Letters
3. Goodman J, Carmichael F. Coronavirus: “deadly masks” claims debunked.
Table 2. Oxygen Saturation Before, While, and After Wearing
Nonmedical Face Masks
SpO2, mean (SD), %
No. of participants 25
Before mask wearing, SpO2 reading
1 96.1 (1.3)
2 95.8 (2.1)
3 96.3 (1.6)
Pooled mean SpO2, % (95% CI)a 96.1 (95.5-96.7)
While mask wearing, SpO2 reading
1 96.4 (1.2)
2 96.5 (1.3)
3 96.7 (1.1)
Pooled mean SpO2, % (95% CI)a 96.5 (96.1-97.0)
After mask wearing, SpO2 reading
1 96.4 (1.3)
2 96.4 (1.4)
3 96.2 (1.4)
Pooled mean SpO2, % (95% CI)a 96.3 (95.8-96.8)
Abbreviation: SpO2, oxygen saturation measured using a portable oximeter.
a
95% CIs are 2-sided.
exclusion of patients who were unable to wear a mask for medi-
cal reasons, investigation of 1 type of mask only, SpO2 mea-
surements during minimal physical activity, and a small sample
size. These results do not support claims that wearing non-
medical face masks in community settings is unsafe.
Noel C. Chan, MBBS
Karen Li
Jack Hirsh, MD, DSc
Author Affiliations: Department of Medicine, McMaster University, Hamilton,
Ontario, Canada.
Accepted for Publication: October 19, 2020.
Published Online: October 30, 2020. doi:10.1001/jama.2020.21905
Corresponding Author: Noel C. Chan, MBBS, C5-116 DBCVRI, 237 Barton St E,
Hamilton, ON L8L 2X2, Canada (noel.chan@taari.ca).
Author Contributions: Dr Chan had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the data
analysis.
Concept and design: Chan, Hirsh.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Chan, Hirsh.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Chan, Li.
Administrative, technical, or material support: Chan, Li.
Supervision: Chan, Hirsh.
Conflict of Interest Disclosures: Dr Chan reported receiving a speaker’s fee
from Bayer outside of the submitted work. No other disclosures were reported.
1. Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schünemann HJ; COVID-19
Systematic Urgent Review Group Effort (SURGE) Study Authors. Physical
distancing, face masks, and eye protection to prevent person-to-person
transmission of SARS-CoV-2 and COVID-19: a systematic review and
meta-analysis. Lancet. 2020;395(10242):1973-1987. doi:10.1016/S0140-6736
(20)31142-9
2. Doung-Ngern P, Suphanchaimat R, Panjangampatthana A, et al. Case-control
study of use of personal protective measures and risk for severe acute
respiratory syndrome coronavirus 2 infection, Thailand. Emerg Infect Dis. 2020;
26(11):1973-1987. doi:10.3201/eid2611.203003
2324 JAMA December 8, 2020 Volume 324, Number 22 (Reprinted)
© 2020 American Medical Association. All rights reserved.
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BBC website. Posted July 24, 2020. Accessed August 15, 2020. https://www.
bbc.com/news/53108405
4. Centers for Disease Control and Prevention. Considerations for wearing
masks: help slow the spread of COVID-19. Updated August 7, 2020. Accessed
October 4, 2020. https://www.cdc.gov/coronavirus/2019-ncov/prevent-
getting-sick/cloth-face-cover-guidance.html
5. Greenhalgh T, Javid B, Matthew BJ, Inada-Kim M. What is the efficacy and
safety of rapid exercise tests for exertional desaturation in COVID-19? Centre for
Evidence-Based Medicine website. Posted April 21, 2020. Accessed October 4,
2020. https://www.cebm.net/covid-19/what-is-the-efficacy-and-safety-of-
rapid-exercise-tests-for-exertional-desaturation-in-covid-19/
6. Rodríguez-Molinero A, Narvaiza L, Ruiz J, Gálvez-Barrón C. Normal
respiratory rate and peripheral blood oxygen saturation in the elderly
population. J Am Geriatr Soc. 2013;61(12):2238-2240. doi:10.1111/jgs.12580
Neurodevelopmental Outcomes at Age 5 Years
After Prophylactic Early High-Dose Recombinant
Human Erythropoietin for Neuroprotection
in Very Preterm Infants
Although recombinant human erythropoietin (rhEpo) has been
shown to be neuroprotective in experimental and clinical
studies,1,2 prophylactic early high-dose rhEpo did not im-
prove neurodevelopment
among 2-year-olds who had
Supplemental content
been born very preterm in a
randomized clinical trial.3 We report the prespecified second-
ary neurodevelopmental outcomes of the trial cohort at early
school age.
