Conditions: Idiopathic Scoliosis
Keywords: tissue microdialysis spinal fusion surgical site infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12
Healthy volunteers: no

Brief summary:
The purpose of this research study is to compare the current standard of care for prophylactic Cefazolin administered every 3 hours intravenously with continuous infusion of Cefazolin during pediatric spinal surgery.

Detailed description:
Determine the skeletal muscle and adipose tissue disposition of prophylactic Cefazolin using microdialysis sampling in a cohort of patients diagnosed with idiopathic scoliosis undergoing posterior spinal fusion (PSF) for administration of Cefazolin by either continuous infusion or intermittent bolus.

Arms:
arm 1: The first regimen will consist of a bolus dose of Cefazolin 30mg/kg up to a maximum of 2000mg IV administered prior to surgical incision. The same pre-operative dose of Cefazolin will be repeated every 3 hours until the completion of surgery. Two will paraspinal muscle microdialysis catheters and two subcutaneous microdialysis catheters will be inserted. arm 2: The second regimen will consist of an initial bolus dose of 30 mg/kg up to maximum of 2000 mg. Following the initial bolus dose a continuous Cefazolin drip will start until the end of surgery. Cefazolin drip dose will be 10 mg/(kg\*h) up to maximum of 667 mg/h.Two microdialysis catheters will be inserted into a paraspinal muscle and two microdialysis catheters will be inserted subcutaneously.

Interventions: intervention 1: Bolus dose of Cefazolin intervention 2: Continuous Cefazolin drip intervention 3: Paraspinal muscle microdialysis catheters intervention 4: Subcutaneous microdialysis catheters
Intervention descriptions: intervention 1: Mode of Cefazolin administration will be a intermittent bolus intervention 2: Mode of Cefazolin administration will be a continuous drip intervention 3: Two dialysis probes will be inserted into a paraspinal muscle intervention 4: Two dialysis probes will be inserted into a paraspinal subcutaneous region

Protocol document:
Prot_SAP_001.pdf: 
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NCT03190668 
 
Project Title:  
Skeletal muscle and adipose tissue concentrations of cefazolin 
comparing two different dosing regimens during pediatric posterior 
spinal fusion surgery 
PI: Christoph Seubert, MD 
Dated: 05/22/2023 (Final) 
 
 
 


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Protocol 
Project Title:  
Skeletal muscle and adipose tissue concentrations of cefazolin 
comparing two different dosing regimens during pediatric posterior 
spinal fusion surgery 
Investigators: 
 
PI:  
 
 
Christoph Seubert, MD  
Co-Investigators: 
Yichao Yu, BS 
 
 
 
 
Taran Sangari, MD 
 
 
 
 
Laurel Blakemore, MD 
 
 
 
 
Joseph LaGrew II, MD 
 
 
 
 
Elham Amini,Pharm.D 
 
 
 
 
 
Abstract: The study intendeds to compare the current standard of care for prophylactic 
cefazolin administered every 3 hours intravenously with continuous infusion of cefazolin 
during pediatric spinal surgery. Pharmacokinetics, skeletal muscle disposition and 
subcutaneous adipose tissue penetration of cefazolin under both modes of administration 
will be determined using a clinical microdialysis technique.  
Background:  Surgical site infection (SSI) after posterior spinal fusion surgery (PSFS) is 
a devastating complication that frequently requires medical and surgical management 
beyond the expected recovery time. SSI’s are a common cause of nosocomial infection. 
The United States Centers for Disease Control and Prevention (CDC) has developed 
criteria that define surgical site infection (SSI) as infection related to an operative 
procedure that occurs at or near the surgical incision within 30 days of the procedure or 
within 90 days if prosthetic material is implanted at surgery. SSIs are often localized to the 
incision site but can also extend into deeper adjacent structures (1).  


