
Specific safety measures to prevent protocol non-compliance include the 
following: study team will have a brief after enrollment of each patient and prior 
to infusion initiation to review pertinent protocol elements, which will be 
debriefed to medical team (both in email and in person); a study team member 
will check-in with medical team and bedside nursing team twice per day to ensure 
compliance and answer any questions; a study team member will check in at 
major checkpoints (specifically at dosing change and at discontinuation); there 
will be a request for nursing to be calling study team at medication 
discontinuation for added layer of safety; a study member will be available for 
contact from care providers at all times; only study team members are able to 
direct order changes in epic pertaining to MgSO4 dose or frequency of level 
checks, resident physicians specifically are not to change these orders (medical 
team attending or fellow physicians may change dosing per protocol if level > 3.5 
mg/dL); study team will additionally contact both bedside nursing team and 
medical team following completion of infusion to review current safety profile 
(specifically lab trends, infusion dosing, appropriateness of timing, and active 
problem list to ensure no adverse events secondary to MgSO4). In regards to OR 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
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safety, a study staff member will be specifically in-hospital on the day of 
procedure. This staff member will go to the OR every 2 hours at the time 
magnesium levels are drawn to provide a helpful reminder of blood draw 
requirement, ask if there are any questions regarding the study drug, and help 
address any new concerns. Data regarding magnesium levels (and all labs) as 
well as intra-operative vitals (such as heart rate and blood pressures) and 
medication deliveries/changes are auto-populated into the patient’s electronic 
medical record in real-time. We do not anticipate that the anesthesia team 
should have to report any additional data for the study team to help guide 
dosing magnesium dosing adjustments. The study team member will follow up 
the result of this level. If there is a needed dosing change based on the level, 
that study team member will return to the OR to provide a helpful reminder to 
change the dose (in the case this has not yet been done). If the anesthesia 
provider is too busy to draw a level or change the dose, which is not 
anticipated, study team will seek out an available anesthesiologist (i.e. on call 
provider) to come pause the infusion until able to further discuss. If a study 
staff member is not forecast to be available for day of procedure, that patient 
will be excluded from consent. If a study staff member becomes unavailable on 
day of procedure, that patient will be removed from the study. 
A data integrity monitor (external to the direct research team) will be involved 
throughout this project. The study monitor will ensure that the investigation is 
conducted according to protocol design and regulatory requirements. The 
monitor will provide ongoing monitoring of data validity and regulatory issues 
(e.g. eligibility determinations, consent form process, SAE reporting, IRB actions, 
disclosures of conflict of interest). 
Study records will be monitored at regular intervals by the study monitor. The 
monitor will perform source data verification and as such must be given access to 
the participant’s primary source documentation, such as paper or electronic 
medical records, consent to participate in the study, visit dates, demographic 
information, medical history, physical examination, vital signs, copies of 
laboratory reports, AEs, concomitant medications, drug accountability (etc.), that 
support data entries in the REDCap database. 
The PI will be provided copies of monitoring reports shortly after the monitoring 
visit. Findings will be noted and followed up in the subsequent monitoring visit. 
The study will be monitored by CTSI in accordance with its institutionally 
approved monitoring plan. 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 35 of 49 
Template Revised On: 09/01/2019 
18.2. Data Safety Monitoring:  The following safety data will be collected starting at the 
baseline visit through the end of study visit to establish any change from baseline 
parameters, and for monitoring adverse events:  
• Confirm that participant met inclusion/exclusion criteria 
• Confirm that delivered magnesium dose is appropriate with intended 
protocol dosing (i.e. 50 mg/kg bolus, 15 mg/kg/hr infusion) 
• hypotensive events: including value and interventions needed (pressors, 
fluid bolus, etc) 
• 
respiratory decline: specifically if needing to increase to higher level of 
support (nasal cannula to high flow, high flow to positive pressure, etc), 
interventions required for respiratory compromise, relation to sedation 
• 
arrhythmia: include type, EKG results (if done), interventions required 
• 
hypocalcemia: specifically if ionized calcium < 4 (or age-appropriate 
norm), interventions required 
• 
hyperkalemia: include value (if higher than normal range), interventions 
required 
• 
hyperphosphatemia: include value (if higher than normal range), 
interventions required 
• 
hypermagnesemia: include if > 3.5, confirm that dose was decreased per 
protocol guideline 
• 
for all of above, comment on whether side effects deemed secondary to 
magnesium 
Safety data will be captured in the CRFs for each visit. Any AEs and SAEs will also be 
recorded in the REDCap database. Any safety event meeting the IRB’s urgent reporting 
criteria will be reported to the IRB within its published timelines, and similarly to the 
FDA as outlined at conclusion of this section.  
A pediatric ICU physician external to the research team will serve as the safety monitor 
for this protocol.  The safety monitor will not be enrolling any research participants or 
caring for patients as part of this protocol.  The safety monitor is qualified to review 
the patient safety data generated by this study because of her/his expertise in 
pediatric intensive care.  
 
After the first 3 patients have completed their study duration, the safety monitor will 
be responsible for reviewing adverse events and participant data for any clinically 
significant trends, followed by providing a short one page summary regarding findings.  
Safety data collected will include the above list, as well as any other unforeseen events 
which are deemed potentially secondary to magnesium.  As long as meeting safety 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 36 of 49 
Template Revised On: 09/01/2019 
efficacy, the data and adverse event review will be completed after every 5 patients 
for duration of the study, unless any clinically relevant items deem alteration of these 
review intervals.  Any serious or unexpected events will be thoroughly investigated 
followed by a short report independent of the above 3 and 5 patient review intervals.  
PI is responsible for notifying safety monitor via telephone or email of any events 
within 1 day that she or trial team are made aware. 
 
We do not predict any adverse events to occur at our protocol dosing based on 
available literature.  If a SAE, Unanticipated Problem Involving Risks to participants or 
Others (UPIRTSO) or other event causing risk to the research participants occurs, the 
clinical research team will notify safety monitor immediately.  Safety monitor will 
assure the study is conducted in accordance with the investigator’s agreement, the 
investigational plan, the IND and other applicable FDA regulations, and conditions of 
approval imposed by the reviewing IRB or FDA.  Research will be suspended 
immediately if any life-threatening events occur due to magnesium. 
 