Methods | This was a randomized, double-blind, placebo-
controlled, multicenter phase 3 trial with a primary objective
of investigating the effect of early high-dose rhEpo (3000 IU/kg
intravenously vs saline within 3, at 12-18, and at 36-42 post-
natal hours) on the neurodevelopment of 2-year-olds who had
been born very preterm (ie, <32 weeks’ gestation). Enroll-
ment occurred at 5 Swiss perinatal centers in 2005-2012, with
the date of last neurodevelopmental evaluation in January
2018. Details of the trial, the study protocol (Supplement 1),
and short-term safety data have been published.3,4
At age 5 years, the following were assessed: (1) a measure
of general intelligence, the Mental Processing Composite
(norm, 100 [SD, 15]; higher values indicating better function)
of the Kaufman Assessment Battery for Children, first edition
(the prespecified second edition was not available at the start
of the study)3,4; (2) cerebral palsy (graded according the Gross
Motor Function Classification System3) and severe hearing and
visual problems3; and (3) somatic growth. Fine motor func-
tion was a prespecified outcome but was not reliably as-
sessed in all centers. Behavior will be reported separately.
We used generalized estimating equations to account for
the cluster structure of outcomes with same-birth siblings.
Because we used an exchangeable working correlation struc-
ture for continuous outcomes, the estimated mean differ-
ences differ slightly from the mean group’s differences. For
binary outcomes, we used an independence working correla-
tion structure. Comparisons between groups of children at
age 5 years were performed including participants as origi-
nally randomized and including only children who com-
pleted the allocated treatment (R software, version 3.1.028),
jama.com
 Letters

Table 1. Characteristics of Participants and Their Family Members at Age 5 Years

Characteristics Recombinant human erythropoietin (n = 177) Placebo (n = 168)

Gestational age, mean (SD), wk 29.2 (1.7) 29.2 (1.7)
Sex, No. (%)
Female 69 (39) 72 (43)
Male 108 (61) 96 (57)
Singleton, No. (%) 106 (60) 110 (65)
Birth weight, mean (SD), g 1218 (325) 1207 (356)
z score −0.09 (0.74) −0.10 (0.87)
Birth head circumference, mean (SD), cm 27.0 (2.1) [n = 175] 26.9 (2.3) [n = 167]
z score −0.09 (0.65) −0.17 (0.73)
Complete course of antenatal steroids, No. (%) 170 (97) 159 (95)
Chorioamnionitis (placental histology), No. (%) 52 (29) [n = 176] 47 (28)
pH of umbilical artery, mean (SD) 7.39 (0.69) 7.46 (0.47)
Apgar score at 5 min, mean (SD) 7.7 (1.6) 7.4 (1.9)
Mechanical ventilation, mean (SD), d 2.5 (5.1) [n = 175] 3.2 (7.0)
Bronchopulmonary dysplasia, No. (%) 57 (32) 59 (35)
Intraventricular hemorrhage grade ≥2, No. (%) 6 (3) 5 (3)
Cystic periventricular leukomalacia, No. (%) 2 (1.1) 1 (0.6)
Sepsis, No. (%) 22 (12) 22 (13)
Necrotizing enterocolitis, No. (%) 4 (2) 6 (3.6)
Retinopathy of prematurity grade ≥3, No. (%) 1 (0.6) 0
Patent ductus arteriosus (treatment needed), No. (%) 49 (28) 52 (31)
Socioeconomic status, mean (SD)a 5.6 (2.3) [n = 171] 5.6 (2.3) [n = 167]
Age of mother, mean (SD), y 32.4 (4.8) 32.9 (5.6)
MDI at age 2 y, mean (SD)b 93.8 (16.1) [n = 169] 95.2 (16.8) [n = 152]
Survival at 2 y without neurodevelopmental impairment, 144 (84) [n = 168] 136 (88) [n = 154]
No. (%)
a b
Socioeconomic status was estimated by a validated 12-point scale based on Mental Development Index (MDI) of the Bayley Scales of Infant Development,
maternal education and paternal occupation, with higher scores indicating second edition.
lower status.

