Conditions: Recovery Following Cholecystectomy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 88
Healthy volunteers: no

Brief summary:
Study Objective The aim of the proposed study is to examine the effect of Q4 hour multidose IV acetaminophen on patients' readiness for discharge. In doing so the investigators will also investigate the various factors that could potentially contribute to a patient's readiness for discharge such as overall opioid consumption, time to rescue medication, incidence of postoperative nausea and vomiting, pain scores, and perioperative stress markers and their overall correlation with IV acetaminophen intake.

Detailed description:
This is a randomized, double-blind, placebo-controlled, two-arm parallel study.. Patients 50kg or more will receive either 1000mg IV acetaminophen or placebo with the first dose given preoperatively in the holding area followed by re-dosing every four hours from that point up to a maximum of 4 doses or 4000mg in 24 hours. Patients \<50 kg will receive 12.5mg/kg to a maximum of 75 mg /per kg/per day as per the label dose with repeat dosing Q4 hours.

After pre-oxygenation, general anesthesia will be induced with lidocaine (1 mg/kg Ideal Body Weight), propofol (1-2 mg/kg Actual Body Weight), and fentanyl (up to 5 mcg/kg Actual Body Weight). Additionally all subjects with receive 2 mg midazolam. Tracheal intubation will be facilitated with rocuronium (0.6 - 1.2 mg/kg Actual Body Weight). Anesthesia will be maintained with air/oxygen (60%/40%) and desflurane. A remifentanyl infusion (0.05-2mcg/kg/min Ideal Body Weight) will be continued throughout the entire case with no further analgesics being administered. All patients will receive ondansetron 4 mg prior to the end of operation as well as additional antiemetics in the PACU as judged by the attending anesthesiologist. Patients will be awakened and extubated in the OR meeting standard extubation criteria. Once extubated all patients will then be transferred to the PACU where they will be assessed via the SPEEDs criteria 5 minutes after arrival and then every 15 minutes for the duration of their PACU stay. While in the PACU, all patients will be assessed for pain using the Visual Analog Scale. Pain will be treated as per our protocol with 0.2mg IV hydromorphone for mild pain (VAS 1-3), 0.4 mg IV hydromorphone for moderate pain (VAS 4-6), and 0.6 mg IV hydromorphone (VAS 7-10). As soon as a patient meets all the SPEEDs criteria he/she will be transferred to phase II of the recovery. In phase II, if need be, pain will be managed according to the following orders: 0.2mg intravenous hydromorphone for mild pain (VAS 1-3), 0.4 mg intravenous hydromorphone for moderate pain (VAS 4-6) and 0.6mg intravenous hydromorphone for severe pain (VAS 7-10).

The patient's readiness for discharge will be our primary outcome. Each patient will be assessed within 5 minutes of arriving in the PACU and then every 15 minutes thereafter until subject reaches maximum score. The assessment will be done using the SPEEDs criteria, which has recently been shown to be as specific and more sensitive for phase 1 nursing interventions and therefore more accurate in predicting which patients are fast-track eligible as compared to the standard Modified Aldrete 2 and Fast-Track criteria (38).

The secondary outcomes will include:

1. Post-operative pain scores a. Assessed every 15 minutes during the recovery period using the Visual and Numerical Analog Scales for 2 hours and then every 4 hours thereafter until discharge.
2. Time to first rescue medication a. 0.2mg intravenous hydromorphone for mild pain (VAS 1-3) b. 0.4mg intravenous hydromorphone for moderate pain (VAS 4-6) c. 0.6 mg intravenous hydromorphone for severe pain (VAS 7-10)
3. Total dosage of post-operative opioids given.
4. Incidence of post operative nausea and vomiting and need for additional antiemetics.
5. Phase II satisfaction survey:

a. This will focus on three of the following factors rated on a scale of 1 to 5, with 1 being dissatisfied/unlikely while 5 being most satisfied/very likely.

i. How satisfied are you with the overall experience? ii. How likely are you to recommend this anesthetic and analgesic to others? iii. How likely would you ask for a similar anesthetic and analgesic in the future if need be? f) Concentration of the plasma stress markers including cortisol, norepinephrine, epinephrine, and C Reactive Protein (CRP).

a. Changes in mediator levels in the IV acetaminophen versus placebo groups will be compared. Plasma samples will be collected before administration of any drug (after placement of IV lines), before incision, and 60 minutes after arrival in PACU. Blood \[15millLiters\] will be collected at the time points described above from an additional intravenous catheter placed in the patient's arm. These specimens will be placed in vacutainer tubes with no anti-coagulant. Blood will be drawn with a syringe attached directly to the angiocatheter which has been placed intravenously. To prevent hemolysis, blood will be transferred without a needle, to a vacutainer whose top has been removed. The vacutainer top will be replaced and specimens labeled with study name, subject's study IDentification number, sample number (1, 2, 3,), and dated. Bloods from the first two time points will be kept refrigerated until the final sample is obtained postoperatively. They will be centrifuged, serum removed, aliquoted and stored at -80 degrees C until analysis. All samples will be run in duplicate on with plates and reagents of the same lot. Any samples varying greater than 15% between duplicates

Arms:
arm 1: Patients will receive 100 milliliters of normal saline with the first dose given preoperatively in the holding area followed by re-dosing every four hours from that point up to a maximum of 4 doses in 24 hours. Blinded medication will be prepared by research pharmacist. arm 2: Patients 50kg or more will receive either 1000mg IV acetaminophen with the first dose given preoperatively in the holding area followed by re-dosing every four hours from that point up to a maximum of 4 doses or 4000mg in 24 hours. Patients \<50 kg will receive 12.5mg/kg to a maximum of 75 mg /per kg/per day as per the label dose with repeat dosing Q4 hours. Blinded medication will be prepared by research pharmacist in 100mL of normal saline