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Studies have reported the risk of SSI in PSFS ranging from 1.3 to 6.3% (2). The 
neuromuscular subgroup patients with spastic quadriplegia (cerebral palsy) have the 
highest incidence of infection (14.3%) compared to adolescent patients with idiopathic 
scoliosis (1. 5%) (3). 
SSI can be prevented with adequate perioperative administration of prophylactic 
antibiotics. β lactam antibiotics are frequently recommended as a primary choice for 
perioperative prophylaxis in surgical patients owning to their broad-spectrum activity and 
generally good safety and tolerability profiles. Cefazolin, a first-generation cephalosporin, 
has been used as a suitable antibiotic for PSFS because of its spectrum of activity (e.g., 
against Staphylococcus species and gram-negative bacilli such as E. coli) and adequate 
tissue concentrations (4).   
Achieving and maintaining goal tissue concentrations of prophylactic antibiotics near the 
surgical site is crucial to maximize their effectiveness. Tissue microdialysis is a technique 
used in clinical pharmacology to sample directly and continuously the free, unbound drug 
concentrations, including perioperative antibiotics, in the interstitial fluid of various tissues 
(5,6). In brief, the probe is continuously perfused at a low flow rate with an aqueous 
solution (perfusate) that closely resembles the (ionic) composition of the surrounding 
tissue fluid. Once the probe is implanted into the tissue, substances present in the 
extracellular fluid at concentration (ctissue) are filtered by diffusion out of the extracellular 
fluid into the probe, resulting in a concentration (cdialysate) in the perfusion medium. The 
solution moving through the probe (dialysate) is collected at certain time intervals for 
analysis. 
Because of constant perfusion of fresh perfusate, equilibrium between extracellular tissue 
fluid and the perfusion medium is incomplete, resulting in ctissue > cdialysate. The factor by 
which the concentrations are interrelated is termed recovery. To obtain intestinal 
concentration from dialysate, microdialysis probes need to be calibrated.  
Currently, the only published study by Himebauch et.al prospectively evaluated the 
skeletal muscle disposition of prophylactic cefazolin using microdialysis sampling in a 
pediatric cohort with idiopathic scoliosis undergoing PSFS. They found that the skeletal 


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muscle concentrations of cefazolin achieved with 30mg/kg given every four hours for the 
duration of surgery was likely to be effective for intraoperative SSI prophylaxis against 
methicillin-sensitive Staphylo-coccus aureus (MSSA) but might not be effective for 
intraoperative SSI prophylaxis against Gram-negative pathogens (7). Our study will be 
performed in a cohort of patients with adolescent idiopathic scoliosis having PSFS. During 
surgery, unbound cefazolin concentration at interstitial fluid of skeletal muscle and 
adipose tissue will be measured by clinical microdialysis technique. The comparison of 
cefazolin disposition in cohorts with two different modes of cefazolin administration will be 
recorded in skeletal and adipose tissue. End result of the study will be determination of 
the target attainment for unbound cefazolin of each administration regimen for 
intraoperative SSI prophylaxis against methicillin-sensitive Staphylo-coccus aureus 
(MSSA) and Gram-negative bacilli. 
Specific Aims:  Determine the skeletal muscle and adipose tissue disposition of 
prophylactic cefazolin using microdialysis sampling in a cohort of patients diagnosed with 
idiopathic scoliosis undergoing posterior spinal fusion (PSF) for administration of cefazolin 
by either continuous infusion or intermittent bolus. 
Research Plan:  Following Institutional Review Board approval, we plan to recruit up to 
20 subjects to participate in this study.  The patients will be recruited from the Pediatric 
Orthopedic Clinic and identified by Dr. Blakemore who will first introduce the study to the 
potential subjects.  If the potential subject and Legally Authorize Representative (LAR) 
expresses interest in the research, they will be given a letter introducing the study during 
their visit.  If they continue to express interest in learning more about the study, the 
surgeon and/or surgeons’ coordinator will notify the research coordinator who will meet 
with the patient and family in the pre-surgical clinic to discuss the study in detail.  If by 
chance the subject does not go to the pre-surgical clinic, the subject will be contacted by 
phone with the IRB approved phone script.    Potential study participants will have time to 
read the consent, have all study related questions answered, and discuss the study with 
their family, if desired before consent is obtained.  Consent will take place either in the 
pre-surgical clinic or in the preoperative area.  


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Study Patient Population:  Study will be conducted in up to 20 patients, male or female 
between the ages of 12 to 20-year-old. Recruitment of patients will be from the Pediatric 
Orthopedic Clinic.  
Study Design: We propose a randomized controlled prospective pharmacokinetic study of 
two regimens of intravenous cefazolin used at our institution.  
Inclusion  
The general inclusion will be those patients who: 
• Diagnosis of idiopathic scoliosis 
• Planned posterior spinal fusion surgery (PSFS) 
• Age: 12-20 years old 
• American Society of Anesthesiology status I or II undergoing posterior spinal 
fusion for at least 6 levels 
• No known allergy to cefazolin 
Exclusion 
The Exclusion criteria will include: 
• Known allergy to cefazolin 
• Anatomical or other abnormalities that precluded insertion of a microdialysis 
catheter into the selected paraspinal muscle  
• Known renal or hepatic insufficiency or failure 
Randomization (see statistical methods and data analysis part) 
Group l - Subjects randomized to Group l will receive the first regimen:  
The first regimen will consist of a bolus dose of Cefazolin 30mg/kg up to a maximum of 
2000mg IV administered prior to surgical incision. The same pre-operative dose of 
cefazolin will be repeated every 3 hours until the completion of surgery.   
 