with a 2-sided significance threshold at P < .05. Missing data
were not imputed. The ethical committees of the University
Children’s Hospital Zurich and the Canton Zurich and the
Swiss Agency for Therapeutic Products approved the study
protocol. Written informed consent was obtained from the
parents of each infant.
Results | Among 448 randomized infants, 228 were random-
ized to receive rhEpo and 220 to placebo. Outcome data at a
mean age of 5.8 (SD, 0.4) years were available for 177 chil-
dren (78%) in the rhEpo group and 168 (76%) in the placebo
group, with similar neonatal and sociodemographic base-
line characteristics (Table 1). Of 345 children included in the
analysis, 5 received a lower treatment dose than allocated
(rhEpo: n = 4; placebo: n = 1), while 32 received supplemen-
tal rhEpo to treat anemia of prematurity (rhEpo: n = 17; pla-
cebo: n = 15).
In the analysis including participants as originally ran-
domized (n = 345), mean scores were not significantly differ-
ent between groups on the Mental Processing Composite
(rhEpo: 96.0 [SD, 12.6]; placebo: 97.3 [SD, 13.6]; mean differ-
ence, −1.4; 95% CI, −3.7 to 0.8; P = .29) (Table 2). The analysis
including only children who completed the allocated treat-
ment (n = 308) revealed similar results (mean difference, −0.7;
95% CI, −3.1 to 1.6; P = .60). None of the other prespecified sec-
ondary neurodevelopmental outcomes were significantly dif-
ferent between groups.
Discussion | There were no statistically significant differences
in neurodevelopmental outcomes at 5 years in children born
very preterm treated with prophylactic early high-dose rhEpo
vs saline. Although the present findings contrast with those
of a previous meta-analysis,1 they confirm the results of the
primary 2-year outcome analysis of this trial3 and another large
trial5 and do not support prophylactic administration of short-
term, high-dose rhEpo immediately after birth for a neuro-
protective purpose in preterm infants.
A previous trial reported better cognitive outcomes at age
3.5 to 4 years in 39 children born very preterm and treated
with rhEpo or darbepoetin vs 14 control children.6 Explana-
tions for the absence of any neurodevelopmental effect of
rhEpo in the present trial may be the treatment’s short dura-
tion, the enrolled population with a low brain damage rate,
the administration of rhEpo to 15 of 168 children in the pla-
cebo group, or that rhEpo does not improve neurodevelop-
ment. The loss to follow-up of 23% of randomized partici-
pants and the consequent decrease of study power represent
2 major study limitations.