Interventions: intervention 1: Acetaminophen intervention 2: normal saline
Intervention descriptions: intervention 1: patients 50kg or more receive1000mg in 100milliliters of normal saline every 4 hours to a maximum dose 4000mg/24 hours. \<50kg receive 12.5mg/kg to a maximum of 75mg/kg/24 hours. intervention 2: 100mL of normal saline every 4 hours to a maximum administration of 400mL

Protocol document:
Prot_SAP_001.pdf: 
 
 
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Department of Anesthesiology 
Rutgers, The State University of New Jersey 
185 S. Orange Avenue, MSB E-538 
Newark, NJ 07103 
p. 973-972-5007 
f. 973-972-0582 
 
A multi-center, randomized, double-blind, pilot study on the effect of intravenous multi-dose acetaminophen on 
readiness for discharge in patients undergoing surgery with general anesthesia 
Principal Investigator:  Alex Bekker, MD, PhD 
Co-Investigators: Michael Gajewski, DO, Dennis Grech, MD, Joel Yarmush, MD, MPH (New York Methodist 
Hospital, Brooklyn, NY) 
 
Background Information 
Delays in the post-anesthesia care unit (PACU) account for an increase in both patient morbidity and hospital cost 
(1). Some have estimated that a single extra minute of delay in the PACU can account for a $20 increase in cost (2).  
It has been shown that PACU delays place patients at an increased risk of severe adverse events due to insufficient 
medical and nursing coverage, inadequate communication, and lack of visiting facilities for patients’ families (1). 
Additionally, as delays stack up throughout the day, a bottleneck in OR departure occurs further escalating costs 
owing to the expense of “recovering” patients in the operating room (3).  These delays are attributable to any 
number of hospital factors such as unavailability of transport, scarcity of resources, OR holds, lack of ward space, 
and indetermination as to when a PACU patient can be discharged to another unit (4-7).  These factors are 
oftentimes hard to correct as they are dependent on numerous services and multiple levels of hospital 
infrastructure, however there are some patient-specific factors such as the patients cardiovascular and pulmonary 
status, nausea, vomiting, pain, and the type of anesthetic used, which are modifiable, and could contribute to a 
more streamlined and efficient perioperative process.  
 
Fast tracking patients has been used as a streamlining strategy to minimize PACU delays, decrease healthcare cost, 
and improve patient morbidity.  It allows stable patients to be discharged from same day surgeries sooner as long 
as they meet criteria set forth by a variety of validated assessments (8-10). Appropriate patient fast tracking is 
associated with earlier ambulation, return to intestinal motility, and liberation from tubes, catheters, and drains 
(11). This strategy has shown substantial cost-savings with no change in patient outcomes and no significant rates 
of reoperation or readmission (11-13). Interventions that would allow a greater number of patients to be 
appropriately fast tracked could demonstrate cost savings as they would help prevent delays in the system.  
 
A potential intervention lies in administering IV acetaminophen, a non-opioid analgesic drug indicated for patients 
with mild to moderate pain, management of moderate to severe pain with adjunctive opioid analgesics, and for 
reduction of fever (14). It demonstrates a rapid onset of action, a serum peak concentration at the end of the 15 
minute infusion and a total duration between 4-6 hours, all ideal for ambulatory surgery (14-17). The intravenous 
form is associated with twice the plasma and effect site concentrations when compared to the oral version of the 
drug (18) and is especially helpful when patients are unable to tolerate enteral formulations. When used 
perioperatively, IV acetaminophen has been shown to reduce postoperative nausea and vomiting, reduce 
postoperative opioid consumption, and improve early pain outcomes at rest and during movement (17, 19-22). 
Such improvements are of particular interest as these are oftentimes the very reasons why patients do not meet 
early PACU discharge criteria (7, 23).  
 
 
Study Rationale Both single- and multiple-dose IV acetaminophen regimens have been separately researched. 
Since most studies demonstrate numerous benefits, it is difficult to determine which regimen is optimal in the 
perioperative period. Both regimens have shown efficacy in improving pain scores, decreasing narcotic 
consumption, decreasing postoperative nausea/vomiting, and decreasing time to ambulation (17, 19-22, 24-32). In 
addition, preoperative/prophylactic vs. therapeutic regimens of IV acetaminophen have also been investigated. It 
has been shown that, when started postoperatively, or continued throughout that period, IV acetaminophen 
reduces morphine consumption, increased time to rescue medication, decreases pain intensity, decreases pain 
scores, and improves global assessment (17, 24, 26, 27, 31). The preoperative trials evaluating earlier 
administration (i.e. prior to surgical incision), have also demonstrated similar results with a significant reduction in 
nausea and vomiting, improved pain outcomes, decreased narcotic requirements, and faster recovery (25, 32-34). 


 
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However, some studies show that when given after the onset of pain, IV acetaminophen has been found to have 
“no significant impact” on PONV (19). Although it has been demonstrated  that receiving 1,000 mg every 6 hours 
did not show a statistically significant difference from dosing the drug at 650 mg every 4 hours (21), the study was 
powered to investigate the difference in outcomes compared to the drug dose not the interval. Subsequently it has 
also been shown that any single dose over 1000mg is not associated with improved outcomes (20) and is therefore 
not manufacturer or FDA recommended to exceed this single dose. To date, however, no study has compared the 
standard Q6 hour dosing to the alternate of 1gm Q4 hour (up to the allowable 4 gm per day maximum) which is 
the minimal allowable dosing interval as set forth by the FDA and is perhaps a more ideal dosing regimen for 
quicker, ambulatory procedures allowing for steadier plasma concentrations ( 14) and a possible clinical and 
economic benefit. 
 