An Annual Report will be compiled by the research team and will include a list and 
summary of AEs. In addition, the Annual Report will address (1) whether AE rates are 
consistent with pre-study assumptions; (2) reason for dropouts from the study; 
(3) whether all participants met entry criteria; (4) whether continuation of the study is 
justified on the basis that additional data are needed to accomplish the stated aims of 
the study; and (5) conditions whereby the study might be terminated prematurely.  
 
The Annual Report will be sent to the safety monitor and will be forwarded to the IRB 
and FDA. The IRB and other applicable recipients will review progress of this study on 
an annual basis. 
 
Below outlines definitions and specifics regarding relevant events: 
 
Safety and Adverse Events 
A.  Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries will be regarded as adverse events, 
whether or not considered intervention-related.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
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• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
 
Classification of an Adverse Event 
Mild: Events require minimal or no treatment and do not interfere with the participant’s daily activities 
—— Moderate: Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. — — Severe: Events interrupt a 
participant’s usual daily activity and may require systemic drug therapy or other treatment. Severe 
events are usually potentially life-threatening or incapacitating. Of note, the term “severe” does not 
necessarily equate to “serious”. 
Of note, we do not intend to report mild side effects which are known to frequently occur in TPIAT and 
Liver transplants.  For example, we will not report individual episodes of nausea/emesis, post-operative 
pain, ventilator adjustments (unless an escalation to new mode of respiratory support), non-sustained 
hypertension/hypotension on routine vital checks, anticipated returns to OR (for example to close 
abdomen after initial surgery).  Similarly, known/predicted intraoperative fluctuations in coagulopathy, 
bleeding, and vitals trends will not routinely be reported, unless not responding to expected 
interventions per OR team.  All of the above will be reported if medical team experts (i.e. surgeon or 
anesthesiologist in OR, intensivist in PICU) believe these above symptoms are contributing to an atypical 
course or a worsening in patient’s expected trajectory. 
Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and her/his clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect. 
Probably related: There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time 
after administration of the study intervention, is unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition. —— Possibly Related: There is some 
evidence to suggest a causal relationship (e.g., the event occurred within a reasonable time after 
administration of the trial medication). However, other factors may have contributed to the event (e.g., 
the participant’s clinical condition, other concomitant events). Although an AE may rate only as “possibly 
related” soon after discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or “definitely related”, as appropriate. —— Not Related: The AE is completely 
independent of study intervention administration, and/or evidence exists that the event is definitely 
related to another etiology. There must be an alternative, definitive etiology documented by the 
clinician. 
 
 
Serious Adverse Event 


MEDICAL PROTOCOL (HRP-590) 
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post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
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Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• 
fatal 
• 
life-threatening 
• 
requires or prolongs a hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
a congenital anomaly or birth defect 
• 
an important medical event based on appropriate medical judgment or that requires medical or 
surgical intervention to prevent one of the above outcomes listed in this definition 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of 
the other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not 
result in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious.  
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, the 
study treatment follow-up is defined as 7 days following the last administration of study treatment or 
until discharge from the ICU (whichever occurs first). 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition will be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting condition.  At the end 
of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse 
event will also be recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator will instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.   
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any 
condition responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for an adverse event.  


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
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Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless 
it is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
B.  Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document (i.e. within 24 hours of event notification), and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related signs, symptoms, 
and abnormal diagnostic procedures results will be recorded in the source document, though should be 
grouped under one diagnosis. 
All adverse events occurring during the study period must be recorded.  The clinical course of each 
event will be followed until resolution, stabilization, or until it has been determined that the study 
treatment or participation is not the cause.  Serious adverse events that are still ongoing at the end of 
the study period must be followed up to determine the final outcome.  Any serious adverse event that 
occurs after the study period and is considered to be possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
C.  Reporting of Serious Adverse Events 
1. 
IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be submitted to the IRB 
within 5 working days if it falls under the UPIRTSO guidelines.  Copies of each report and documentation 
of IRB notification and receipt will be kept in the Clinical Investigator’s binder. 
2. 
FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission of any unexpected fatal 
or life-threatening experience associated with the use of the drug as soon as possible but no later than 
7 calendar days from the sponsor’s original receipt of the information. 
If a previous adverse event that was not initially deemed reportable is later found to fit the criteria for 
reporting, the study sponsor will submit the adverse event in a written report to the FDA as soon as 
possible, but no later than 15 calendar days from the time the determination is made. 
 


MEDICAL PROTOCOL (HRP-590) 
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post-operative transplant patients in the pediatric ICU.  
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Agency 
Criteria for 
Reporting 
Timeframe 
Form to Use  
Submission 
address/fax numbers  
U of MN IRB 
SAE: fatal, life-
threatening or 
serious, 
unexpected, at 
least possibly 
related  
5 working days 
MedWatch 3500A 
Form 
RNI in ETHOS 
FDA 
SAE: fatal, life-
threatening, 
unexpected, at 
least possible 
related 
7 calendar days  
MedWatch 3500a 
Form but 
alternative formats 
are acceptable 
(e.g. summary 
letter) 
Fax: 1 (800) FDA - 
0178 
SAE: serious, 
unexpected, at 
least possibly 
related 
15 calendar days 
 
 
 
 
19. 
Provisions to Protect the Privacy Interests of Participants 
19.1. Protecting Privacy:  Patients will be given opportunity in initial consent process as 
to whether there are any members of medical or research team they wish to 
interact or not interact with, desires which will be maintained.  The only members 
which should have direct contact, however, will include the PI and co-
investigators (if on medical staff).  Autonomy will be emphasized to all members 
of research team, including transplant surgeon (co-investigator) or PACCT 
physician performing initial consent, with respect for any patient who wishes not 
to enroll in our intervention.  This will be emphasized to medical team involved in 
PICU care of patients as well.  We do not otherwise anticipate any privacy 
concerns as our intervention is not dependent on any other underlying attributes 
other than the transplantation procedure itself.  HIPAA compliance measures are 
otherwise routine at the institution where study is taking place.  Comorbidities 
and transplant indication will not be identified in either control or experimental 
group, which should further limit potential of identifying information in final 
written product. 
19.2. Access to Participants: The research team will need access to medical chart in 
order to collect data regarding the primary and secondary outcomes, as this is the 


