Norepinephrine Administration Through a Midline Catheter in an Intermediate Care Unit - a Retrospective Study of Complications and Patient Outcomes
Conditions: Septic Shock, Norepinephrine Adverse Reaction, Hypotension and Shock
Sponsor: Region Skane

Norepinephrine in Midline 
Protocol version 1.0 
September 7th, 2023 
 
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Study protocol - Norepinephrine administra5on through a midline catheter in 
an intermediate care unit - a retrospec5ve study of complica5ons and pa5ent 
outcomes. 
 
List of abbrevia-ons 
ML = Midline catheter 
NE = Norepinephrine 
ICU = Intensive Care Unit 
IMCU = Intermediate Care Unit 
CVC = central venous catheter 
PVC = peripheral venous catheter 
COPD = chronic obstruc@ve pulmonary disorder 
 
Principal Inves-gator, Research Team, and Study site: 
Principal Inves@gator: Gustav Torisson, PhD 
Co-inves@gators: Hannes Hartman, PhD, Marcus Ohlson, PhD, Viktor Månsson, PhD, Hanna 
Karlsson, Ajnaz Afrasiabi 
Contact: gustav.torisson@med.lu.se 
Study site: Skåne University Hospital 
 
Research Synopsis 
Study -tle: Norepinephrine administra-on through a midline catheter in an 
 
intermediate care unit - a retrospec-ve study of complica-ons and pa-ent outcomes. 
 
Study popula-on: Adult pa@ents with circulatory failure, requiring vasopressor support, 
treated at IMCUs at Skåne university hospital 2019 - 2023 
 
Study design: Retrospec@ve chart review 
 
Sample size: 500 - 1000 
 
Study Dura-on: Chart review 6 months, data analysis 2 months 
 
Primary Objec-ve: 
1. To determine the occurrence of major complica@ons when norepinephrine is 
administered in a midline catheter. 
 
Secondary Objec-ves: 
2. To describe minor complica@ons 
3. To describe what propor@on of pa@ents that received a central line. 
4. To describe pa@ent outcomes 
 
 
 

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Background and ra-onale 
 
Sepsis is a life-threatening condi@on with a case fatality rate of 15-30%.(1) The incidence of 
sepsis is increasing, with the largest increase among the oldest old.(2) Western popula@on 
projec@ons indicate a substan@al increase of the oldest popula@on and it is reasonable to 
assume an increase in the number of sepsis pa@ents. (3) Many sepsis pa@ents are treated at 
the highest level of care, in intensive care units (ICUs), and the strain on ICUs may increase 
substan@ally due to increased caseloads.  
 
Sepsis treatment consists of an@bio@cs and suppor@ve treatment (ven@lator if respiratory, 
dialysis if renal etc.).(4-6) Sepsis pa@ents oaen have circulatory failure, resul@ng in low blood 
pressure and poor end organ perfusion. If circulatory failure remains despite ﬂuid 
resuscita@on, the condi@on is labelled sep@c shock, with a mortality rate of 40%. Then, 
guidelines recommend ini@a@ng treatment with vasopressors, drugs that increase blood 
pressure, primarily NE.(1, 4, 5) In recent years, there has been a trend towards reducing the 
amount of ﬂuids given and to start NE earlier.(7, 8) Thus, there is reason to believe also that 
an increasing propor@on of sepsis pa@ents will be eligible for NE treatment.  
 