 


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Group II - Subjects randomized to Group ll will receive the second regimen:  
The second regimen will consist of an initial bolus dose of 30 mg/kg up to maximum of 
2000 mg. Following the initial bolus dose a continuous cefazolin drip will start until the end 
of surgery. Cefazolin drip dose will be 10 mg/(kg*h) up to maximum of 667 mg/h. 
Research Related Procedures:  Serial skeletal muscle and adipose tissue microdialysis 
samples will be obtained during the PSFS to measure unbound cefazolin concentrations 
in the interstitial fluid of both skeletal muscle and adipose tissue.  
A set of four microdialysis catheters (CMA63; M Dialysis AB, Solna, Sweden) will be 
inserted percutaneously after induction of anesthesia. Two dialysis probes will be inserted 
into a paraspinal muscle, with each catheter tip terminating approximately two vertebral 
bodies superior to the superior edge of the planned incision. And the other two probes 
will be inserted subcutaneously. The insertion procedure will be performed following a 
similar procedure as used in clinical practice for intravenous catheterization: The skin at 
the site of probe insertions is cleaned and disinfected. The surface of the skin is punctured 
by a needle. Thereafter, the probe is implanted into the tissue with help of an introducer, 
which is then removed, leaving the flexible probe under the surface of the skin in the 
tissue of interest. Each microdialysis system will be connected to a pump (107 
Microdialysis Pump) with a flow rate of 1 μl/min for microdialysis sample collection. Prior 
to probe calibration, microdialysis catheters will be perfused with cefuroxime (calibrator; 
10 μg/mL) in normal saline, where cefuroxime acts as a marker antibiotic of similar 
molecular size and physiochemical properties to the study antibiotics. Cefuroxime will 
assist in the determination of the rate of movement of molecules across the dialysis 
membrane according to the retrodialysis method. Microdialysis samples (approximately 
30 μL for each dialysate sample) will be taken at 30-min intervals (+ or – 5 minutes) 
throughout the operative procedure. The recovery of cefazolin in the Microdialysate 
solution will be interpolated from the loss of calibrator (cefuroxime) across the 
microdialysis membrane: 


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Cefazolin Recovery%
= 100 × 𝐶𝐶𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐,𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝−𝐶𝐶𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐,𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝐶𝐶𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐,𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
× 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑒𝑒𝑒𝑒𝑒𝑒 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 
where the recovery ratio of cefazolin recovery and cefuroxime recovery can be 
predetermined by in vitro microdialysis. Therefore, the interstitial concentration of 
cefazolin can be calculated using the following equation: 
𝐶𝐶𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑖𝑖𝑖𝑖, 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡= 100 ×
𝐶𝐶𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐,𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅% 
Microdialysis catheters will be removed from the designated tissue using aseptic 
technique before emergence from anesthesia. All microdialysis samples will be stored at 
-80ºC until analysis. 
Plasma samples (approximately 2 mL each collected in K2EDTA-containing tubes) will 
be obtained from an arterial catheter timed relative to each cefazolin dose (pre-dose, 5, 
15 (+or- 5 minutes), 30(+or- 5 minutes), 60(+or- 5 minutes), 90(+or- 5 minutes), 120(+or- 
5 minutes), 180(+or- 5 minutes) and every 60 min afterwards(+or- 5 minutes) until the 
end of surgery) and at the time of skin closure for standard cefazolin administration. If the 
patient receives continuous infusion, the plasma samples will be collected at 0 (pre-dose), 
5, 15(+or- 5 minutes), 30(+or- 5 minutes), 60(+or- 5 minutes), 90(+or- 5 minutes), 
120(+or- 5 minutes), 180(+or- 5 minutes), and every 60 min afterwards (+or- 5 minutes) 
until the end of surgery. Thus for a 6 hour procedure the blood collected should not 
exceed 22 ml or less than 5 Tsp. Blood samples will be centrifuged at 3000 rpm for 15 
mins and plasma will be transferred and stored at -80ºC until analysis. Both plasma and 
microdialysis samples will be analyzed utilizing validated high-performance liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) methodology. The probability 
of target attainment for unbound cefazolin concentrations at target site for MSSA and 
Gram-negative pathogens will be calculated in both groups. 
In order to put the PK information into perspective the following information will be 
collected from the patient’s chart: patients age, sex, height, BMI, type of surgery, baseline 