Despite the numerous benefits of IV acetaminophen, many of the studies thus far have not been able to make a 
correlation between some of the primary and secondary outcomes, such as with the presumed reduction in opioid 
consumption being the cause of decreased incidence in PONV (19). This suggests that an alternative mechanism 
exists and could potentially be explained by IV acetaminophen unknown effect on perioperative stress. It is well 
established that patients undergoing surgery have a surge of cortisol, epinephrine, norepinephrine, as well as C-
reactive protein (CRP) (35). In response, sympathetic activation, free radical production, complement system 
activation, and a shift towards metabolic catabolism all occur to keep the body in homeostasis (35, 36). 
Furthermore, it is well known that increases in these stress markers are associated with common postoperative 
complications, such as with pain and gastrointestinal distress, and with physiologic changes like increased cardiac 
demand and impaired pulmonary function (37). These responses are the focus of management in the PACU as 
their augmentation could hasten recovery. As benefits in prophylactic IV acetaminophen have been implicated, a 
decrease in this stress surge remains to be proven.  
 
IV acetaminophen has proven benefits in managing some of the most common patient problems such as nausea, 
vomiting, pain, and functionality, all of which when not under control have negative impacts on patient recovery. 
By administering the drug prior to noxious stimuli, therefore allowing peak concentrations at surgical incision, and 
continuing treatment throughout the entire perioperative period via multiple frequent dosing the drug, IV 
acetaminophen may mitigate surgical stress response, achieve better pain control, and prevent the negative 
outcomes which halt patients from a speedy recovery. Subsequently, any interval of time saved in patient recovery 
translates into more efficient hospital management with improved cost savings and possibly improved patient 
satisfaction.  
 
Study Objective 
The aim of the proposed study is to examine the effect of Q4 hour multidose IV acetaminophen on patients’ 
readiness for discharge. In doing so we will also investigate the various factors that could potentially contribute to 
a patient’s readiness for discharge such as overall opioid consumption, time to rescue medication, incidence of 
postoperative nausea and vomiting, pain scores, and perioperative stress markers and their overall correlation 
with IV acetaminophen intake. 
 
Methods 
i. 
Overall Study Design and Plan: 
This is a randomized, double-blind, placebo-controlled, two-arm parallel study. 
Ninety subjects (45 in each arm) will be enrolled. Subjects, over the age of 18, undergoing same-day laparoscopic 
cholecystectomy under general anesthesia will be screened for eligibility to participate in the study. Subjects will 
be screened, recruited, and randomized during the preadmission visit or the day of surgery. Eligible subjects will be 
randomized to one of the two treatment groups in a 1:1 ratio to receive either IV acetaminophen or matching 
placebo. Both men and women will be recruited, and there is no limitation as to racial and ethnic origin. 
Participation in the study will not alter the patient’s anesthetic management. Routine anesthesia monitors used 
during general anesthesia will be applied as per ASA guidelines. Patients 50kg or more will receive either 1000mg 
IV acetaminophen or placebo with the first dose given preoperatively in the holding area followed by re-dosing 


 
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every four hours from that point up to a maximum of 4 doses or 4000mg in 24 hours. Patients <50 kg will receive 
12.5mg/kg to a maximum of 75 mg /per kg/per day as per the label dose with repeat dosing Q4 hours. 
After pre-oxygenation, general anesthesia will be induced with lidocaine (1 mg/kg Ideal Body Weight), propofol (1-
2 mg/kg Actual Body Weight), and fentanyl (up to 2 mcg/kg Actual Body Weight). Additionally all subjects with 
receive 2 mg midazolam. Tracheal intubation will be facilitated with rocuronium (0.6 – 1.2 mg/kg Actual Body 
Weight). Anesthesia will be maintained with air/oxygen (60%/40%) and desflurane. A remifentanyl infusion (0.05-
2mcg/kg/min Ideal Body Weight) will be continued throughout the entire case with no further analgesics being 
administered. All patients will receive ondensentron 4 mg prior to the end of operation as well as additional 
antiemetics in the PACU as judged by the attending anesthesiologist. Patients will be awakened and extubated in 
the OR meeting standard extubation criteria. Once extubated all patients will then be transferred to the PACU 
where they will be assessed via the SPEEDs criteria 5 minutes after arrival and then every 15 minutes for the 
duration of their PACU stay. While in the PACU, all patients will be assessed for pain using the Visual Analog Scale. 
Pain will be treated as per our protocol with 0.2mg IV hydromorphone for mild pain (VAS 1-3), 0.4 mg IV 
hydromorphone for moderate pain (VAS 4-6), and 0.6 mg IV hydromorphone (VAS 7-10). As soon as a patient 
meets all the SPEEDs criteria he/she will be transferred to phase II of the recovery.  In phase II, if need be, pain will 
be managed according to the following orders: 0.2mg intravenous hydromorphone for mild pain (VAS 1-3), 0.4 mg 
intravenous hydromorphone for moderate pain (VAS 4-6) and 0.6mg intravenous hydromorphone for severe pain 
(VAS 7-10). 
ii. 
Sample Size Justification: 
The primary outcome of the study is the proportion of patients achieving discharge-readiness status at end of 2-
hours post-surgery. It is a categorical variable with binary outcomes (yes vs. no). The study hypothesizes that 
among those who received multiple doses of I.V. acetaminophen a higher proportion of patients would be ready 
for discharge at 2-hours post-surgery compared to patients who received routine care. 
For the purposes of sample size calculation we assumed that about 50% patients in the control arm would be 
ready for discharge by end of 2-hr post-surgery. We used a two-sided alpha error rate of 5% (or significance at 
alpha of <0.05 level) and a power of 80%.  With these inputs, we computed that we will need a total of 78 patients, 
39 in each arm to detect a difference of at least 30% between the two arms i.e. about 80% or more patients in I.V. 
acetaminophen arm will be ready for discharge at 2-hours post-surgery. We will be enrolling 45 patients in each 
arm (total of 90 patients). At an alpha of 0.05, this study will have 86% power in detecting at least 30% difference 
between the two treatment arms. 
iii. 
IV Acetaminophen Administration: 
The study drug will be given via intravenous infusion beginning after a placement of the IV line in the holding area 
once the patient is checked in the day of surgery. The dose will be fixed at 1000mg for those over 50kg while 
patients under 50kg will receive 12.5mg/kg all infused over 15 minutes. 
iv. 
Inclusion criteria: 
1. Male and female patients 18 years of age or over.  
2. Undergoing ambulatory laparoscopic cholecystectomy. 
3. ASA physical status 1, 2, or 3. 
v. 
Exclusion criteria: 
1. Cognitively impaired (by history) and unable or unwilling to consent 
2. Chronic steroid or opioid user (as prescribed for a chronic systemic illness) 
3. Pregnant 
4. Patients who have been informed by a physician that they have liver or kidney disease  