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 Letters

Table 2. Comparison of Neurodevelopment and Growth Outcome Data Between Study Groups at Age 5 Years
Recombinant Mean difference
human erythropoietin or odds ratio
Outcomes (n = 177) Placebo (n = 168) (95% CI) P value
Comparison including children as originally randomized
Secondary outcomes
Mental Processing Composite, 96.0 (12.6) 97.3 (13.6) −1.44 (−3.66 to 0.79)b .29
mean (SD)a
Cerebral palsy, No. (%) 11 (6) 5 (3) 2.16 (0.88 to 5.29)c .16
d
GMFCS score 3-5 3 (2) 2 (1) 0.56 (0.09 to 3.65)c .61
Severe hearing problem, No. (%) 1 (0.6) [n = 172] 3 (2) [n = 160] 0.31 (0.05 to 2.07)c .31
Severe vision problem, No. (%) 4 (2) [n = 176] 1 (0.6) [n = 165] 3.81 (0.60 to 24.14)c .23
Body weight, mean (SD), g 19.7 (4.0) [n = 173] 19.5 (2.9) [n = 164] 0.36 (−0.26 to 0.98)b .34
z score −0.31 (1.32) [n = 173] −0.33 (1.07) [n = 164] 0.08 (−0.13 to 0.29)b .52
Body length, mean (SD), cm 113.5 (6.8) [n = 171] 114.1 (6.1) [n = 163] −0.46 (−1.64 to 0.72)b .52
z score −0.25 (1.30) [n = 171] −0.12 (1.18) [n = 163] −0.08 (−0.30 to 0.15)b .57
Head circumference, mean (SD), cm 50.9 (1.6) [n = 169] 50.9 (1.7) [n = 159] 0.13 (−0.17 to 0.43)b .49
z score −0.57 (1.23) [n = 169] −0.58 (1.28) [n = 159] 0.09 (−0.14 to 0.32)b .52
Comparison including only children who completed allocated treatment
Secondary outcomes
Mental Processing Composite, 96.6 (12.3) 97.1 (13.4) −0.7 (−3.1 to 1.6)b .60
mean (SD)a
Cerebral palsy, No. (%) 8 (5) 5 (3) 1.6 (0.6 to 4.1)c .42
GMFCS score 3-5d 3 (2) 2 (1) 0.9 (0.1 to 6.2)c .93
Severe hearing problem, No. (%) 1 (0.6) [n = 152] 3 (2) [n = 145] 0.3 (0.0 to 2.1)c .32
Severe vision problem, No. (%) 2 (1) 1 (0.7) [n = 149] 1.9 (0.2 to 14.5)c .59
Body weight, mean (SD), g 19.8 (4.0) [n = 152] 19.4 (2.8) [n = 148] 0.4 (−0.3 to 1.0)b .36
z score −0.28 (1.33) [n = 152] −0.33 (1.06) [n = 148] 0.08 (−0.15 to 0.31)b .56
Body length, mean (SD), cm 113.6 (6.7) [n = 150] 114.2 (6.2) [n = 147] −0.5 (−1.7 to 0.8)b .53
z score −0.22 (1.29) [n = 150] −0.10 (1.20) [n = 147] −0.09 (−0.33 to 0.16)b .56
Head circumference, mean (SD), cm 51.0 (1.6) [n = 148] 50.9 (1.6) [n = 143] 0.1 (−0.2 to 0.5)b .44
z score −0.51 (1.21) [n = 148] −0.56 (1.23) [n = 143] 0.08 (−0.16 to 0.32)b .59
a c
The Mental Processing Composite of the Kaufman Assessment Battery for Odds ratio.
Children has a mean score of 100 (SD, 15); higher scores indicate better d
The Gross Motor Function Classification System (GMFCS) score ranges from 1
outcome. to 5; lower scores indicate better outcome.
b
Mean difference.

Giancarlo Natalucci, MD Drafting of the manuscript: Natalucci.

Bea Latal, MD
Brigitte Koller, RN
Christoph Rüegger, MD
Beate Sick, PhD
Leonhard Held, PhD
Jean-Claude Fauchère, MD
for the Swiss EPO Neuroprotection Trial Group
Author Affiliations: Department of Neonatology, University Hospital Zurich,
Zurich, Switzerland (Natalucci, Koller, Rüegger, Fauchère); Child Development
Center, University Children’s Hospital Zurich, Zurich, Switzerland (Latal);
Epidemiology, Biostatistics, and Prevention Institute (EBPI), University of
Zurich, Zurich, Switzerland (Sick, Held).
Corresponding Author: Giancarlo Natalucci, MD, Department of Neonatology,
University Hospital Zurich, Frauenklinikstrasse 10, CH-8091 Zurich, Switzerland
(giancarlo.natalucci@usz.ch).
Accepted for Publication: September 14, 2020.
Author Contributions: Drs Natalucci and Fauchère had full access to all of the
data in the study and take responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Natalucci, Latal, Sick, Fauchère.
Acquisition, analysis, or interpretation of data: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Sick, Held.
Obtained funding: Natalucci, Fauchère.
Administrative, technical, or material support: Natalucci, Latal, Koller, Rüegger,
Fauchère.