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renal function, intraoperative urine output, blood loss, albumin level, amount of albumin 
received during surgery, total allogenic and autologous transfusion, total intraoperative 
dose of cefazolin and other co-medications received during surgery will be recorded.  This 
information will be collected on all patients.   
Standard of Care:  These patients routinely receive cefazolin as part of their perioperative 
antibiotic regimen. Patients routinely receive 30mg/kg of cefazolin intravenously to the 
max up to 2000mg every 3 hours until the end of surgery. Placement of microdialysis 
catheter will be for the study purposes only. Please note that under the infusion regimen, 
patients will receive the same amount of antibiotic over time as the current standard of 
care. Continuous infusion is at this time considered a practice option used by some 
colleagues locally. 
Anesthetic technique will be at the discretion of the staff anesthesiologist and consist of a 
total intravenous anesthetic utilizing propofol with an opioid infusion. Anesthetic 
administration will be standardized according to a clinical pathway. 
 
Statistical methods, data analysis and interpretation 
Yichao Yu, BS will be the statistician for the study. 
(1) Design. Single-center, randomized dosing regimen pharmacokinetic study  
(2) Hypothesis.  The null hypothesis is that the probability of target attainment for 
unbound cefazolin in skeletal muscle and adipose tissue are same for continuous 
infusion of prophylactic cefazolin and the current standard mode of 
administration. 
Key pharmacokinetic parameters (Cmax, tmax, t1/2, CL, AUC) for cefazolin will be 
determined from time profiles in plasma, subcutaneous adipose tissue and 
muscle by means of a commercially available software (Phoenix® WinNonlin®, 
Pharsight Corporation, CA, USA). Plasma and tissue concentrations of cefazolin 
will also be related to published minimum inhibitory concentration (MIC) values 
to determine the time above MIC (fT>MIC), which is the major outcome variables 


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of cefazolin pharmacokinetic and pharmacodynamics (Cef-PD) factor in vivo for 
the comparison of two different modes of administration of prophylactic cefazolin.  
(3) Statistical Methods. Statistical analysis and plots will be performed using 
Microsoft Excel (Microsoft Corp, Redmond, Washington, USA) and R studio (R 
Studio Inc, Boston, Massachusetts, USA). The probability of target attainment for 
unbound cefazolin can be determined as fT>MIC/Ttotal; ratios will be expressed 
as mean ± SD. The major analysis will be a comparison of median fT>MIC/Ttotal 
between two dosing regimen by the Wilcoxon rank-sum test. A p-value < 0.05, 
two-sided is considered statistically significant. 
(4) Randomization. Up to 20 scoliosis patients will be recruited in this study. Simple 
randomization will be used with each patient has probability 0.5 to be assigned 
in Group I or Group II. Computer program will generate a uniform random 
variable between 0 to 1, with subject be assigned to Group I if the value is less 
than 0.5 and assigned to Group II if the value is greater than 0.5.  
(5) Sample size. This exploratory pilot study will utilize a sample size of n=20. 
Background information needed to perform detailed power analysis are lacking. 
(6) Technical support. The statistical design has been worked out by the 
Department of Pharmaceutics team. Statistical analysis will also be carried out 
by them. 
 
Administrative responsibilities 
Study Resources:  The principal investigator will oversee the data collection, data 
analysis and will maintain the records in confidence. Should any evidence suggest that 
the study protocol require modification, the PI will notify the IRB in a timely manner for 
review and approval. Each subject will be identified by number, not by name, on all data 
forms. To protect confidentiality, all data will be numerically coded and information 
linking the numeric codes to individual participant’s names will be kept in a locked file in 
the PI’s office.  
 


