BACKGROUND:Tuberculous meningitis (TBM) is a severe central nervous system (CNS) infection with high mortality. Moxifloxacin shows potent anti-mycobacterial activity and favorable CNS penetration. However, optimal dosing remains uncertain, particularly with rifampicin, which markedly reduces moxifloxacin exposure. This study aimed to determine optimal moxifloxacin dosing for TBM by accounting for regional CNS pharmacokinetics (PK) and rifampicin co-administration using a cross-species translational physiologically based pharmacokinetic (PBPK) model. METHODS:A PBPK model was developed using high-resolution plasma and CNS microdialysis data from pigs to capture CNS physiology and moxifloxacin distribution. The model was translated to humans using literature-derived physiological parameters and allometric scaling and validated with plasma and CNS PK data from healthy subjects and TBM patients. Simulations of once-daily moxifloxacin doses (400 to 1000 mg), with and without rifampicin, were evaluated using the unbound fAUC₀-₂₄/MIC target of 53. RESULTS:The model reasonably described observed moxifloxacin concentrations in porcine and human CNS compartments. Simulations showed regional PK differences, with highest concentrations in the subarachnoid space and cisterna magna and lowest in brain extracellular fluid. Rifampicin reduced mean CNS exposure by 26 %. Without rifampicin, target attainment was achieved in most CNS compartments, except brain extracellular fluid, at 800 mg once daily, while even doses up to 1000 mg did not reach target levels in most CNS compartments with rifampicin co-administration. CONCLUSION:These results suggest that higher doses might be needed to ensure PK target attainment in TBM, regardless of whether moxifloxacin is combined with rifampicin. The safety of regimens exceeding 800 mg must be rigorously established in clinical trials.

Ganciclovir is often used compassionately for encephalitis due to cytomegalovirus (CMV) and human herpes virus 6b (HHV-6b). Ganciclovir pharmacokinetic studies in the central nervous system (CNS) generally rely on single measurements in the cerebrospinal fluid (CSF) or homogenized brain tissue. Therefore the objective was to compare brain extracellular fluid (ECF) concentrations of ganciclovir with plasma and CSF concentrations in a porcine model, using microdialysis during a 24 h period. Six Danish landrace pigs (female, age 4 months, 31-37 kg) received two weight-adjusted intravenous doses of ganciclovir. Unbound ganciclovir concentrations were determined by microdialysis over 24 h in five compartments: CSF (lateral ventricle, cisterna magna, and lumbar) and brain ECF (cortical and subcortical). Data were compared with paired plasma samples. Ganciclovir concentrations >IC50 for CMV (1.6 µg/mL) were achieved in all compartments. Concentrations >IC90 for CMV (8.3 µg/mL) were only achieved in plasma and the lumbar CSF compartment. The concentration time curves indicated higher lumbar and cisternal CSF concentrations than ECF concentrations. The ECF compartments achieved greater maximum concentration (Cmax), area under the concentration time curve (AUC), and time >IC50 after the second dose, and an accumulation ratio (Rac) >1. The greater Cmax, AUC, time >IC50, and Rac >1 in the ECF compartments with repeated dosages suggest that therapeutic concentrations may be achieved during long-term treatment. A higher loading dose might be warranted to improve early viral inhibition.

Coronavirus 2019 (COVID-19) leads to substantial morbidity and excess mortality all over the world which may be aggravated by the propensity of Severe Acute Respiratory Syndrome Coronavirus 2 to mutate. Mechanisms for development of severe COVID-19 are poorly understood. The air we exhale contains endogenous proteins and represents a highly accessible yet unexploited biological sample that can be collected without use of invasive procedures. We collected exhaled breath condensate samples from 28 patients hospitalised due to COVID-19 at admission and discharge using RTubes™. Bottom-up proteomic analysis of tandem mass-tag-labelled single exhaled breath samples was performed in 25 exhaled breath samples collected at admission and 13 samples collected at discharge using discovery-based nano-liquid chromatography-tandem mass spectrometry. In total, 232 proteins were identified in the exhaled breath samples after stringent data filtering. Most of the exhaled proteins were related to the immune systems function and regulation. The levels of four proteins, KRT77, DCD, CASP14 and SERPINB12 decreased from admission to discharge as patients generally recovered from the infection. These proteins are expressed in lung epithelium or macrophages and are associated with the regulation of inflammation drivers in COVID-19. In particular, the alarmins S100A8 and S100A9 accounted for 8% of the exhaled breath proteins. In conclusion, our study demonstrates that analysis of the exhaled breath protein composition can give insights into mechanisms related to inflammation and response to infections, and hereby also of severe COVID-19.Clinical Trial No: NCT04598620.