Norepinephrine raises blood pressure by making the blood vessels contract.(9) Tradi@onally, 
NE administra@on through a peripheral venous catheter (PVC) has been considered hazardous 
as the short catheter may be misplaced.(10-12) If NE is distributed in the @ssue surrounding 
the blood vessel, a.k.a. extravasa@on, the consequences include ulcera@on, blistering and 
necrosis.(13) Should this occur, the NE infusion must be stopped, an an@dote (regi@ne) should 
be given and surgical revision may be needed.(14) The fear for extravasa@on has meant that 
NE is tradi@onally administered through a central venous catheter (CVC, a 15-20 cm long 
catheter inserted into a large-bore vessel). (15, 16) When a CVC is placed, there is a risk of 
immediate mechanical complica@ons (arterial puncture, hematoma, pneumothorax). Due to 
these risks, only a minority of physicians, typically anesthesiologists, are placing CVCs, which 
could delay vasopressor treatment, pufng the pa@ent at risk. (17)  
 
In the last decade, the midline (ML) catheter has seen increased use. A ML catheter is a 8-20 
cm long catheter placed in a larger vessel in the upper arm (basilic, brachial or cephalic vein), 
with the guidance of ultrasound. (18) A few retrospec@ve studies have evaluated the safety of 
NE administra@on in ML catheters, including one with 250 par@cipants, of whom 150 received 
NE. In this study, a 20 cm long ML catheter was used, with a very low complica@on rate.(19) 
Since the ML catheter is placed in the upper arm, the risks for immediate complica@ons are 
much lower than for a CVC. The catheter is placed by a physician or nurse, and it is easier to 
learn ML placement than CVC placement. Thus, more staﬀ can place midline catheters, 
enabling NE treatment to be ini@ated outside of ICUs.  
 
In Skåne university hospital in southern Sweden, pa@ents with circulatory failure requiring 
vasopressor support have been treated in intermediate care units (IMCUs) since 2019. The 
IMCU provides an intermediate level of care, with a staﬃng ra@o between the full ICU and a 
general ward. In these IMCUs, NE has been administered through ML catheters of 10 cm 
length. These are placed by the IMCUs nurses or physicians. The percep@on is that this rou@ne 
has been safe and that it has spared ICU resources, but this has not been studied. Therefore, 

Norepinephrine in Midline 
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the aim of the current study is to evaluate NE administra@on in ML catheters in the IMCU, 
regarding safety and pa@ent outcomes. 
 
Objec-ves and endpoints 
 
Primary Objec-ves 
 
- 
To determine the propor@on of pa@ents having major complica@ons when NE is 
administered in a ML catheter in an IMCU. 
 
Secondary Objec-ves 
 
- 
To determine the occurrence of minor complica@ons when NE is administered in a ML 
catheter. 
- 
To determine what propor@on of pa@ents that received a central line aaer a ML 
catheter. 
- 
To determine pa@ent outcomes 
 
Primary endpoints 
 
Endpoint 1 – Major complica-on. 
 
A Major complica@on is deﬁned as any of the following: 
 
1. Suspected or conﬁrmed extravasa-on of NE in @ssue, deﬁned as the presence of any 
of the following during NE administra@on: 
o Symptoms such as pain, pallor, indura@on, swelling, cold, mojling, blistering 
or necrosis in the ML area. 
o The use of NE an@dote (Regi@ne / Phentolamine) 
o The need for surgical revision of the area.  
 
2. Deep vein thrombosis, deﬁned as a thrombosis in ML vessel or a pulmonary 
embolism, conﬁrmed by ultrasound or radiology performed within 30 days from ML 
placement.  
 
3. Midline-associated bloodstream infec-on (MLABSI), deﬁned as a a primary 
bloodstream infec@on (BSI) in a pa@ent that had a central line within the 48-hour 
period before the development of the BSI.  
 