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Possible Discomforts and Risks: Microdialysis catheter placement is a safe process as it 
has been done successfully in multiple studies over the years. Any adverse events with 
microdialysis catheter will be monitored up to the resolution of the adverse event and 
reported.  Plastic cannula insertion might cause moderate pain. The procedure of MD 
probe insertion may cause pain comparable to a standard Intramuscular (i.m.) or 
Subcutaneous (s.c.) injection. This pain should vanish after a few minutes. A minor 
hematoma at the site of the probe insertion cannot completely be excluded. The risks of 
drawing blood from a vein include discomfort at the site of puncture; possible bruising 
and swelling around the puncture site; rarely an infection; and, uncommonly, faintness 
from the procedure. 
Study participant’s identities will be kept strictly confidential. Confidentiality will be 
maintained by assigning each participant a number, which will be used in all data 
tabulation.  All findings from the study will be reported in a manner that precludes 
identification of any individual participant. These records, like all other study-associated 
records will be kept in the strictest confidence, and stored as encrypted files.  
There is no financial risk associated with participating in this study.  There will be no 
additional charges incurred from participating in this study than what would be normally 
charged if not enrolled within the study 
 
Possible Benefits: Benefit of this study will be to determine if the addition of continuous 
intravenous infusion of antibiotic is superior to scheduled 3 hourly intravenous bolus of 
antibiotic. This will be achieved by evaluating the skeletal muscle and adipose tissue 
disposition of prophylactic antibiotic cefazolin using micro-dialysis sampling for both 
techniques. If the disposition of prophylactic antibiotic regimen using continuous drip in 
addition to schedule doses is superior then this might lead to further decrease in the 
incidence of nosocomial infection during PSFS. 
 
Conflict of Interest: No conflict of interest exists for the PI or any of the Co-
Investigators.  
 
Safety Monitoring and Assessment 
The purpose of this study is to compare two different dosing regimens of prophylactic 


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cefazolin during PSFS by using microdialysis technique, thus there is low risk 
associated with the study.  
Safety review plan and Monitoring  
The principal investigator (PI) will be responsible for ensuring participants’ safety 
includes review of adverse events as well as study progress, data integrity and study 
outcomes. The monitoring procedures are delineated in the protocol. Only subjects who 
meet all inclusion criteria in the protocol will be enrolled in the study. 
Adverse event reporting plan 
All risks have been described in the consent form. All adverse events experienced by 
the participant during the time frame specified in the protocol need to be reported. Every 
adverse event that is reported to either the principal investigator or the designated 
research associates by medical staff caring for the subject will be documented.  
As a subset of the reported adverse events, all serious adverse events, whether should 
they occur, whether study-related or expected, will be documented in serious and 
unexpected AE reporting form and reported by the principal investigator to the IRB 
within five days of discovery. 
In addition, the principal investigator will follow the procedure in the UF IRB Adverse 
Event Evaluation and Reporting Guide. Any unanticipated problems involving risks to 
subjects or others will also be reported to UF IRB per the IRB-01 Definitions and 
Reporting Guide. Aggregate reports of adverse events will be prepared at the end of the 
study for IRB review. 
 
 
 
 


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References:  
(1) Anderson DJ, Sexton DJ, et al. Epidemiology of surgical site infection in adults. 
www.uptodate.com/contents/epidemiology-of-surgical-site-infection-in-adults 2015 
(2) Allareddy, Veerajalandhar et al. “Infection Related Never Events in Pediatric Patients 
Undergoing Spinal Fusion Procedures in United States: Prevalence and Predictors.” Ed. 
David W. Dowdy. PLoS ONE 8.11 (2013): e77540. PMC. Web. 30 Nov. 2016. 
(3) Deep wound infection following pediatric scoliosis surgery: incidence and analysis of 
risk factors. Sami Aleissa, David Parsons, John Grant, James Harder, Jason Howard. 
Can J Surg. 2011 Aug; 54(4): 263–269 
(4)  Bratzler D, Dellinger E, Weinstein R, et al. Clinical practice guidelines for antimicrobial 
prophylaxis in surgery. American Journal Of Health-System Pharmacy [serial online]. 
February 2013;70(3):195-283. Available from: Academic Search Premier, Ipswich, MA. 
Accessed November 30, 2016. 
(5) Chaurasia CS, Müller M, Bashaw ED, et al. AAPS-FDA Workshop White Paper: 
microdialysis principles, application, and regulatory perspectives. Pharm Res 2007; 24: 
1014–25 
(6) Joukhadar C, Müller M. Microdialysis: current applications in clinical pharmacokinetic 
studies and its potential role in the future. Clin Pharmacokinet 2005; 44: 895–913 
(7) A. S. Himebauch, W. N. Sankar, et al. Skeletal muscle and plasma concentrations of 
cefazolin during complex paediatric spinal surgery. Br J Anaesth. 2016 Jul; 117(1): 87–
94. Published online 2016 Jun 9.