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only place data is stored/located.  We will only search chart in specific areas that 
our outcome measures are located, and will avoid all other unnecessary 
information.  Some of the data elements need more diligent, subjective searches 
than what can be consistently and reliably obtained by computer data extraction 
techniques (which were discussed during development process).  Specifically, the 
EMR will be accessed for appropriate patient by MRN, followed by selecting the 
appropriate surgical encounter, followed by only specific portals in epic where 
intended data elements are located (i.e. Intake/Output or results review -> 
magnesium level, etc).  The PI and co-investigators, however, will have more 
frequent and expanded access to chart in circumstances where they are the 
medical provider taking care of patient for the day (unrelated to research itself), 
since that person may be directly involved in patient care.  All of the patients are 
otherwise within the co-investigator’s (transplant surgeon) and PI’s (PICU 
physician) practice area. 
20. 
Compensation for Research-Related Injury 
20.1. Compensation for Research-Related Injury: In the event that research-related 
activities result in an injury, treatment will be provided to the participant (e.g., 
first aid, emergency treatment, and follow-up care as needed). Care for such 
injuries will be billed in the ordinary manner to the participant or the participant’s 
insurance company. 
20.2. Contract Language: n/a 
21. 
Consent Process 
21.1. Consent Process (when consent will be obtained): 
Experimental Group: consent will be obtained, before any research procedure 
occurs, in the initial meeting between the transplant surgeon (co-investigator) or 
PACCT physician and parents (with or without patient) when discussions 
regarding their procedure are had.  This is done in a private setting, though 
dependent on situation (i.e. surgeon office, hospital conference room if more 
emergent, etc).  Parents will be given opportunity to address questions per usual 
routine, and will use standard 'teach back' technique to elicit understanding from 
parents.  Written consent will be obtained and stored in patient chart.  If a liver 
transplant candidate develops more acutely, consent will be attempted while 
inpatient prior to any procedure initiation.  Any patient contact, including if pre-
admission consent is performed, will include adherence to COVID precautions per 
hospital guidelines. When receiving consent/assent over the phone, study staff 
will hand a copy of the consent, HIPAA and assent if applicable through a small 
door on the side of the patient’s room. There will be another study coordinator 
on the phone via conference call to witness/attest to the consent process. Study 
staff will create a consent narrative not to file for each enrolled patient to 


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document the consent process in detail which will be signed by both the 
consenting coordinator as well as the coordinator serving as the witness.  
Control Group: we intend for a waiver of consent for data review of control group 
given both that treatment was at an academic institution and information will be 
de-identified. 
21.2. Waiver or Alteration of Consent Process (when consent will not be obtained):  
There will be no waiver or alteration of consent process for the experimental 
group.  We intend for a waiver of consent for the retrospective control group.  
The control group of this research is not FDA-regulated as patients were given 
standard of care treatment. No investigational drug was given to these 
participants. The research does not involve non-viable neonates. The research 
does not involve newborn dried blood spots. The research could not practicably 
be carried out without a waiver. For the control group, the research involves no 
more than Minimal Risk to the participants. The waiver will not adversely affect 
the rights and welfare of the subjects. 
21.3. Waiver of Written/Signed Documentation of Consent (when written/signed 
consent will not be obtained): n/a 
21.4. Non-English Speaking Participants: non-english participants are likely over the 
course of the study.  Participants who do not speak English may be enrolled.  
Consent short forms will be used for those participants who will not be able to 
understand the consent form written in English.  The short form will be used in 
conjunction with an oral presentation of the consent information by a translator.  
We will make use of in-person interpreters through the UMN's extensive 
interpreter service for any participants whom English is not preferred 
language.  An impartial witness who is fluent in both English and the language 
spoken by the participant/representative will be present during the entire 
consent discussion to attest to the adequacy of the consent process and to the 
participant’s voluntary consent.  The interpreter may serve as a witness. 
21.5. Participants Who Are Not Yet Adults (infants, children, teenagers under 18 years 
of age):  all patients will be consented or assented (if age 8-17 years) in 
accordance with HRP-013 and Minnesota state regulations.  We anticipate all of 
our patients to be under 18 years old and therefore children.  In the rare event 
that children are emancipated, we will consider legal council if 
unclear.  Registration of these patients confirms guardianship and so will 
determine appropriate person to consent.  Consent is required by 1 parent 
(research is greater than minimal risk with the potential of benefit).  Discussions 
will be provided regarding pain control in children, and assent will be allotted to 
those at least 8 years old. Any patient contact, including if pre-admission consent 
is performed, will include adherence to COVID precautions per hospital 
guidelines. When entering the room isn’t reasonable due to infection risks, assent 


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will be obtained over the phone with the parent also on the call (i.e., either in the 
room with the patient or conference called into the phone so that they are able 
to hear their child’s questions, concerns, and response to participating). 
21.6. Cognitively Impaired Adults, or adults with fluctuating or diminished capacity to 
consent:  per above consent process, if a patient turns 18 while study is ongoing, 
and does not have capacity to consent, consent will be deferred to parent. 
21.7. Adults Unable to Consent: n/a 
22. 
Setting 
22.1. Research Sites: All research will be conducted in the PICU at the University of 
Minnesota Masonic Children’s Hospital located at 2450 Riverside Avenue in 
Minneapolis, Minnesota. Recruitment may occur at a private UMN setting during 
the initial consent for transplantation if this occurs outpatient (i.e. for TPIATs 
primarily).  This will primarily occur in the transplant physician (co-investigator) 
office or TPIAT physician’s office, as outlined in consent sections.  For inpatient 
settings required in the PICU, consent will preferentially occur in a family 
conference room. 
22.2. International Research: n/a 
23. 
Multi-Site Research: n/a 
24. 
Coordinating Center Research: n/a 
 
