Airflow and Hip Prosthesis Infections: A Registry Study Comparing Laminar vs. Turbulent Flow in the Danish Hip Arthroplasty Register.
Conditions: Hip Prosthesis Infection
Sponsor: University Hospital Bispebjerg and Frederiksberg

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Protocol 
 
 
Table of contents 
TITLE PAGE ...................................................................................................................................... 2 
ABSTRACT ....................................................................................................................................... 3 
AMENDMENTS AND UPDATES ............................................... FEHLER! TEXTMARKE NICHT DEFINIERT. 
TIMELINE ............................................................................... FEHLER! TEXTMARKE NICHT DEFINIERT. 
RATIONALE AND BACKGROUND ...................................................................................................... 3 
DATA SOURCES ................................................................................................................................... 6 
VARIABLES ......................................................................................................................................... 7 
METHODS ........................................................................................................................................ 7 
STUDY POPULATION: .................................................................................................................................... 7 
EXPOSURE: ................................................................................................................................................. 7 
FOLLOW-UP: ............................................................................................................................................... 7 
NULL HYPOTHESIS: ....................................................................................................................................... 7 
ALTERNATIVE HYPOTHESIS: ............................................................................................................................ 7 
ENDPOINTS: ............................................................................................................................................... 8 
STATISTICAL ANALYSIS: ............................................................................................................................... 10 
MISSINGNESS ................................................................................................................................... 11 
ETHICAL ASPECTS ............................................................................................................................... 11 
PERSPECTIVES ................................................................................................................................... 12 
REFERENCES .................................................................................................................................. 12 
APPENDIX A ..................................................................................................................................... 16 
 
 
 

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Title page 
 
Title:  
Airflow and Hip Prosthesis Infections: A Register Study Comparing Laminar vs. Turbulent 
Flow in the Danish Hip Arthroplasty Register. 
Brief objectives: 
The aim of this study is to evaluate the association of laminar airflow versus turbulent airflow 
ventilation on prosthetic joint infection and on any revision. 
 
Research team: 
Primary investigator: Jacob Moflag Svensson, MD, Department of Orthopedic surgery, 
Bispebjerg and Frederiksberg Hospital. 
Main Supervisor: Søren Overgaard, MD, DMsc, Professor, Head of Research, Department of 
Orthopedic surgery, Bispebjerg and Frederiksberg Hospital. 
Secondary Supervisor: Espen Jimenez Solem, MD, Chief physician, Associate Professor, 
PhD, Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital. 
Statisticians: Anne Helms Andreasen, Statistician, Center for Clinical Research and 
Prevention, Frederiksberg Hospital. 
Janne Pedersen, Statistician, PhD, Associate Professor, Center for Clinical Research and 
Prevention, Frederiksberg Hospital. 
Database manager and programmer: Cathrine Uhrbrand Fox Maule, Data scientist, Center for 
Clinical Research and Prevention, Frederiksberg Hospital 
Patient representative: Nanna Kæstel Petersen, Danish Hip Arthroplasty register  
 
Study registration number in Pactius Region Hovedstaden: 
P-2019-796. 
 
Potential conflict of interests: 
None reported. 
 
 

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Abstract 
 
Background: During surgery, bacteria in the air in the operating room (OR) is considered a 
cause of periprosthetic joint infection (PJI). Previously, turbulent airflow (TAF) has been used 
in ORs. Later, laminar airflow (LAF) has been developed, which minimize the number of 
colony forming units in the air. However, most studies show no benefit of LAF regarding PJI 
incidence. 
Aim: To evaluate the association of LAF versus TAF ventilation on primary PJIs in 90 and 
365 days in total hip arthroplasties (THAs) using the Danish hip arthroplasty register (DHR) 
and the Danish microbiology register (MiBa) 
Methods: All THAs performed in Denmark in 2010-2020 are identified in DHR. Through 
DHR, revisions and type of ventilation system is identified. PJI is defined using a validated 
method combining MiBa with DHR, where infection is defined as two or more positive 
identical bacteria cultures or is registered by the surgeon as PJI. The risk of PJI s in THAs 
performed in TAF are compared with THAs performed in LAF using Cox regression models 
adjusting for confounders. 
Use and relevance: PJIs are extremely costly and cause a significant morbidity and mortality 
for the patient. When constructing or renovating a hospital, it is crucial to choose a ventilation 
system that minimizes PJIs, while being cost-efficient. Previous studies on LAF vs TAF are 
based on data from national registers. Since registration of PJI is reported immediately to 
DHR and other arthroplasty registers after surgery, the microbiology results are not taken into 
consideration when the revision cause is reported. This study is novel, because it gives a more 
accurate picture of the PJI incidence and can be part in guiding the decisions when renovating 
or designing new hospitals, in order to decrease the risk of PJI. 
Rationale and background 
 