Secondary Endpoints 
 
• Minor complica-on, deﬁned as either of: 
o Accidental dislodgement of midline catheter (resul@ng in premature removal) 
o Occlusion of midline catheter (impossible to inject in catheter) 
o Leakage  
o Inﬁltra@on of other ﬂuids than NE 
o Other complica@ons (phlebi@s, major bleeding, nerve damage, local infec@on) 

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• Central line aQer ML catheter: deﬁned as the pa@ent receiving a central line aaer ML 
catheter inser@on. 
• Pa-ent outcomes 
o IMCU discharge des@na@on (regular hospital ward or occasionally home / ICU 
escala@on / died in the IMCU) 
o IMCU, ICU, hospital length-of-stay 
o In-hospital mortality 
 
 
 
Study design and methodology 
 
This is a retrospec@ve study using chart review as the primary methodology. Skåne university 
hospital is a 900-bed university-aﬃliated hospital in southern Sweden. Adult (≥ 18 years) 
pa@ents who have received NE in ML catheters in an IMCU at Skåne university hospital 
between 2019 and 2023 will be eligible. Case-ﬁnding will be performed through a database 
query to the regional data-hos@ng planorm. Manual screening will be done to ensure that all 
episodes fulﬁl this case deﬁni@on. The only exclusion criterion is that the pa@ent has ac@vely 
made the electronic medical record unavailable.  
 
Episodes fulﬁlling the eligibility criterion will be subjected to chart review, which will be done 
consecu@vely. The @me that NE is ini@ated in a midline catheter will be considered the 
baseline. The chart review will be performed according to a protocol with prespeciﬁed 
deﬁni@ons, see separate document. Data in the following domains will be collected: 
 
1. Domain: Background data 
• Age at baseline 
• Sex 
• Length in cen@meters (may be retrieved from earlier hospitalisa@ons) 
• Weight in kilograms (as close to baseline as possible, ± 3 months is ok) 
• Body mass index (derived from length and weight) 
• Home care (no/home care / nursing home) 
• Comorbidi@es (Admission and Discharge notes will be scru@nized, any men@oning 
or ICD-10 code will be noted, results as yes/no) 
- 
Chronic cardiac disease (ischemic heart disease, heart failure, arrhythmias, 
valve disease or other) 
- 
Chronic pulmonary disease (COPD, lung ﬁbrosis, asthma, bronchiectasis, other) 
- 
Chronic renal disease (renal failure, previous transplanta@on, single kidney, 
polycys@c kidney disease, other) 
- 
Dialysis (hemodialysis or peritoneal dialysis) 
- 
Ac@ve malignancy (malignancy where treatment or surveillance is s@ll ongoing) 
- 
Diabetes mellitus (any form) 
- 
Chronic hepa@c disease (cirrhosis, steatosis, untreated hepa@@s, other) 
- 
Autoimmune disease (connec@ve @ssue disease, inﬂammatory bowel disease, 
neurologic disease, other) 

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- 
Transplanta@on (solid organ or stem-cell transplanta@on at any point 
previously) 
- 
Previous venous thromboembolism (any deep vein thrombosis, pulmonary 
embolism) 
• An@coagulant therapy (ongoing treatment before baseline with drugs ac@ng on 
the venous side – DOAC / Warfarin / LMH, regardless of reason) 
• Immunosuppression (ongoing treatment before baseline with a drug from group 
L01 or L04 in the ATC classiﬁca@on OR steroids in a dose equivalent to 10mg 
Prednisolone or higher). 
• Ceiling of care (a ceiling of care decision, that escala@on is not considered 
beneﬁcial to the pa@ent, documented before baseline or during the period that NE 
is administered in a ML catheter. None / no ICU Escala@on / No Cardio-pulmonary 
resuscita@on).  
• Central line at baseline (yes or no. Did the pa@ent have a central line at baseline, 
e.g., a dialysis catheter or subcutaneous venous port?) 
 