25. 
Resources Available 
25.1. Resources Available: PI and co-investigator have multiple other research 
colleagues available for assistance if needed.  As stated above, it is difficult to 
predict how many potential participants we will have since transplant is a 
dynamic field year-to-year, but based on previous years we predict ~10-20 
patient per year.  The co-investigator (PICU fellow) is allotted multiple blocks each 
year to research, so most of this time will be devoted to conducting and 
completing our project, including following up on chart review progress, 
additional external grant applications, manuscript writing.  Multiple other 
members will also be assisting with various tasks, including a research 
coordinator who will help with database creation (OnCore and REDCap) and 
ongoing study monitoring.  Data integrity and safety monitoring members are 
available through UMN services.  Biostatistician will be hired through grant 
funding for data analysis.  We anticipate that the combination of these 
contributors will be enough resource for the project.  The UMN Masonic PICU is a 
24-bed unit with capability for all current standard-of-care modalities needed in 
critical care.  PI has a fellow office where able to review research data privately.  
Patients have access to various therapies (PT/OT/ST, music therapy) for their 


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care, as well as all common pediatric specialties within the UMN system should 
consultation be needed - including psychological.  PI and co-investigator will plan 
for cumulative update meetings with research team no less than every 6 months.  
We do not anticipate clinical service from medical team to be burdened by any of 
the protocol interventions, and project will be discussed with unit manager. 
26. 
References 
General Review 
1. Eizaga Rebollar R, García Palacios MV, Morales Guerrero J, Torres LM. Magnesium sulfate 
in pediatric anesthesia: the Super Adjuvant. Paediatr Anaesth. 2017 May;27(5):480-489. doi: 
10.1111/pan.13129. Epub 2017 Feb 28. Review. PubMed PMID: 28244167. 
 
Adult Supportive Data 
2. Tramer MR, Schneider J, Marti RA, Rifat K. Role of magnesium sulfate in postoperative 
analgesia. Anesthesiology. 1996 Feb;84(2):340-7. PubMed PMID: 8602664. 
 
3. Koinig H, Wallner T, Marhofer P, Andel H, Hörauf K, Mayer N. Magnesium sulfate reduces 
intra- and postoperative analgesic requirements. Anesth Analg. 1998 Jul;87(1):206-10. PubMed 
PMID: 9661575. 
 
4. Levaux Ch, Bonhomme V, Dewandre PY, Brichant JF, Hans P. Effect of intra-operative 
magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic 
surgery. Anaesthesia. 2003 Feb;58(2):131-5. PubMed PMID: 12562408. 
 
5. Bhatia A, Kashyap L, Pawar DK, Trikha A. Effect of intraoperative magnesium infusion on 
perioperative analgesia in open cholecystectomy. J Clin Anesth. 2004 Jun;16(4):262-5. PubMed 
PMID: 15261316. 
 
6. Steinlechner B, Dworschak M, Birkenberg B, Grubhofer G, Weigl M, Schiferer A, Lang T, 
Rajek A. Magnesium moderately decreases remifentanil dosage required for pain management 
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16490760. 
 
7. Murphy JD, Paskaradevan J, Eisler LL, Ouanes JP, Tomas VA, Freck EA, Wu CL. Analgesic 
efficacy of continuous intravenous magnesium infusion as an adjuvant to morphine for 
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8. Salah Abdelgalil A, Shoukry AA, Kamel MA, Heikal AMY, Ahmed NA. Analgesic 
Potentials of Preoperative Oral Pregabalin, Intravenous Magnesium Sulfate, and their 
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9. Shah TH, Rubenstein AR, Kosik ES, Heimbach SW, Madamangalam AS. Parturient on 
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10. Sousa AM, Rosado GM, Neto Jde S, Guimarães GM, Ashmawi HA. Magnesium sulfate 
improves postoperative analgesia in laparoscopic gynecologic surgeries: a double-blind 
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11. De Oliveira GS Jr, Castro-Alves LJ, Khan JH, McCarthy RJ. Perioperative systemic 
magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials. 
Anesthesiology. 2013 Jul;119(1):178-90. doi: 10.1097/ALN.0b013e318297630d. Review. 
PubMed PMID: 23669270. 
 
12. Murphy JD, Paskaradevan J, Eisler LL, Ouanes JP, Tomas VA, Freck EA, Wu 
CL.Analgesic efficacy of continuous intravenous magnesium infusion as an adjuvant to 
morphine for postoperative analgesia: a systematic review and meta-analysis. Middle East J 
Anaesthesiol. 2013 Feb;22(1):11-20. Review. PubMed PMID: 23833845. 
 
13. Albrecht E, Kirkham KR, Liu SS, Brull R. Peri-operative intravenous administration of 
magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia. 2013 Jan;68(1):79-
90. doi: 10.1111/j.1365-2044.2012.07335.x. Epub 2012 Nov 1. Review. PubMed PMID: 
23121612. 
 
49. Hwang JY, Na HS, Jeon YT, Ro YJ, Kim CS, Do SH. I.V. infusion of magnesium sulphate 
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16. Xiao F, Xu W, Feng Y, Fu F, Zhang X, Zhang Y, Wang L, Chen X. Intrathecal magnesium 
sulfate does not reduce the ED50 of intrathecal hyperbaric bupivacaine for cesarean delivery in 
healthy parturients: a prospective, double blinded, randomized dose-response trial using the 
sequential allocation method. BMC Anesthesiol. 2017 Jan 17;17(1):8. doi: 10.1186/s12871-
017-0300-z. PubMed PMID: 28095795; PubMed Central PMCID: PMC5240204. 
 
Pediatric Supportive Analgesia Data 
14. Hamed MA, Al-Saeed MA. The Efficacy of Intravenous Magnesium Sulfate versus 
Intravenous Paracetamol on Children Posttonsillectomy Pain and Analgesic Requirement: A 
Randomized Controlled Study. Anesth Essays Res. 2018 Jul-Sep;12(3):724-728. doi: 
10.4103/aer.AER_113_18. PubMed PMID: 30283184; PubMed Central PMCID: PMC6157232. 
 