Prosthetic joint infection (PJI) is one of the most feared complication after total hip 
arthroplasty (THA), with increased mortality and morbidity, as well as a significant cost for 
society (1–4). Since the 1960s, in addition to systemic prophylactic antibiotics and antibiotic-
laden bone cement, efforts have been made to make the air in the operating rooms (OR) as 
clean as possible with filtering and replacement of the air (5).  
 
This has led to the current official PJI incidence of 0.57-0.80 % in the first year after surgery 
according to the Danish Hip Arthroplasty Register (DHR) and the Swedish Hip Arthroplasty 

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Register (SHAR), even though the true incidence of PJI probably is about 40 % higher, due to 
under-registration in the registers following revision surgery (6,7).  
 
The risk of PJI is potentially affected by contamination in the OR (5,8–10), patient related 
risk factors (11,12) and prosthesis factors. The prosthesis factors include type of implant and 
implant fixation method. Cemented implants have a lower overall revision rate, although the 
results are not unanimous when it comes to revision due to PJI (13–16). 
 
The risk of contamination in the OR is affected by the cleanliness of the air (5,17–21). There 
are two different types of ventilation systems used to achieve a clean environment in an OR. 
The first is turbulent airflow (TAF), where the air is continuously replaced with filtered ultra-
clean air that trickles down from the ventilation shaft. The second is laminar airflow (LAF) 
where the ultra-clean air flows in a single direction, with the goal to prevent particles carrying 
bacteria, that are floating in the air, to land on the patient or sterile equipment (17,22).  
 
LAF decreases the bacterial load significantly in the OR, measured in CFUs (17–21). 
However, the number of CFUs has not been found to correlate with the incidence of PJI in 
real world data, where most studies show no advantage of LAF compared to TAF. Only one 
major observational study shows that LAF decreases the risk of infection in a subgroup of 
LAF (23). All other register studies show no difference between LAF and TAF or a higher 
risk for PJI with LAF (24–28). There are no randomized, controlled trials (RCTs) comparing 
modern-day ventilation systems when it comes to the PJI incidence in THAs. 
 
There are no randomized, controlled trials (RCTs) comparing modern-day ventilation systems 
when it comes to the PJI incidence in THAs. However, in 1982, an RCT was conducted by 
Lidwell et al., comparing different ultraclean air flow systems, including LAF, with standard 
operating room ventilation at the time. In this study, there was a significant difference in PJI 
incidence with 2.2 % PJIs in the standard OR group and 1.0 % in the ultraclean group. 
However, these standard ORs had much higher bacterial contamination, with a median of 164 
CFUs/m3 (29), compared to modern-day TAF ORs, that have a median ranging from 4,5-22 
CFU/m3 (18,19,22). The ultraclean group had a median of 2-10 CFUs/m3, thus it resembles 
modern-day TAF ORs, both in bacterial load and PJI rate (29). 
 

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Due to additional costs in building and maintaining LAF systems, a public analysis was 
conducted in Denmark in 2011 to compare the cost-effectiveness of LAF and TAF. When 
considering the estimated annual costs, which included operational expenses, depreciation, 
and interests, LAF ORs were estimated to cost 508,732 DKK per year, whereas TAF ORs 
were projected to cost 304,530 DKK per year. As a result, there was an annual cost difference 
of 204,202 DKK (€27,000) per unit, with LAF being 67 % more expensive than TAF. A PJI 
was estimated to cost the society around 204,000 DKK in the same year (4). 
 
An issue in the previous studies on PJI in LAF and TAF are that they are epidemiological and 
rely solely on the PJI diagnosis reported to the different registers. However, diagnosing a PJI 
is not always evident in a clinical setting. It has been shown that the DHR is lacking both 
registration of revisions and later confirmed PJI (30), and a lack of registered PJI revisions 
has also been observed in the Swedish hip arthroplasty register (SHAR) (7). 
 