Supervision: Natalucci, Latal, Fauchère.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by the Swiss National Science
Foundation (grant 3200B0-108176/1), the Roche Foundation for Anemia
Research, and the Matching Fund of the Medical Faculty, University of Zurich
(December 2009). Dr Natalucci was supported by the Swiss National Science
Foundation (grant PZOOP3_161146). Dr Rüegger received an internal research
grant (protected time) from the University Hospital Zurich.
Role of the Funder/Sponsor: No funders had any role in the design and
conduct of the study; collection, management, analysis, and interpretation of
the data; preparation, review, or approval of the manuscript; or decision to
submit the manuscript for publication.
Trial Registration: ClinicalTrials.gov Identifier: NCT00413946
Group Information: The members of the Swiss EPO Neuroprotection Trial
Group are listed in reference 3.
Data Sharing Statement: See Supplement 2.
Additional Contributions: We thank Hans Ulrich Bucher, MD, Department of
Neonatology, University Hospital Zurich, who provided helpful suggestions

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and assistance in the follow-up study. Dr Bucher received no compensation for
his role.
1. Fischer HS, Reibel NJ, Bührer C, Dame C. Prophylactic early erythropoietin for
neuroprotection in preterm infants: a meta-analysis. Pediatrics. 2017;139(5):
e20164317. doi:10.1542/peds.2016-4317
2. Ohlsson A, Aher SM. Early erythropoiesis-stimulating agents in preterm or
low birth weight infants. Cochrane Database Syst Rev. 2020;2:CD004863. doi:
10.1002/14651858.CD004863.pub6
3. Natalucci G, Latal B, Koller B, et al; Swiss EPO Neuroprotection Trial Group.
Effect of early prophylactic high-dose recombinant human erythropoietin
in very preterm infants on neurodevelopmental outcome at 2 years:
a randomized clinical trial. JAMA. 2016;315(19):2079-2085. doi:10.1001/jama.
2016.5504
4. Fauchère JC, Koller BM, Tschopp A, et al. Safety of early high-dose
recombinant erythropoietin for neuroprotection in very preterm infants. J Pediatr.
2015;167(1):52-57. doi:10.1016/j.jpeds.2015.02.052
5. Juul SE, Comstock BA, Wadhawan R, et al; PENUT Trial Consortium.
A randomized trial of erythropoietin for neuroprotection in preterm infants.
N Engl J Med. 2020;382(3):233-243. doi:10.1056/NEJMoa1907423
6. Ohls RK, Cannon DC, Phillips J, et al. Preschool assessment of preterm
infants treated with darbepoetin and erythropoietin. Pediatrics. 2016;137(3):
e20153859. doi:10.1542/peds.2015-3859
COMMENT & RESPONSE
Intravenous Acetaminophen in Postoperative
Patients
To the Editor In the randomized clinical trial on the effect of in-
travenous acetaminophen (paracetamol) on postoperative hy-
poxemia after abdominal surgery, the authors did not find
a significant opioid-sparing effect of intravenous acetamino-
phen and therefore no statistically significant reduction in the
adverse effect of hypoxemia.1
Acetaminophen given at a dosage of 1 g every 6 hours
would not have reached steady-state plasma concentrations
until late into the period of the study. It is therefore possible
that the beneficial effects, such as opioid sparing, would not
have been appreciated within the time frame of the trial.
A 2-g loading dose of acetaminophen achieves steady-state
plasma concentration rapidly and can be followed by 1 g
every 6 hours to maintain the steady state. In my personal
experience, timing of administration of the loading dose of
acetaminophen just prior to emergence from anesthesia
seems to have a favorable analgesic effect.
A 2-g loading dose has been found to be better than 1 g
in minor surgery2,3 and has been found to be safe.3 The prac-
tice of loading with 2 g of acetaminophen is increasingly used
in clinical practice4 and has found its way into some hospital
guidelines in the United Kingdom.
Acetaminophen in combination with nonsteroidal anti-
inflammatory drugs has been shown to reduce morphine re-
quirements in a meta-analysis.5
S. Ravi Shankar, MBBS, MD
Author Affiliation: Bedfordshire Hospitals NHS Foundation Trust, Bedford,
England.