15. Cho HK, Park IJ, Yoon HY, Hwang SH. Efficacy of Adjuvant Magnesium for 
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17. Jabbour HJ, Naccache NM, Jawish RJ, Abou Zeid HA, Jabbour KB, Rabbaa-Khabbaz LG, 
Ghanem IB, Yazbeck PH. Ketamine and magnesium association reduces morphine consumption 
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2014 May;58(5):572-9. doi: 10.1111/aas.12304. Epub 2014 Mar 17. PubMed PMID: 24635528. 
 
18. Na HS, Lee JH, Hwang JY, Ryu JH, Han SH, Jeon YT, Do SH. Effects of magnesium 
sulphate on intraoperative neuromuscular blocking agent requirements and postoperative 
analgesia in children with cerebral palsy. Br J Anaesth. 2010 Mar;104(3):344-50. doi: 
10.1093/bja/aep379. Epub 2009 Dec 30. PubMed PMID: 20042475. 
 
Pediatric other related benefits 
19. Kawakami H, Mihara T, Nakamura N, Ka K, Goto T. Effect of magnesium added to local 
anesthetics for caudal anesthesia on postoperative pain in pediatric surgical patients: A 
systematic review and meta-analysis with Trial Sequential Analysis. PLoS One. 2018 Jan 
2;13(1):e0190354. doi: 10.1371/journal.pone.0190354. eCollection 2018. Review. PubMed 
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20. Amer MM, Abdelaal Ahmed Mahmoud A, Abdelrahman Mohammed MK, Elsharawy AM, 
Ahmed DA, Farag EM. Effect of magnesium sulphate on bi-spectral index (BIS) values during 
general anesthesia in children. BMC Anesthesiol. 2015 Sep 22;15:126. doi: 10.1186/s12871-
015-0108-7. PubMed PMID: 26395085; PubMed Central PMCID: PMC4579582. 
 
21. Kim EM, Kim MS, Han SJ, Moon BK, Choi EM, Kim EH, Lee JR. Magnesium as an 
adjuvant for caudal analgesia in children.Paediatr Anaesth. 2014 Dec;24(12):1231-8. doi: 
10.1111/pan.12559. Epub 2014 Oct 15. PubMed PMID: 25315126. 
 
Mixed or unconvincing pediatric data 
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24. Karaaslan K, Yilmaz F, Gulcu N, Sarpkaya A, Colak C, Kocoglu H. The effects of 
levobupivacaine versus levobupivacaine plus magnesium infiltration on postoperative analgesia 
and laryngospasm in pediatric tonsillectomy patients. Int J Pediatr Otorhinolaryngol. 2008 
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26. Brousseau DC, Scott JP, Badaki-Makun O, Darbari DS, Chumpitazi CE, Airewele GE, 
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Leonard J, Hulbert ML, Powell EC, Liem RI, Hickey R, Krishnamurti L, Hillery CA, Nimmer 
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28. Sun J, Wu X, Zhao X, Chen F, Wang W. Pre-emptive peritonsillar infiltration of magnesium 
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31. Shanbag P, Mauskar A, Masavkar S. Intravenous magnesium sulphate infusion as first-line 
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34. Egelund TA, Wassil SK, Edwards EM, Linden S, Irazuzta JE. High-dose magnesium sulfate 
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35. Tatsuki M, Miyazawa R, Tomomasa T, Ishige T, Nakazawa T, Arakawa H. Serum 
magnesium concentration in children with functional constipation treated with magnesium 
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36. McGuire JK, Kulkarni MS, Baden HP. Fatal hypermagnesemia in a child treated with 
megavitamin/megamineral therapy. Pediatrics. 2000 Feb;105(2):E18. PubMed PMID: 
10654978. 
 
37. Vaiyani D, Irazuzta JE. Comparison of Two High-Dose Magnesium Infusion Regimens in 
the Treatment of Status Asthmaticus. J Pediatr Pharmacol Ther. 2016 May-Jun;21(3):233-8. 
doi: 10.5863/1551-6776-21.3.233. PubMed PMID: 27453701; PubMed Central PMCID: 
PMC4956331. 
 
38. Veyna RS, Seyfried D, Burke DG, Zimmerman C, Mlynarek M, Nichols V, Marrocco A, 
Thomas AJ, Mitsias PD, Malik GM. Magnesium sulfate therapy after aneurysmal subarachnoid 
hemorrhage. J Neurosurg. 2002 Mar;96(3):510-4. doi: 10.3171/jns.2002.96.3.0510. PubMed 
PMID: 11883835. 
 
39. Boet R, Mee E. Magnesium sulfate in the management of patients with Fisher Grade 3 
subarachnoid hemorrhage: a pilot study. Neurosurgery. 2000 Sep;47(3):602-6; discussion 606-
7. doi: 10.1097/00006123-200009000-00014. PubMed PMID: 10981747. 
 
40. Albrecht E, Kirkham KR, Liu SS, Brull R. Peri-operative intravenous administration of 
magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia. 2013 Jan;68(1):79-
90. doi: 10.1111/j.1365-2044.2012.07335.x. Epub 2012 Nov 1. Review. PubMed PMID: 
23121612. 
 
41. Ozcan PE, Tugrul S, Senturk NM, Uludag E, Cakar N, Telci L, Esen F. Role of magnesium 
sulfate in postoperative pain management for patients undergoing thoracotomy. J Cardiothorac 
Vasc Anesth. 2007 Dec;21(6):827-31. doi: 10.1053/j.jvca.2006.11.013. Epub 2007 Feb 7. 
PubMed PMID: 18068060. 
 


MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Magnesium sulfate as adjuvant analgesia and its effect on opiate use by 
post-operative transplant patients in the pediatric ICU.  
VERSION DATE: 06/09/2022 
 
Page 49 of 49 
Template Revised On: 09/01/2019 
42. Glover ML, Machado C, Totapally BR. Magnesium sulfate administered via continuous 
intravenous infusion in pediatric patients with refractory wheezing. J Crit Care. 2002 
Dec;17(4):255-8. doi: 10.1053/jcrc.2002.36759. PubMed PMID: 12501154. 
 
Hypomagnesemia 
43. Uslu Gökceoğlu A, Comak E, Dogan CS, Koyun M, Akbas H, Akman S. Magnesium 
excretion and hypomagnesemia in pediatric renal transplant recipients. Ren Fail. 2014 
Aug;36(7):1056-9. doi: 10.3109/0886022X.2014.917561. Epub 2014 May 15. PubMed PMID: 
24828469. 
 