The PJI diagnosis in the DHR can be greatly improved, if combined with the Danish 
Microbiology Database (MiBa) (31). When validating the diagnosis PJI in DHR, the 
sensitivity was found to be only 67 %. When using an algorithm including data from MiBa, 
sensitivity increased to 90 %, without providing more false positives. A simplified algorithm 
utilizing MiBa data exhibited no statistically significant difference when compared to the 
more extensive algorithm employed in the validation study by Gundtoft et al. (30,31). This 
simplified algorithm, which doesn’t require access to medical records, will be applied in the 
criteria for the primary outcome. 
Additionally, previous studies show that one positive bacterial sample at a clinically aseptic 
revision increases the risk of an occult infection, diagnosed later at a re-revision (32). This 
will be investigated as well.  
 
Thus, using these new and well validated methods, the investigators aim to estimate the risk 
of PJI with LAF versus TAF ventilation better than has been done in previous studies. 
 
 
 

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Data sources 
 
The Danish Civil Registration System (Centrale Person Register, CPR) contains 
information including vital status and time of emigration on all Danish residents (33). All 
Danish residents and citizens are assigned a unique and permanent individual identification 
number (CPR number) at birth or upon immigration. It enables an unambiguous linkage 
between different registers and allows an individual follow-up over time (34).  
The Danish National Patient Register (NPR) collects data of all Danish residents contact to 
a public hospital, including date, performed examinations or surgical procedures and 
diagnosis, classified by International Classification of Diseases (ICD) (35). The data includes 
both outpatient and inpatient contacts and is linked with the patient’s CPR number (36). 
The Danish Hip Arthroplasty Register (DHR) collects data including type of OR 
ventilation from all THAs performed in Denmark, including primary THAs as well as 
revisions (37). It is mandatory for all surgeons performing THAs to report to the register, 
which results in high completeness. The data is previously validated (38). In the case of a 
revision, the surgeon reports the indication immediately after surgery (39). The revisions 
performed within 90 and 365 days are located in the DHR, which also contains information 
from the NPR about revisions. 
The Danish Microbiology Database (MiBa) automatically collects all microbiology results 
from all departments of clinical microbiology in Denmark since 2010, which are then stored 
electronically using the patient’s CPR number as patient identifier (40). The register 
completeness is previously validated (41). The data will more specifically be extracted from 
the Healthcare-Associated Infections Database – HAIBA, a part of MiBa. 
The Danish National Prescription Register (DNPR) collects detailed information on 
redeemed prescriptions in Denmark since 1995. It is previously validated and has a high 
degree of completeness and is frequently used in epidemiological research (42). 
Income Statistics Register – The register contains income data on more than 160 variables 
including salaries and savings of people with a Danish income and is widely used in research. 
Each individual is identified with an unambiguous CPR number (43). 
Danish Education Register – The register has a high coverage on education level, both 
among people born in Denmark and immigrants and is widely used in research. Each 
individual is identified with an unambiguous CPR number (44). 

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Variables 
 
The investigators will look at several variables and adjust for these where needed. The 
variables obtained from DHR is body mass index (BMI), age, gender, time of surgery, 
diagnosis, type of prosthesis and fixation method, whether cement is used and if it contains 
antibiotics, previous operations on the same hip and ASA score. ASA score and BMI are only 
available from 2017 and onwards in DHR. 
 
From NPR, concomitant diagnoses will be obtained to produce an Elixhauser comorbidity 
score, and socioeconomic factors, such as income and education will be obtained from the 
Danish Income Statistics Register and Education Register. 
Methods 
 
The data is reported according to the RECORD guidelines (45) and is stored in the servers of 
Statistics Denmark, where the data will be analyzed. 
 
Study population:  
 
All people ≥18 years receiving a primary total hip arthroplasty in Denmark between 
01.01.2010-31.12.2020 registered in DHR are included. Patients receiving a THA due to a hip 
tumor or metastasis are excluded, as well as patients with erroneous registration in DHR. 
Exposure: 
 
Surgery performed in an OR with LAF compared with surgery in an OR with TAF. 
Follow-up: 
 
Follow-up starts on the operation day and ends 365 days postoperatively. Follow-up is also 
ended at time of any revision, death or emigration. 
Null hypothesis: 
 
There is no difference in the risk of PJIs after a THA performed in a LAF OR as opposed to in 
a TAF OR. 
Alternative hypothesis:  
 
There is a lower or higher risk of PJIs after a THA performed in a LAF OR as opposed to in a 
TAF OR. 

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Endpoints: 
 
Primary endpoint:  
 
Revision due to infection, measured at t=90 days and t=365 days. Revision is defined as the 
first surgical intervention in the same hip after a primary THA with debridement, 
replacement, or removal of prosthetic parts. 
 