 
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5. History of substance abuse (alcohol or drug) 
6. Diagnosis of obstructive sleep apnea 
7. Allergy to acetaminophen  
8. Chronic use of other products that contain acetaminophen 
vi. 
Endpoints: 
The patient’s readiness for discharge will be our primary outcome. Each patient will be assessed within 5 minutes 
of arriving in the PACU and then every 15 minutes thereafter until subject reaches maximum score. The 
assessment will be done using the SPEEDs criteria, which has recently been shown to be as specific and more 
sensitive for phase 1 nursing interventions and therefore more accurate in predicting which patients are fast-track 
eligible as compared to the standard Modified Aldrete 2 and Fast-Track criteria (38).  
The secondary outcomes will include: 
a) Post-operative pain scores 
a. Assessed every 15 minutes during the recovery period using the Visual and Numerical Analog 
Scales for 2 hours and then every 4 hours thereafter until discharge. 
b) Time to first rescue medication  
a. 0.2mg intravenous hydromorphone for mild pain (VAS 1-3) 
b. 0.4mg intravenous hydromorphone for moderate pain (VAS 4-6) 
c. 
0.6 mg intravenous hydromorhone for severe pain (VAS 7-10) 
c) Total dosage of post-operative opioids given. 
d) Incidence of post operative nausea and vomiting and need for additional antiemetics. 
e) Phase II satisfaction survey: 
a. This will focus on three of the following factors rated on a scale of 1 to 5, with 1 being 
dissatisfied/unlikely while 5 being most satisfied/very likely. 
i. How satisfied are you with the overall experience? 
ii. How likely are you to recommend this anesthetic and analgesic to others? 
iii. How likely would you ask for a similar anesthetic and analgesic in the future if need be?  
f) 
Concentration of the plasma stress/inflammatory markers including cortisol, norepinephrine, 
epinephrine, interleukins 6, 8, 10 and CRP. 
a. Changes in mediator levels in the IV acetaminophen versus placebo groups will be compared. 
Plasma samples will be collected before administration of any drug (after placement of IV lines), 
before incision, and 60 minutes after arrival in PACU.  Blood [15mL] will be collected at the time 
points described above from an additional intravenous catheter placed in the patient’s arm.  
These specimens will be placed in vacutainer tubes with no anti-coagulant. Blood will be drawn 


 
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with a syringe attached directly to the angiocatheter which has been placed intravenously.  To 
prevent hemolysis, blood will be transferred without a needle, to a vacutainer whose top has 
been removed. The vacutainer top will be replaced and specimens labeled with study name, 
subject’s study ID number, sample number (1, 2, 3,), and dated. Bloods from the first two time 
points will be kept refrigerated until the final sample is obtained postoperatively.  They will be 
centrifuged, serum removed, aliquoted and stored at -80 degrees C until analysis.  All samples 
will be run in duplicate on with plates and reagents of the same lot. Any samples varying greater 
than 15% between duplicates will be repeated. Serum collected by NewYork-Presbyterian 
Methodist Hospital will be transported to Rutgers – NJMS, MSB. Samples will be placed into dry 
ice and transported by car in compliance with IATA regulations by person with IATA Shipping 
Training.  
vii. 
Methods and Procedures 
1. Data monitoring plan: Adverse events will include events reported by the subject or noted by the 
medical staff and thought to be associated with the research. Unanticipated problems and adverse 
events will be gathered by study investigators. Adverse events will be evaluated at each study visit. 
Any serious adverse effects will be reported to the IRB according to regulatory requirements.  
The principal investigator Dr. Michal Gajewski will be primarily responsible for monitoring the study.  
The study principal investigator will evaluate the data to determine whether to continue the study or 
to change the protocol to decrease risk. 
 