44. Chen Y, Xu F, Hu L, Liu C, Li J. Significance of postoperative changes in hemodynamics 
and biochemical indices in pediatric recipients of live-donor liver transplants. Transplant Proc. 
2013 Nov;45(9):3320-4. doi: 10.1016/j.transproceed.2013.04.013. PubMed PMID: 24182810. 
 
45. Singhi SC, Singh J, Prasad R. Hypo- and hypermagnesemia in an Indian Pediatric Intensive 
Care Unit. J Trop Pediatr. 2003 Apr;49(2):99-103. doi: 10.1093/tropej/49.2.99. PubMed PMID: 
12729292. 
 
Others referred to in protocol 
46. Moran RA, Klapheke R, John GK, Devlin S, Warren D, Desai N, Sun Z, Walsh C, Kalyani 
RR, Hall E, Stein EM, Kalloo AN, Zaheer A, Hirose K, Makary MA, Singh VK. Prevalence and 
predictors of pain and opioid analgesic use following total pancreatectomy with islet 
autotransplantation for pancreatitis. Pancreatology. 2017 Sep - Oct;17(5):732-737. doi: 
10.1016/j.pan.2017.07.005. Epub 2017 Jul 12. PubMed PMID: 28733148. 
 
47. Bellin MD, Forlenza GP, Majumder K, Berger M, Freeman ML, Beilman GJ, Dunn TB, 
Pruett TL, Murati M, Wilhelm JJ, Cook M, Sutherland DE, Schwarzenberg SJ, Chinnakotla 
S. Total Pancreatectomy With Islet Autotransplantation Resolves Pain in Young Children With 
Severe Chronic Pancreatitis. J Pediatr Gastroenterol Nutr. 2017 Mar;64(3):440-445. doi: 
10.1097/MPG.0000000000001314. PubMed PMID: 28231072; PubMed Central PMCID: 
PMC5327823. 
 
48. Hutchins J, Castro C, Wang Q, Chinnakotla S. Postoperative pain control with paravertebral 
catheters after pediatric total pancreatectomy and islet autotransplantation: a retrospective 
cohort study. Paediatr Anaesth. 2016 Mar;26(3):315-20. doi: 10.1111/pan.12840. Epub 2016 
Jan 8. PubMed PMID: 26749428. 

ICF_001.pdf: 
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Title of Research Study: Magnesium sulfate as adjuvant analgesia and its effect on opiate use 
of post-operative transplant patients in the pediatric ICU
Investigator Team Contact Information:
For questions about research appointments, the research study, research results, or other 
concerns, call the study team at: 
Investigator Name: Gwenyth Fischer MD
Department: Pediatric Critical Care
Phone Number: 612-625-9950
Email Address: fisch662@umn.edu
Co-Investigator: Joseph Resch MD
Phone Number: 702-575-4648
Email Address: resch066@umn.edu
If you are the parent or guardian of a child under 18 years old, you will be asked to read and 
sign this document to give permission for your child to participate in this study. If you are a 
study participant who previously signed a study assent form and then turned 18 years old while 
in the study, you will now be asked to sign this consent form; the phrase “your child” 
throughout this document refers to you, the study participant. 
Your child’s surgeon, who is also responsible for this research study, is interested in both your 
child’s clinical care and the conduct of this research study. You have the right to discuss this 
study with another person who is not part of the research team before deciding whether to 
participate in the research.
Supported By: This research is supported by the UMMC Children’s Hospital Pediatric ICU.


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Key Information About This Research Study
The following is a short summary to help you decide whether or not to be a part of this research study. 
More detailed information is listed later on in this form.
What is research?
Doctors and investigators are committed to your care and safety. There are important differences 
between research and treatment plans:
<
The goal of research is to learn new things in order to help groups of people in the future. 
Investigators learn things by following the same plan with a number of participants, so they do 
not usually make changes to the plan for individual research participants. Your child, as an 
individual, may or may not be helped by volunteering for a research study.  
<
The goal of clinical care is to help you get better or to improve your quality of life. Doctors can 
make changes to a clinical care plan as needed.
Research and clinical care are often combined. One purpose of this informed consent document 
is to provide you clear information about the specific research activities of this study. 
Why am I being asked to take part in this research study?
We are asking you to allow your child to take part in this research study to see if a different kind of 
medication can reduce pain in your child after his or her surgery, decrease the amount of other pain 
medicines used, and learn how to better treat children receiving transplants in the future. Since your 
child is receiving an organ transplant, he or she is eligible for this study.
What should I know about a research study?
!
Someone will explain this research study to you.
!
Whether or not you allow your child to take part is up to you.
!
You can choose not to allow your child to take part.
!
You can agree to allow your child to take part and later change your mind.
!
Your decision will not be held against you.
!
You can ask all the questions you want before you decide.
Why is this research being done?
The purpose of this research is to see whether we can use an electrolyte medication (called magnesium) 
to decrease children’s pain after transplant procedures, and help limit the amount of other pain 
medication more typically used (called opiates). 
Children who receive transplant surgery endure a significant amount of pain, and often require a high 
amount of opiate pain medication (such as morphine) to treat their pain.  Opiate medications have a 
high number of side effects.  We are trying to find safer options to treat pain so that children do not 
need to take as many opiate medications. 
Magnesium is found in many common foods, and is already used to treat conditions like headaches and 
asthma attacks.  However, it has not been previously studied as a pain medication after transplant 