2. Domain: current episode 
• Infec@on yes or no (was an infec@on / sep@c shock the main reason for star@ng 
NE?) 
• Reason for NE ini@a@on (if infec@on => infec@on focus, otherwise other reason, 
e.g., cardiogenic shock, hemorrhage) 
• Vital signs (These are from the Na@onal Early Warnings Scale (NEWS), taken before 
baseline, if several the one closest to baseline is noted. These may be registered 
as a NEWS documenta@on, in free text in the chart or on the monitoring sheet, 
the one closest to baseline is chosen). Vital signs include: 
- 
Respiratory rate, breaths / minute 
- 
Systolic blood pressure, mmHg 
- 
Diastolic blood pressure, mmHg 
- 
Mean arterial pressure (derived from systolic and diastolic) 
- 
Mental state (A = alert, V = responsive to verbal s@muli, P = responsive to pain, 
U = unresponsive. Anything except A => altered consciousness) 
- 
Heart rate, beats per minute 
- 
SpO2, peripheral oxygen satura@on in % 
- 
Temperature, °C 
- 
Fever (derived from temperature, if ≥ 38.0) 
- 
Supplemental oxygen, liters / minute (if HFNC / NIV and FiO2, Liters / minute is 
es@mated from FiO2 (L/m = (FiO2 – 21%) / 4)) 
• Laboratory values (these are taken before baseline as close to baseline as possible, 
but could be taken aaer if within speciﬁed limits below) 
- 
Lactate, mmol/L (ok up to 2 hours aaer baseline) 
- 
Crea@nine, umol/L (ok up to 12 hours aaer baseline) 
- 
C-reac@ve protein mg/L, (ok up 24 hours aaer baseline) 
• Acute kidney injury (yes/no, yes if crea@nine > 100 umol/L and no chronic kidney 
disease) 
• Blood cultures taken at baseline (yes/no, yes if cultures are taken within ±48 h of 
baseline, signalling the suspicion of infec@on) 

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• Baseline blood culture results (name of species aaer contamina@on removal, as 
speciﬁed before).(20) 
 
3. Domain Midline (this is taken from the speciﬁc midline note in the charts) 
• ML in date (date of midline inser@on) 
• ML side (lea or right arm) 
• ML model (name of midline model used) 
• ML diameter (in G, 18G or 20G, later converted to mm or Fr) 
• ML vein (basilic, brachial, or cephalic vein) 
• ML out date (date om midline removal) 
• ML dwell @me, days (derived from in and out dates) 
• Number of ML (was another ML inserted aaer the “index” ML?) 
 
4. Domain NE 
• NE start date@me (the date and @me that NE was started in a ML = baseline) 
• NE stop date@me (the date and @me that NE was stopped in ML, either due to no 
further need for NE or due to ICU escala@on and CVC inser@on (in this situa@on, 
we presume that NE infusion is switched to CVC if not documented otherwise)) 
• NE dura@on, hrs (the diﬀerence between start and stop. If NE has been paused 
and then restarted, the pause is manually subtracted) 
• NE max dosage, ug x kg-1 x min-1 (the highest dose of NE given in ML) 
 
5. Domain Complica-ons 
• Extravasa@on (yes or no, any men@oning of extravasa@on, inﬁltra@on, pain, 
indura@on, swelling, pallor, cold, mojling, blistering, necrosis in the midline area. 
Any use of an@dote (phentolamine / Regi@ne) or need for surgery in the midline 
area. Everything wrijen in charts between NE start and NE stop is scru@nized. In 
addi@on, the charts are queried using all the above terms).  
• Deep venous thrombosis (yes or no. If an ultrasound / radiology has demonstrated 
a deep vein thrombosis in the midline area, from ML in date and up to 30 days 
aaer. Also, pulmonary embolisms on CT or scin@graphy without any other 
explana@on) 
• Catheter-related bloodstream infec@on (yes or no. Is there a posi@ve blood culture 
taken from ML in date to ML out date + 7 days, with primary growth that is not 
explained by another infec@on?) 
• Any major complica@on (yes or no, derived from above, any of extravasa@on, 
thrombosis, or catheter-related bloodstream infec@on) 
• Minor complica@ons (inﬁltra@on (of other medica@on than NE), dislodgement, 
leakage, phlebi@s, local infec@on, occlusion of catheter, or other such as bleeding, 
skin reac@on to dressing etc. This should be documented in the midline 
documenta@on, but free text will also be scru@nized, including queries for terms 
above) 
• Premature removal of ML (yes or no. Was the ML prematurely removed (as in 
before the need for an intravenous access was over) due to a complica@on) 
• CVC aaer ML (yes or no. Did the pa@ent receive a central line aaer ML in date?) 
 