A follow-up time of 90 and 365 days respectively is chosen, since 90 days is the 
recommended surveillance period in the United States and is traditionally the limit between 
early and late infections, whereas it is important to have a follow up of a year not to miss up 
to 20 % of the infections (46,47). At 1 year, 80-90 % of the surgically requiring infections that 
will occur in the lifetime of the hip prosthesis have taken place. After 1 year, the infection rate 
drastically decreases and is less likely to be due to contamination during surgery (30,47). 
 
PJI is considered present when at least one of the following two criteria exists. 
  
1. 
Two or more intraoperative deep-tissue samples of the same bacteria, isolated from at 
least three deep-tissue samples. 
2. 
Deep infection is reported to DHR by the surgeon upon revision surgery. 
 
The definition of PJI is based on the studies by Gundtoft et al. (30,31), where it has been 
concluded, that the validity of the PJI diagnosis is greatly improved when using these criteria, 
which are validated specifically for DHR. The original study by Gundtoft et al. used an 
extensive algorithm to determine if a PJI was present. However, there was no statistically 
significant difference between the extensive algorithm and a simplified algorithm, that defines 
a PJI as two or more positive identical bacterial samples (30). 
 
The investigators definition is in line with international consensus (48) and does not differ 
greatly from the definition made by the European Bone and Joint Infection Society (EBJIS) 
(49), although erythrocyte sedimentation rate, aspiration of joint fluid, white blood cell count 
in joint fluid and histological examination of intraoperative tissue biopsies are not routinely 
used in Denmark. Thus, these criteria are not used. Sinus tract communication with the hip 
joint or an opening to the hip joint is expected to cause the surgeon to register the diagnosis 
“infection” in DHR upon revision. Data for this analysis will be extracted from DHR and 

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HAIBA. For the revision surgery to be registered in HAIBA, at least three biopsies at the 
revision surgery are required, hence this is a part of the criteria (50). 
 
Secondary endpoints: 
 
1) Revision registered as aseptic loosening in DHR. 
2) Any revision registered in DHR.  
 
Aseptic loosening is a separate endpoint, since it has been shown that aseptic loosening might 
in fact turn out to be a PJI and is thus a point of interest (32,51,52). 
 
Sensitivity analyses: 
 
In addition, the following sensitivity analyses will be made: 
a) Alternative outcome: Primary revision registered as PJI or with at least one positive 
biopsy of a bacterium. 
b) Alternative outcome: Primary revision reported to DHR with at least one positive 
biopsy of a bacterium AND the prescription of a relevant antibiotic, specified in 
appendix A. 
c)  Analysis for the primary endpoint, but for data collected between 2017-2020, 
allowing for adjustment for BMI and ASA as possible confounders, as these variables 
are only registered in this period 
 
A sensitivity analysis is made for a) and b), since Milandt et al. have shown that having one 
positive intraoperative bacterial culture increases the risk of an occult infection, that is later 
diagnosed upon re-revision. When there was only one unexpected positive culture 
(unexpected meaning not registered as PJI in DHR), first-time revisions were associated with 
an increased relative risk of 2.63 for subsequent re-revision specifically for PJI. However, this 
association was not observed for the patients with two or more unexpected positive cultures, 
which were much more likely to receive antibiotics and be treated as PJI, after the 
microbiology results were obtained. This is most likely, because one positive culture has been 
interpreted as contamination (32). A sensitivity analysis is made for c), since DHR only have 
ASA and BMI registered starting in 2017 and thus this cannot be adjusted for prior in the data 
prior to 2017. 
 

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EBJIS have proposed a term called PJI-likely which include 1 positive unexpected positive 
culture. PJI-likely is based on international consensus (48,49); however, the definition relies 
on analyses that are not commonly performed in routine practice in Denmark, as stated in the 
description of the primary endpoint. Since it is not possible to use these criteria in Danish 
register studies, the investigators have instead decided to do sensitivity analyses based on the 
validation of infections in the DHR by Gundtoft et al. (30) and the findings of Milandt et al. 
(32). 
 
Statistical analysis: 
 
Descriptive results for continuous variables will be shown as mean(SD)/median(range) 
depending on the distribution of the variables. Categorical variables will be presented using 
frequencies and percentages. Persons operated in LAF and TAF ORs are compared using t-
tests/Wilcoxon-tests and chi-square tests, respectively. This is supplemented with cumulative 
incidence plots showing risk of infection (primary outcome) for LAF and TAF, regarding 
revision due to other causes and death as competing events. The two groups are compared 
using Grays test. To fulfill the requirements at Statistics Denmark about data on individual 
persons, a smooth curve is used to make the plot rather than the statistical correct step-
function. Information at time 90 and 365 days after the operation will be presented. This type 
of plot will be used for all endpoints. 
 