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surgery in children. The use of magnesium in this study is investigational is not approved by the FDA as a 
pain medication. 
How long will the research last?
We expect that your child will be in this research study throughout his or her time in the pediatric ICU 
after the operation (typically a few days to 1 week).  This will not require any additional participation or 
otherwise affect your child’s standard care.
What will my child and I need to do to participate?
If you consent for your child to be in this research, magnesium would be used as part of your child’s pain 
control in the ICU after the operation, something which the surgery and medical teams evaluate every 
day.  Your child will also have several blood draws to monitor his or her magnesium levels.
More detailed information about the study procedures can be found under “What happens if I say yes, I 
want my child to be in this research?”
Is there any way that being in this study could be bad for my child?
There are some rare reported side effects with use of magnesium, including lowering the blood 
pressure, causing slowing or abnormal heart rhythms, and slowing reflexes.  Very high levels of 
magnesium can cause muscle weakness or paralysis, lethargy or depression of the nervous system which 
can cause respiratory failure.  This depression may be increased with concomitant opioids, 
neuromuscular agents, cardiac glycosides, and benzodiazepines.  All of these are monitored for and can 
be reversed in the pediatric ICU.  The intended levels of magnesium used in this study are well below 
those which cause these side effects.
There will be some extra blood collections due to magnesium monitoring.  It is possible that extra blood 
loss could contribute to anemia.  To avoid this we will match up most of the magnesium checks with 
other blood draws routinely done with your child’s transplant regimen. 
There is a chance that the information we collect about your child could be accidentally shared with 
people who don’t need to see it.  We store this information securely to reduce this risk.
Will being in this study help my child in any way?
We cannot promise any benefits to your child or others from your taking part in this research. However, 
possible benefits include better pain control, less need for opiate pain medications (like morphine), less 
complications from opiate or sedative medications, less nausea and vomiting.
What happens if I do not want my child to be in this research?
There are no known alternatives, other than deciding not to allow your child to participate in this 
research study.   Whether or not your child participates in this study, his or her pain will be controlled 
following standard care, including with the use of opiate medications.
Detailed Information About This Research Study
The following is more detailed information about this study in addition to the information listed above.


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How many people will be studied?
We expect around 30 children here will be in this research study and receive study medication.
What happens if I say “Yes, I want my child to be in this research”?
If you decide you want your child to be in this research, magnesium will be given to your child from the 
time he or she is in the operating room for 48 hours or until the time that he or she leaves the PICU and 
moves to the general pediatric floors, whichever comes first. Magnesium will be given continuously 
through the IV in your child’s hand or arm. We use your child’s existing IV from his or her standard 
medications, so your child will not experience an extra needle stick.
Every four to six hours while your child is receiving magnesium, we will draw 1 ml (1/5 teaspoons) of 
blood to check your child’s magnesium levels. We match most of these blood draws up with the other 
blood draws your child will receive for routine standard of care, so your child will not experience as little 
extra disruption as able.
What happens if I say “Yes”, but I change my mind later?
You can request that your child leaves the research study at any time. Your child can leave the research 
study at any time and no one will be upset by your decision.  
If you decide to have your child leave the research study, we will continue to manage your child’s pain 
with our other medications. 
If you decide to have your child leave the research study, tell the study doctor.  He can reflect this in 
your child’s medical chart.  This makes sure that no further magnesium is given for this research study, 
and that additional blood samples are not drawn.  Please keep in mind that magnesium may need to be 
given for your child’s standard care whether or not he or she remains in this research study.  No new 
data will be collected, however we will use any preceding data when the overall study concludes.
Choosing not to allow your child to be in this study or to stop your child from being in this study will not 
result in any detriment to you or your child. This means that your choice not to be in this study will not 
negatively affect your right to any present or future medical care.
If your child stops being in the research, information about your child that has already been collected 
may not be removed from the study database. You will be asked whether the investigator can collect 
information from your child’s routine medical care, such as your child’s medical records after your child 
leave the study. If you agree, you will be asked to sign an additional consent form (i.e. Clinical Data 
Collection after Withdrawal Consent Addendum) and HIPAA authorization to document your agreement 
to participate in ongoing data collection.
Can my child be removed from the research?
It’s possible that we will have to ask your child to leave the study before he or she finishes it.  If this 
happens, we will tell you why.  We will also help arrange other care for your child, if needed.
Will it cost anything for my child to participate in this research study?
Taking part in this research study will not lead to any costs to you or your child. The study pays for all 


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study-related costs, such as study treatment or lab tests that are performed for research purposes. 
Health care services that are performed for your child’s standard care will be billed in the usual manner, 
to you or your insurance company. You should check with your insurance to see what services will be 
covered and what you will be responsible to pay.   
What happens to the information collected for the research, including my health 
information?
We try to limit the use and sharing of your information, including research study records, any medical 
records and any other information about you, to people who have a need for  this information.  But 
we cannot promise complete confidentiality.  
Overview
If you participate in this study, your information, including your health information, will be used and 
shared for purposes of conducting this research.  As described later in this Consent Form, your 
information may also be used and shared for publishing and presenting the research results, future 
research, and any optional elements of the research you agree to in this Consent Form, which may 
include creating audio and video recordings of you.   If you sign this Consent Form, you are giving us 
permission to use and share your health information for these purposes, and if we are using your 
medical records, you are giving permission to any health care providers who are treating you to share 
your medical records with us.  
What health information will be made available?
Health information about you to be used and shared for the research includes those items checked by 
the research team below:
 Your medical records, which may include records from hospital and clinic visits, emergency room 
visits, immunizations, medical history and physical exams, medications, images and imaging reports, 
progress notes, psychological tests, EEG/EKG/ECHO reports, lab and pathology reports, dental records 
and/or financial records.  These records may be used and shared for as long as this research continues.
 Information collected as part of this research study, including research procedures, research visits, 
and any optional elements of the research you agree to, all as described in this Consent Form.  This 
information might not be part of your medical record, and may include things like responses to surveys 
and questionnaires, and information collected during research visits described in this Consent Form.
Who will access and use my health information?
If you agree to participate in this study, your information will be shared with:

The University of Minnesota research team and any institutions or individuals collaborating on 
the research with us;


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
Others at the University of Minnesota and M Health/Fairview who provide support for the 
research or who oversee research (such as the Institutional Review Board or IRB which is the 
committee that provides ethical and regulatory oversight of research at the University, systems 
administrators and other technical and/or administrative support personnel, compliance and 
audit professionals (Such as the Quality Assurance Program of the Human Research Protection 
Program (HRPP)) , individuals involved in processing any compensation you may receive for your 
participation, and others);

The research sponsor(s), any affiliates, partners or agents of the sponsor(s) involved in the 
research, organizations funding the research, and any affiliates, partners or agents of the 
funding organization(s) involved in the research;