2. Data Storage: All of the patient data used in this study will be kept confidential and will be used for 
professional purposes only. Patient records will be coded and kept in locked files within locked rooms 
or in password protected computers. Only those investigators directly involved in the protocol will 
have access to these records. Though the information collected in this study may be published, no 
patient will be identified by name. After completion of the study data will be kept for six years before 
secure disposal. 
3. Risk/Benefit Assessment: Other than general risk of anesthesia and surgery, there are a few risks 
associated with the study drug, mainly nausea, vomiting, headache and insomnia as reported on the 
Ofirmev Prescribing Information (reference). Anyone with an increased risk for hepatotoxicity has 
been excluded from the study. The risks from the blood draws are the risks of any routine blood 
draw. These include discomfort or minor swelling at the site. There are no risks to the questionnaires. 
Acetaminophen is a non-opioid analgesic which may be of benefit during as well as after surgery. This 
study will elucidate whether a standing dose given every four hours will have a beneficial effect on 
patient recovery after surgery and which factors may be of greatest importance.  
4. Subject Identification, Recruitment, and Consent: Study flyers approved by the IRB will be distributed 
to the surgeons’ offices and given to patients who come to Pre-Admission Testing. After a general 
discussion regarding the study and the informed consent, patients will be approached when they 
arrive at same-day admission and we will formally obtain consent after answering their questions and 
concerns about the study. In addition, this study in particular poses little risk to the patient. Patients 
will be approached if possible at pre-surgical testing but more likely on the day of their procedure and 
spoken to in a closed room or a private area. The patient may have family included, if he/she prefers. 
We will be approaching all subjects (male and female) who are undergoing same-day laparoscopic 
cholecystectomy and who, from the OR schedule, are at least 18 year of age. A verbal explanation of 


 
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the study will be given followed by a written consent form. Study staff members are experienced at 
consenting patients for anesthesiology studies. One is an MD anesthesiologist with clinical research 
experience and another is an experienced coordinator with over 5 years of experience.  
Subjects who do not have the capacity to consent for surgery will not be recruited. All other 
subjects will be recruited. For any patient who might be illiterate, consents will be read to him or 
her and witnessed by available staff or family member.  
5. Costs to the subject 
All study related costs will be paid by Departmental Internal funding. After IRB approval we will apply 
for funding from the Mallinckrodt Research Grant.  
Patients will not receive payment for participation in the study. 
viii. 
Statistical Analysis 
Data will be sent to the Department of Surgery, Rutgers University-New Jersey Medical School for analyses by an 
independent biostatistician (A.D.). To assess the success of randomization patients’ demographic and clinical 
characteristics, values of biological markers (drawn before drug administration or induction) will be compared 
using Student’s t-tests for continuous measures (where assumptions of normality are met); Mann Whitney U tests 
for ordinal data; Pearson chi-square or Fishers exact test for categorical data. Using Mann Whitney U test will be 
used to compare pain scores upon arrival in PACU, at intervals of 30-minutes, 1-hour, 2-hours, 4-hours, and at 
discharge. Serum epinephrine, serum norepinephrine, C reactive protein, and serum cortisol levels will be 
compared before induction, end of surgery, and prior to discharge using Student t-tests. In addition, to account for 
baseline values, ANCOVA models will also be used. Fisher’s exact test will be used to compare proportion of 
patients who received rescue hydromorphone, oxycodone, and anti-emetics. Additionally, Student t-tests will be 
used to compare total dosage of rescue hydromorphone and oxycodone used by patients in the two arms. All 
statistical tests will be two sided with statistical significance at alpha of 0.05. SAS 9.4 statistical software will be 
used for data analysis.    
ix. 
Study drug storage 
 
In accordance with University hospital policy all study medications and placebo will be dispensed by the research 
pharmacist.  
 
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26. Cakan, Turkay, et al. "Intravenous paracetamol improves the quality of postoperative analgesia but does 
not decrease narcotic requirements." Journal of neurosurgical anesthesiology 20.3 (2008): 169-173. 
27. Cattabriga, Iolter, et al. "Intravenous paracetamol as adjunctive treatment for postoperative pain after 
cardiac surgery: a double blind randomized controlled trial." European Journal of Cardio-Thoracic 
Surgery 32.3 (2007): 527-531. 
28. Gimbel, J., et al. "Efficacy and safety of IV acetaminophen in the treatment of pain following primary total 
hip arthroplasty: results of a double-blind, randomized, placebo-controlled, multiple-dose, 24 hour 
study." 24th Annual Meeting of the American Academy of Pain Medicine. 2008. 
29. Hong, Jeong-Yeon, et al. "Paracetamol reduces postoperative pain and rescue analgesic demand after 
robot-assisted endoscopic thyroidectomy by the transaxillary approach." World journal of surgery 34.3 
(2010): 521-526. 
30. Jokela, R., et al. "The influence of ondansetron on the analgesic effect of acetaminophen after 
laparoscopic hysterectomy." Clinical Pharmacology & Therapeutics 87.6 (2010): 672-678. 
31. Memis, Dilek, et al. "Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-
related adverse effects after major surgery in intensive care unit." Journal of critical care 25.3 (2010): 458-
462. 