For the primary endpoint, two Cox regression analyses will be performed with the time to PJI 
as outcome. One model will only cover the first 90 days of follow-up, the other will cover all 
365 days of follow-up. Censoring is made at time of revision due to other causes than PJI, 
death, emigration, and end of follow-up (365 days after operation), whichever comes first.  
Bilateral THA will be included in the model as two observations with inclusion of a time-
dependent variable conditioning on the status of the other hip (53). A robust sandwich 
covariance matrix estimate is used to account for the intrapersonal dependence. 
 
The model will include the following potential confounders:  
Education, age, comorbidities, gender, previous hip surgery, primary diagnosis, type of 
cement, type of fixation, year of surgery, income and duration of surgery. ASA and BMI will 
be adjusted for in sensitivity analysis c). A direct acyclic graph is used when determining the 
variables needed to adjust for.  
 

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The linearity assumption for continuous confounders is checked by including these as cubic 
splines with 3 to 7 knots and using the model with lowest AIC, as suggested by Harrell (54). 
The proportional hazards assumption for the Cox-regression models is assessed using plots 
for the cumulative sum of martingale residuals. If the assumption is violated for the exposure 
(LAF/TAF), the time-axis will be split into smaller parts in which the assumption is fulfilled, 
and a separate Cox regression is made for each part. If the proportional hazard assumption is 
violated for confounders, time-dependent covariates is used for these.  
 
Similar Cox-regression models will be used to analyze both secondary endpoints, as well as 
for the sensitivity analysis of the primary endpoint. 
The assumptions of proportional hazards for these endpoints are checked as described for the 
model for the primary endpoint. 
All tests will be two-sided and a p-value of <0.05 will be considered statistically significant. 
Statistical analysis will be conducted using SAS version 9.4 (SAS Institute Inc.). 
 
Missingness 
 
Thanks to the Danish registers, there is no loss to follow-up for the primary and secondary 
endpoints, nor for the endpoints of the sensitivity analyses. Information for most of the 
confounders is based om mandatory registration in DHR, thus it is expected a very limited 
amount of missing data in the confounders (less than 5 % with missing information about 
one/several confounders). The missingness is not likely to be associated with the exposure, 
thus the complete case analysis is expected to be valid (55).  
 
If the missingness is found to be more pronounced, multiple imputation will be used to create 
a full analysis data set. The imputation will use 100 samples. Multiple imputation will be 
made using R (The R Foundation). Results from analysis on the full analysis data set as well 
as for the complete case analysis will be presented.  
Ethical aspects 
 
The study is registered in Pactius, Region Hovedstaden. The study is approved by the Danish 
Health Data Authority. Since it is an observational study, an approval by an ethical committee 
is not needed. An approval from the Danish Society for Patient Safety is not needed since this 
study solely uses anonymized data from registers and not from medical records. The protocol 
is uploaded to clinicaltrials.org to maximize transparency of the research process. 

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Perspectives 
 
When constructing or renovating a hospital, it is crucial to choose a ventilation system that 
minimizes PJIs, while being cost-efficient. Previous studies on LAF vs TAF are based on data 
from national registers. Since registration of PJI is reported immediately to DHR and other 
registers after surgery, the microbiology results are not taken into consideration when the 
revision cause is reported. This study is novel, because it gives a more accurate picture of the 
PJI incidence and can be part in guiding the decisions when renovating or designing new 
hospitals, in order to decrease the risk of PJI. 
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16 
Appendix A 
List of antibiotics screened for 2 weeks after revision, originating from the study by Lidgren 
et al. from 2014 (56), adapted to Danish conditions 
 
J01CA04 Amoxicillin 
J01CR02 Amoxicillin and clavulanic acid 
J01CE02 Phenoxymethylpenicillin 
J01CF05 Flucloxacillin  
J01CF01 Dicloxacillin 
J01FA01 Erythromycin 
J01FA06 Roxithromycin 
J01FA09 Clarithromycin 
J01FA10 Azithromycin 
J01XC01 Fucidin 
J04AB02 Rifampicin  
J01FF01 Clindamycin 
J01XX08 Linezolid 
J01XD01 Metronidazole  
J01MA02 Ciprofloxacin  
J01MA12 Levofloxacin  
J01MA14 Moxifloxacin 
J01EE01 Sulfametoxazol and trimetoprim