Organizations who provide accreditation and oversight for research and the research team, and 
others authorized by law to review the quality and safety of the research (such as U.S. 
government agencies like the Food and Drug Administration, the Office of Human Research 
Protections, the Office of Research Integrity, or government agencies in other countries); and

Organizations that process any payments that may be made to you for participating in this 
study, and any other individuals or organizations specifically identified in this Consent Form.
Additional sharing of your information for mandatory reporting
If we learn about any of the following, we may be required or permitted by law or policy to report this 
information to authorities:

Current or ongoing child or vulnerable adult abuse or neglect;

Communicable, infectious or other diseases required to be reported under Minnesota’s 
Reportable Disease Rule;

Certain wounds or conditions required to be reported under other state or federal law; or

Excessive use of alcohol or use of controlled substances for non-medical reasons during 
pregnancy.
How will my information be used in publications and presentations?
We may publish the results of this research in scientific, medical, academic or other journals or reports, 
or present the results at conferences.  Information that makes it easy to identify you (such as your name 
and contact information, SSN and medical records number) will not be part of any publication or 
presentation.  If you have an extremely unique or rare condition that is not shared by many others, it is 
possible that some people may be able to determine your identity even without these identifiers.
Do I have to sign this Consent Form and give my permission to make my information, including my 
health information, available for use and sharing?
No, you do not have to sign this Consent Form.  But if you do not sign, you will not be able to participate 
in this research study.  Treatment available outside of the study, payment for such treatment, 


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enrollment in health insurance plans and eligibility for benefits will not be impacted by your decision 
about signing this Consent Form.
Does my permission for making my health information available for use and sharing ever expire?
No, there is no expiration date.
May I cancel my permission for making my health information available for use and sharing?
Yes.  You may cancel your permission at any time by writing to the researcher at the address on the first 
page of this Consent Form.  If you cancel your permission, you will no longer be in the research study. 
You may also want to ask someone on the research team in canceling will affect any research related 
medical treatment.   If you cancel your permission, any health information about you that was already 
used and shared may continue to be used and shared for the research study and any optional elements 
of the study to which you agree in this Consent Form. 
What happens to my health information after it is shared with others?
When we share your information with others as described in this Consent Form, privacy laws may no 
longer protect your information and there may be further sharing of your information.  
Will I be able to look at my records?
It is possible that the research team may not allow you to see the information collected for this study.   
However, you may access any information placed in your medical records after the study is complete.  
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include your name or any other direct identifiers such as your contact 
information.  The Web site may include a summary of the results of this research. You can search this 
Web site at any time.
Will I receive research test results?
Most tests done on samples in research studies are only for research and have no clear meaning for 
health care. The investigator(s) will not contact you or share your child’s individual test results. 
Will anyone besides the study team be at my consent meeting?  
You may be asked by the study team for your permission for an auditor to observe your consent 
meeting. Observing the consent meeting is one way that the University of Minnesota makes sure that 
your child’s rights as a research participant are protected. The auditor is there to observe the consent 
meeting, which will be carried out by the people on the study team. The auditor will not document any 
personal (e.g. name, date of birth) or confidential information about you or your child. The auditor will 
not observe your consent meeting without your permission ahead of time.   


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Whom do I contact if I have questions, concerns or feedback about my child’s 
experience?
This research has been reviewed and approved by an IRB within the Human Research Protections 
Program (HRPP). To share feedback privately with the HRPP about your research experience, call the 
Research Participants’ Advocate Line at 612-625-1650  (Toll Free: 1-888-224-8636) or go to 
z.umn.edu/participants.  You are encouraged to contact the HRPP if: 
!
Your questions, concerns, or complaints are not being answered by the research team.
!
You cannot reach the research team.
!
You want to talk to someone besides the research team.
!
You have questions about your rights as a research participant.
!
You want to get information or provide input about this research.
Will I have a chance to provide feedback after the study is over? 
The HRPP may ask you to complete a survey that asks about your child’s experience as a research 
participant. You do not have to complete the survey if you do not want to. If you do choose to complete 
the survey, your responses will be anonymous.  
If you are not asked to complete a survey, but you would like to share feedback, please contact the 
study team or the HRPP. See the “Investigator Contact Information” of this form for study team contact 
information and “Whom do I contact if I have questions, concerns or feedback about my child’s 
experience?” of this form for HRPP contact information.
What happens if my child is injured while participating in this research?
In the event that this research activity results in an injury, treatment will be available, including first aid, 
emergency treatment and follow-up care as needed.  Care for such injuries will be billed in the ordinary 
manner, to you or your insurance company.  If you think that your child has suffered a research related 
injury let the study physicians know right away.  


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Signature Block for Capable Adult:
Your signature documents your permission to take part in this research.  You will be provided a copy of 
this signed document.
_______________________________________________
Printed Name of Participant
_______________________________________________      __________________
Signature of Parent/Legal Guardian                                              Date
_______________________________________________
Printed Name of Parent/Legal Guardian
____________________________________________            __________________
Signature of Person Obtaining Consent                                       Date
______________________________________________________
Printed Name of Person Obtaining Consent


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                                                                      Signature Block for Witness:
WITNESS STATEMENT:
The participant was unable to read or sign this consent form because of the following reason:
 The participant is illiterate
 The participant is visually impaired
 The participant is physically unable to sign the consent form. Please describe: 
______________________________________________________________________
 Other (please specify):
______________________________________________________________________
For the Consent of Non-English Speaking Participants when an Interpreter is Used:
As someone who understands both English and the language spoken by the subject, I represent that the 
English version of the consent form was presented orally to the subject in the subject’s own language, 
and that the subject was given the opportunity to ask questions.
__________________________________________      __________________
Signature of Interpreter
Date
___________________________________________   
Printed Name of Interpreter
OR: 
Statement from a Non-Interpreter:
As someone who understands both English and the language spoken by the subject, I represent that the 
English version of the consent form was presented orally to the subject in the subject’s own language, 
and that the subject was given the opportunity to ask questions.
__________________________________________      __________________
Signature of Individual
Date
___________________________________________   
Printed Name of Individual