 
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32. Ohnesorge, Henning, et al. "Paracetamol versus metamizol in the treatment of postoperative pain after 
breast surgery: a randomized, controlled trial."European Journal of Anaesthesiology (EJA) 26.8 (2009): 
648-653. 
33. Arslan, Mustafa, et al. "Comparing the efficacy of preemptive intravenous paracetamol on the reducing 
effect of opioid usage in cholecystectomy."Journal of research in medical sciences: the official journal of 
Isfahan University of Medical Sciences 18.3 (2013): 172. 
34. Salihoglu, Ziya, et al. "Evaluation of intravenous paracetamol administration on postoperative pain and 
recovery characteristics in patients undergoing laparoscopic cholecystectomy." Surgical Laparoscopy 
Endoscopy & Percutaneous Techniques 19.4 (2009): 321-323. 
35. Desborough JP “The stress response to trauma and surgery.” British Journal of Anesthesia 87.1 (2000): 
109-117 
36. Glantzounis GK et. al. “Laparoscopic surgery-induced changes in oxidative stress markers in human 
plasma” Surgical Endoscopy 15 (2001): 1315-1329 
37. H. Kehlet. Surgical stress and postoperative outcome—from here to where? Reg Anesth, 31 (2006): 47–52 
38. Kyker, Mark, and Brent Burke. "Speeds Criteria vs. Modified Aldrete and Fast-Track Criteria for Evaluating 
Recovery in Outpatients." Open Journal of Anesthesiology 3.07 (2013): 309 
 
 

ICF_000.pdf: 
Title: A multi-center, randomized, double-blind, pilot study on the effect of intravenous multidose acetaminophen on readiness 
for discharge in patients undergoing laparoscopic cholecystectomy under general anesthesia
PI: Michal Gajewski, DO
Page 1 of 8
ICF version 3.8.16
 
 SUBJECT CONSENT TO TAKE PART IN A RESEARCH STUDY
TITLE OF STUDY: A multi-center, randomized, double-blind, pilot study on the effect of 
intravenous multidose acetaminophen on readiness for discharge in patients undergoing 
laparoscopic cholecystectomy under general anesthesia 
Principal Investigator: Michal Gajewski, DO
Co-Investigator: Daniel Rodriguez-Correa, MD (Spanish speaking)
This consent form is part of an informed consent process for a research study and it will provide 
information that will help you to decide whether you wish to volunteer for this research study.  It 
will help you to understand what the study is about and what will happen in the course of the 
Study.
If you have questions at any time during the research study, you should feel free to ask them and 
should expect to be given answers that you completely understand.
After all of your questions have been answered, if you still wish to take part in the study, you 
will be asked to sign this informed consent form.
You are not giving up any of your legal rights by volunteering for this research study or by 
signing this consent form.
Who is conducting this research study?
Dr. Michal Gajewski is the Principal Investigator of this research study.  A Principal Investigator 
has the overall responsibility for the conduct of the study. However, there are often other 
individuals who are part of the research team.
Dr. Gajewski or Dr. Daniel Rodriguez-Correa may be reached at:
Rutgers/NJMS
Department of Anesthesiology MSB E 538
185 South Orange Ave.
Newark, New Jersey 07103
973 972-5007
The study doctor, Dr. Gajewski, or another member of the study team will also be asked to sign 
this informed consent.  You will be given a copy of the signed consent form to keep.
Why is this study being done?
This study is being done as the study doctors wish to study ways to improve recovery after 
surgery. Injury including surgical injury causes inflammation and pain.  Inflammation is the 
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body’s attempt to protect itself and start the healing process. Although mainly a healing 
response, inflammation can have side effects which delay recovery.  The investigators wish to 
determine the effect of intravenous acetaminophen on post- operative surgical pain. An increase 
in pain after surgery can cause distress for patients. The narcotic medications which we give to 
patients to reduce pain have their own side effects.  Acetaminophen has been used for reduction 
of pain.  The study doctors would like to see if receiving acetaminophen prior to, during and 
after surgery can provide:

a lower level of pain

a decrease in pain medication

fewer episodes of nausea and or vomiting

a shorter hospital stay
Why have you been asked to take part in this study?
You have been asked to participate in this study because you are scheduled to undergoing a 
laparascopic removal of your gallbladder under general anesthesia.
Who may take part in this study?  And who may not?
You may take part in this study if:
1. You are 18 years and older.
2. You are not pregnant or nursing
3. You are willing and able to consent
4. You have an American Society of Anesthesiologists (ASA) rating of 1, 2, or 3 as 
determined by your anesthesiologist*
5. You surgery is not an emergency
You may not take part in this study if:
        1. You have an allergy or suspected allergy to acetaminophen
        2. You are a chronic steroid or opioid/narcotic abuser
        3. You have been told by a physician that you have hepatitis or liver disease
        4. You have a history of alcohol abuse
       5.  You use on a daily basis any of these over the counter medications that contain
                  Acetaminophen: 
Actifed, Alka Seltzer, Contac, Anacin, Coricidin, Dayquil, Nyquil, Dimetapp, Dristan, 
Excedrin, Liquiprin, Midol, Panadol, Robitussin, St. Joseph’s Aspirin-Free, Sudafed, 
Sinutab, Theraflu, Tylenol Brand Products, Vanquish, Zicam
     6. You use on a daily basis any of these prescribed drugs that contain acetaminophen:
           Lortab, Endocet, Oxycodone, Percocet, Tramadol, Vicodin,  Hycotab, Fioricet
* This classification is used by anesthesiologists to evaluate the degree of the patient’s physical 
state based on their preexisting condition. Those patients who are healthy with no past medical 
history are classified as ASA 1, those with mild systemic disease (such as well controlled 
hypertension) are ASA 2, while those with severe systemic illness are ASA 3 (i.e. poorly 
controlled hypertension). This system is not intended to predict operative risk but is more so 
utilized to classify patients according to a uniform system. Patients with classifications of 4 and 
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Title: A multi-center, randomized, double-blind, pilot study on the effect of intravenous multidose acetaminophen on readiness 
for discharge in patients undergoing laparoscopic cholecystectomy under general anesthesia
PI: Michal Gajewski, DO
Page 3 of 8
ICF version 3.8.16
above have illnesses that are a constant threat to life and may react unpredictably when given the 
study drug. For this reason only classes 1-3 have been included. 
      