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6. Domain pa-ent outcomes 
• IMCU discharge date 
• IMCU Length-of-stay (IMCU discharge date – baseline) 
• IMCU discharge des@na@on (regular ward / icu escala@on / deceased in IMCU) 
• ICU discharge date  
• ICU Length-of-stay, days 
• Hospital discharge date 
• Hospital Length-of-stay, days 
• In-hospital mortality (yes / no) 
• Final diagnosis (the primary ICD-10 diagnosis at hospital discharge) 
 
 
 
 
 
 
Study popula-on 
 
The study popula@on consists of all adults receiving NE in ML catheters in an IMCU in Skåne 
university hospital between 2019 and 2023. The majority of these will have sep@c shock, 
deﬁned as an infec@on with hypotension that does not respond to ﬂuid therapy in the 
intended way. The outcome in the group with sep@c shock will be described separately, for 
comparison with other sefngs.  
 
Study Dura-on/ Study Timeline: 
 
Stage 1: Review of medical records 2-3 months 
Stage 2: Data synopsis and analysis 1-2 months 
Stage 3: Presenta@on and publica@on 1-2 months 
 
Sta-s-cal Analysis Plan: 
 
For the primary endpoint any major complica@ons, only descrip@ve sta@s@cs will be used, i.e., 
the percentage of episodes with major complica@ons. For extravasa@on, both the propor@on 
of episodes with extravasa@on (percentage total) will be es@mated, as well as events per 1000 
treatment-hours (with NE in ML). For deep vein thromboses, the percentage total and events 
per 1000 catheter-days will be described. For catheter-related BSI, the percentage total and 
events per 1000 catheter-days will be described.  
 
We hypothesize that the propor@on with major complica@ons will be small and that no 
compara@ve sta@s@cs will be feasible to determine risk factors for complica@on.  
 
For secondary endpoint minor complica@ons, only descrip@ve sta@s@cs will be used.  
 
 
Sample size determina-on 

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Two previous studies have examined complica@ons when NE is administered through ML 
catheters, with 1 in 150 and 0 of 238. Thus, as complica@ons seem rare and the focus is purely 
descrip@ve, we performed no power calcula@on but aimed to include as many pa@ents as 
possible.  
 
Informed Consent Process 
In this retrospec@ve chart review, no informed consent will be sought. We hypothesize that 
30-40% of eligible par@cipants will be deceased, due to the severity of the condi@on of 
interest. The study was approved by the Swedish Ethical Review Authority (Nr: 2022-06476) 
 
Privacy and conﬁden-ality 
A unique pa@ent iden@ﬁer will be kept on an encrypted and password protected separate hard 
drive, with only a study iden@ﬁca@on number / code.  
 
The code will then be stored together with clinical data from the medical records, on a 
separate encrypted hard drive. These will be stored in a locked oﬃce and maintained for 10 
years aaer the comple@on of the study. All source data is maintained by Region Skåne as well, 
no new data will be collected in the study.  
 
Risk/Beneﬁt: 
The only risk for par@cipants is the risk of integrity breach. This will be minimized through data 
protec@on rou@nes, as stated above. There will be no individual beneﬁt, but the study will 
provide bejer understanding regarding NE administra@on through ML catheters. This could 
improve treatment for sep@c shock, a cri@cal condi@on with high mortality and an increasing 
caseload. 
 
Conﬂict of Interest: 
None of the inves@gators report any conﬂicts of interest.  
 
Publica-on and Presenta-on Plans: 
Results will be compiled and sent for considera@on to a scien@ﬁc journal in start of 2024. 
 
 
References: 
 
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