Corresponding Author: S. Ravi Shankar, MBBS, MD, Bedfordshire
Hospitals NHS Foundation Trust, Anaesthetics, South Wing, Kempston
Road, Bedford, Bedfordshire MK42 9DJ, England (ravi.shankar@
bedfordhospital.nhs.uk).
Conflict of Interest Disclosures: None reported.
jama.com
© 2020 American Medical Association. All rights reserved.
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Letters
1. Turan A, Essber H, Saasouh W, et al; FACTOR Study Group. Effect of
intravenous acetaminophen on postoperative hypoxemia after abdominal
surgery: the FACTOR randomized clinical trial. JAMA. 2020;324(4):350-358.
doi:10.1001/jama.2020.10009
2. Cornesse D, Senard M, Hans GA, et al. Comparison between two
intraoperative intravenous loading doses of paracetamol on pain after minor
hand surgery: two grams versus one gram. Acta Chir Belg. 2010;110(5):529-532.
doi:10.1080/00015458.2010.11680670
3. Juhl G, Boccard E. Analgesic efficacy and safety of a 2 g loading dose
of iv paracetamol (acetaminophen) versus 1 g following third molar surgery.
Eur J Anaesthesiol. 2005;22:181-182. doi:10.1097/00003643-200505001-
00656
4. Sharma CV, Mehta V. Paracetamol: mechanisms and updates. Contin Educ
Anaesth Crit Care Pain. 2014;14(4):153-158. doi:10.1093/bjaceaccp/mkt049
5. Martinez V, Beloeil H, Marret E, Fletcher D, Ravaud P, Trinquart L. Non-opioid
analgesics in adults after major surgery: systematic review with network
meta-analysis of randomized trials. Br J Anaesth. 2017;118(1):22-31. doi:10.1093/
bja/aew391
In Reply Dr Shankar asserts that 1 g of acetaminophen
(paracetamol) given every 6 hours would not reach steady-
state plasma concentrations until late in our 48-hour
treatment period.1 In fact, pharmacokinetic studies indicate
that 1 g of intravenous acetaminophen given every 6 hours
provides steady plasma concentrations.2 But more impor-
tantly, therapeutic concentrations are reached within 1 hour
of the initial dose, and no further effect is seen with an
increasing dose.3
Shankar’s recommendation to give an initial 2-g dose fol-
lowed by 1 g every 6 hours violates US Food and Drug Admin-
istration labeling, which limits acetaminophen to 4 g in 24
hours. The trials Shankar cites used a single 2-g dose and
were both conducted in patients having minor procedures,
with efficacy evaluation limited to 8 or 24 hours. In contrast,
our patients had major abdominal surgery and required sus-
tained analgesia.
In summary, we used the highest allowed dose of
acetaminophen for 2 postoperative days. Acetaminophen
did not reduce the duration of postoperative hypoxemia,
and pain scores and opioid consumption did not dif-
fer meaningfully.
Alparslan Turan, MD
Daniel I. Sessler, MD
Author Affiliations: Department of Outcomes Research, Cleveland Clinic,
Cleveland, Ohio.
Corresponding Author: Alparslan Turan, MD, Department of Outcomes
Research, Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Ave, P-77,
Cleveland, OH 44195 (turana@ccf.org).
Conflict of Interest Disclosures: None reported.
1. Turan A, Essber H, Saasouh W, et al; FACTOR Study Group. Effect of
intravenous acetaminophen on postoperative hypoxemia after abdominal
surgery: the FACTOR randomized clinical trial. JAMA. 2020;324(4):350-358.
doi:10.1001/jama.2020.10009
2. van der Westhuizen J, Kuo PY, Reed PW, Holder K. Randomised controlled
trial comparing oral and intravenous paracetamol (acetaminophen) plasma
levels when given as preoperative analgesia. Anaesth Intensive Care. 2011;39(2):
242-246. doi:10.1177/0310057X1103900214
3. Hahn TW, Mogensen T, Lund C, et al. Analgesic effect of iv paracetamol:
possible ceiling effect of paracetamol in postoperative pain. Acta Anaesthesiol
Scand. 2003;47(2):138-145. doi:10.1034/j.1399-6576.2003.00046.x
(Reprinted) JAMA December 8, 2020 Volume 324, Number 22 2327