How long will the study take and how many subjects will participate?
We will ask 90 patients to participate in the study.  The study will be performed at University 
Hospital in Newark (approximately 45 patients) and a hospital in Brooklyn, New York 
(approximately 45 patients). The study is expected to take three years. The study will begin the 
day of surgery and end at the time of your discharge from the hospital.
What will you be asked to do if you take part in this research study?
If you decide to participate 
Prior to Surgery
 Screening visit, this visit encompasses discussing the study, answering questions you may have, 
and signing the consent. A brief medical history will be taken by one of the members of the 
study team.  A pain scale called the Visual Acuity Scale will be explained to you.  One member 
of the study team will draw 15mL or 3 teaspoons of blood from the intravenous line that the 
nurse inserts for fluid replacement. (All patients must have this line inserted prior to being 
brought to the Operating Room) This blood will be sent to a laboratory for analysis of 
inflammation markers. You will be randomized to either receive acetaminophen or a placebo 
(sugar water). Randomization is the same as flipping a coin.  Half the study subjects will get the 
acetaminophen and half will get the sugar water.  Your doctors will not know which you will 
receive only the research pharmacist will know. The medication will be given to you through the 
intravenous line.   .
During Surgery
Prior to the surgical incision but while you are comfortably asleep the second blood draw 15mL 
or 3 teaspoons will be drawn for inflammation markers. While you are sleep, if 4 hours has 
elapsed since your first dose of the study drug, you will be given a second dose.   
Following Surgery
You will go to the PACU where all patients go to recover from anesthesia. While you are there a 
member of the study team will assess you at 15 minutes intervals. We will ask you to move your 
legs and arms.  We will ask you your pain score. We will ask you if you know where you are and 
what day it is.  If you require pain medication, it will be given to you.  We will record your 
pain score, the amount of pain medication you receive, and whether you have any nausea or 
vomiting. Sixty minutes after your arrival in the PACU we will draw the third sample of blood 
for inflammation markers. We will document the time you leave the PACU and the time you are 
discharged from the hospital. If 4 hours has elapsed since your last dose of the study medication 
you will receive another dose. This will be repeated if you stay in the hospital longer. You will 
not receive more than 4 doses of the study medication. . You will also be asked to complete a 3 
question survey. This will not take longer than 3-4 minutes. Once you are discharged you have 
completed the study. 
What are the risks and/or discomforts you might experience if you take part in this study?
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Title: A multi-center, randomized, double-blind, pilot study on the effect of intravenous multidose acetaminophen on readiness 
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PI: Michal Gajewski, DO
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There are potential side effects for any medication.  The most serious side effect of intravenous 
acetaminophen is acute liver failure.  This could happen in people who receive doses that exceed 
the recommended daily dose limit. That is why we ask you to be very careful in telling us 
about the medicines you take:
 both those prescribed by a doctor and those that you buy over the counter at the store. 
Another rare occurrence is a serious skin disorder. You will be watched carefully for any 
skin rashes or signs of hypersensitivity to this drug. If these signs are observed the 
medication will be discontinued immediately.
When your blood is drawn, there may be a bruise, or bleeding, or infection, at the place where 
your blood is drawn.  However, infection is rare.
Are there any benefits for you if you choose to take part in this research study?
The benefits of taking part in this study may be:
Less pain after surgery
Decrease in pain medication after surgery
Fewer episodes of nausea and vomiting
Shorter hospital stay
However, it is possible that you might receive no direct personal benefit from taking part in this 
study.
What are your alternatives if you don’t want to take part in this study?
 If you chose not to enter the study then your surgery will go forward as planned. The 
anesthesiologist will evaluate you in accordance with his or her customary practice.
How will you know if new information is learned that may affect whether you are willing to 
stay in this research study?
During the course of the study, you will be updated about any new information that may affect 
whether you are willing to continue taking part in the study.  If new information is learned that 
may affect you after the study or your follow-up is completed, you will be contacted.
Will there be any cost to you to take part in this study?
There will be no cost to you if you chose to participate in the study.
Will you be paid to take part in this study?
You will not be paid for your participation in this research study.
How will information about you be kept private or confidential?
All efforts will be made to keep your personal information in your research record confidential, 
but total confidentiality cannot be guaranteed. All paper data records will be locked in the 
Anesthesia research office.  All electronic data will be stored in a password protected computer. 
Only members of the study team will have access to the data.
A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. law. 
This website will not include information that can identify you. At most, the website will include 
a summary of the results. You can search this website at any time.
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for discharge in patients undergoing laparoscopic cholecystectomy under general anesthesia
PI: Michal Gajewski, DO
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What will happen if you are injured during this study?
Subjects in this study will be exposed to certain risks of personal injury in addition to those 
associated with standard forms of treatment, please see the paragraph on risks (page 5). In 
addition, it is possible that during the course of this study, new adverse effects of intravenous 
acetaminophen that result in personal injury may be discovered. The University will make 
appropriate referrals for medical and/or dental treatment for subjects who sustain personal 
injuries or illnesses as a direct consequence of participation in the research. The subject’s health 
insurance carrier or other third-party payer will be billed for the cost of this treatment; provided 
that the University shall not submit to federally funded programs, e.g., Medicare, Medicaid or 
CHAMPUS, for reimbursement first if submission to such programs is prohibited by law.  No 
financial compensation will be provided by the University and no other type of assistance is 
available from the University. 
While you are in the study, you and/or your health care provider will still have to pay for the 
costs of your regular medical care that are not part of the study(such as laparoscopic 
cholecystectomy and costs associated with your hospital stay).  
What will happen if you do not wish to take part in the study or if you later decide not to 
stay in the study?
Participation in this study is voluntary. You may choose not to participate or you may change 
your mind at any time.
If you do not want to enter the study or decide to stop participating, your relationship with the 
study staff will not change, and you may do so without penalty and without loss of benefits to 
which you are otherwise entitled.
You may also withdraw your consent for the use of data already collected about you, but you 
must do this in writing to: 
Dr. Michal Gajewski or Dr. Daniel Rodriguez-Correa
Rutgers University/New Jersey Medical School 
Department of Anesthesiology –MSB E 538
185 South Orange Ave.
Newark, New Jersey 07103
 At any time, the study doctor can take you out of this study because it would not be in 
your best interest to stay in it. Your study doctor can stop treatment even if you are 
willing to stay in the study. Some circumstances under which your participation may be 
terminated by the study doctor include:

If your surgery is converted to an open procedure

If you have a intraoperative change in you hemodynamic status (blood 
pressure or heart rate)

If you have an allergic or suspected allergic response to the study 
medication

If your anesthesiologist is unable to remove your breathing tube prior to 
your leaving the Operating Room
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Title: A multi-center, randomized, double-blind, pilot study on the effect of intravenous multidose acetaminophen on readiness 
for discharge in patients undergoing laparoscopic cholecystectomy under general anesthesia
PI: Michal Gajewski, DO
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If you decide to withdraw from the study for any reason, you may be asked to return for at least 
one additional visit for safety reasons.
Who can you call if you have any questions?
If you have any questions about taking part in this study or if you feel you may have suffered a 
research related injury, you can call the study doctor:
Michal Gajewski, DO or Daniel Rodriguez-Correa, MD
Department of Anesthesiology
973 972-5007
If you have any questions about your rights as a research subject, you can call:
 Director of Institutional Review Board
(973)-972-3608 Newark
Or the office Human Subject Protection Program
973-972-1149
What are your rights if you decide to take part in this research study?
You have the right to ask questions about any part of the study at any time.  You should not sign 
this form unless you have had a chance to ask questions and have been given answers to all of 
your questions.
 
PERMISSION (Authorization) TO USE OR SHARE HEALTH INFORMATION THAT 
IDENTIFIES YOU FOR A RESEARCH STUDY
Information about you and your health is personal and private, so this information generally 
cannot be used in research without your written permission.  The next few paragraphs tell you 
about how researchers want to use and share your health information in this research study. Your 
information will only be used as described here or as allowed or required by law.  Ask questions 
if you do not understand any part of the research or the use of your health information. If you 
sign this consent form, you agree to let the researchers use your information in the research and 
share it with others as described below.
What is the purpose of the research and how will my information be used? 
You are being invited to take part in this research study which is described at the beginning of 
this form. The purpose of collecting and using your health information for this study is to help 
researchers answer the questions that are being asked in the research.
What information about me will be used? 

age, weight, allergies, blood pressure, heart rate

Medical history or treatment

Medications including over the counter medications

A  questionnaire regarding your surgical experience
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Title: A multi-center, randomized, double-blind, pilot study on the effect of intravenous multidose acetaminophen on readiness 
for discharge in patients undergoing laparoscopic cholecystectomy under general anesthesia
PI: Michal Gajewski, DO
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
Operative report (about this surgery)and anesthesia reports
Who may use, share or receive my information?
The research team may use or share your information collected or created for this study with the 
following people and institutions:

Rutgers University researchers involved in the study;

The Rutgers University Institutional Review Board and Compliance Boards

The Office for Human Research Protections in the U.S. Dept. of Health and Human Services

US Food and Drug Administration 

Researchers involved at New York Methodist Hospital in Brooklyn, New York.
Those persons or organizations that receive your information may not be required by Federal 
privacy laws to protect it and may share your information with others without your permission, if 
permitted by the laws governing them.  
Will I be able to review my research record while the research is ongoing?
No. We are not able to share information in the research records with you until the study is over. 
To ask for this information, please contact the Principal Investigator, the person in charge of this 
research study.  
Do I have to give my permission?
No. You do not have to permit use of your information. But, if you do not give permission, you 
cannot take part in this research study. (Saying no does not stop you from getting medical care or 
other benefits you are eligible for outside of this study.) 
If I say yes now, can I change my mind and take away my permission later?
Yes. You may change your mind and not allow the continued use of your information (and to 
stop taking part in the study) at any time. If you take away permission, your information will no 
longer be used or shared in the study, but we will not be able to take back information that has 
already been used or shared with others. If you say yes now but change your mind later for use of 
your information in the research, you must write to the researcher and tell him of your decision:
 Dr. Michal Gajewski or Dr. Daniel Rodriguez-Correa
Rutgers University/New Jersey Medical School
Department of Anesthesiology –MSB E 538
185 South Orange Ave.
Newark, New Jersey 07103 
How long will my permission last?
Your permission for the use and sharing of your health information will last until the end of the 
study. 
___________________________________________________________________________
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AGREEMENT TO PARTICIPATE
1.  Subject consent:
I have read this entire form, or it has been read to me, and I believe that I understand what has 
been discussed.  All of my questions about this form or this study have been answered.
Subject Name:
Subject Signature:
 Date:
2.  Signature of Investigator/Individual Obtaining Consent:
To the best of my ability, I have explained and discussed the full contents of the study 
including all of the information contained in this consent form.  All questions of the research 
subject and those of his/her parent or legally authorized representative have been accurately 
answered.
Investigator/Person Obtaining Consent (printed name):
Signature:
 Date: 
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