Objective: To describe the clinical features and outcome of brain abscess since introduction of computerised tomography and magnetic resonance imaging. Methods: MEDLINE and Embase were searched using "brain abscess" or "cerebral abscess" from 1970 through 2023 and analyses restricted to study populations hospitalised after 1980. Single-variable meta- analyses were done using a random-effects model. Results: A total of 21,840 patients from 209 studies were included. The mean age was 34 years (95% confidence interval [CI] 30-38) and 11,817/17,406 (66%, 95% CI 64-67) were male. The aetiologies were consistent across time and continents with Streptococcus spp. 2064/6393 (32%, 95% CI 28-36), Staphylococcus spp. 1061/6393 (14%, 95% CI 12-16), and Gram-negative enteric bacteria 696/6393 (9%, 95% CI 7-11) as the most common. Predisposing conditions included otitis media/mastoiditis 1909/6433 (27%, 95% CI 22-33), immunocompromise 1022/4652 (19%, 95% CI 14-24), sinusitis 565/3725 (16%, 95% CI 12-20), and neurosurgery 745/4927 (16%, 95% CI 12-20). The case-fatality was 2444/18,991 (12%, 95% CI 11-14) and good recovery was found in 3419/5409 (63%, 95% CI 58-68). Conclusions and relevance: Brain abscess remains a disease predominantly occurring in men and is caused by contiguous or distant infections. Case fatality and outcome have not improved during recent decades. (c) 2024 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Pigs are increasingly used as a large animal model for pharmacologic CNS research due to the anatomical and physiological similarities between the porcine and human central nervous systems (CNS). However, accessing the cerebrospinal fluid (CSF) in larger pig breeds by conventional lumbar puncture techniques can be challenging due to an oblique orientation of the spinal spinous processes and a limited interlaminar space. Accordingly, an open surgical procedure for inserting a lumbar spinal catheter for continuous CSF sampling at the L4/L5 level in pigs is thoroughly described in this work. After positioning the pig and identifying the anatomical landmarks, a dorsal midline surgical incision is made to expose the spinous processes. By advancing the introducer needle, the spinal catheter is inserted inside the thecal sac of the spinal canal while leaving the bone structures of the spine intact. This method allows continuous infusion into or sampling from the porcine thecal sac with minimal bleeding or CSF leakage. The procedure is simple, time-efficient, and reproducible across different experimental setups, offering significant potential for various pre-clinical studies, including pharmacokinetic research, surgical training, and spinal cord injury models.

BackgroundBrain abscess (BA) is a rare, but severe infection and experimental BA animal models may prove crucial for advances in treatment. This review describes the development of experimental BA models and the clinical advances obtained from these, in a historical perspective.Material and methodsExperimental BA studies from inception until June 15, 2022, were included by searching the PubMed and Embase databases. Inclusion required the use of an experimental BA animal model. Non-bacterial BA models, in vitro studies, veterinarian case-reports, and articles written in non-English language were excluded. Bias was not systematically assessed, and the review was not registered at the PROSPERO.Results79 studies were included. The majority of animal BA models have been based on small rodents using Staphylococcus aureus. The models have delineated the natural development of BA and provided detailed descriptions of the histopathological characteristics consisting of a necrotic centre surrounded by layers of inflammatory cells and fibroblasts encapsulated by a dense collagenous layer. Radiological studies of animal BA have been shown to correlate with the corresponding stages of human BA in both computed tomography and magnetic resonance imaging and may guide diagnosis as well as the timing of neurosurgical intervention. Moreover, pharmacokinetic studies of the intracavitary penetration of various antimicrobials have helped inform medical treatment of BA. Other studies have examined the diverse effects of corticosteroids including decreased cerebral oedema, intracranial pressure, and intracavitary drug concentration, whereas concerns on decreased or weakened capsule formation could not be confirmed. Finally, studies on the immunological response to BA have highlighted potential future immunomodulatory targets.ConclusionsAnimal models have been vital for improvements in the management of BA. Experimental BA models resembling human disease including polymicrobial infection by oral cavity flora in large animals are needed.

Background Oral cavity bacteria are the most frequent etiology of brain abscess. Yet, data on the clinical presentation and outcome are scarce.Methods We performed a nationwide, population-based study comprising all adults (aged >= 18 years) with brain abscess due to oral cavity bacteria in Denmark from 2007 through 2020. Prognostic factors for unfavorable outcome (Glasgow outcome scale, 1-4) were examined using modified Poisson regression to compute adjusted relative risks (RRs) with 95% confidence intervals (CIs).Results Among 287 identified patients, the median age was 58 years (interquartile range, 47-66), and 96 of 287 (33%) were female. Preexisting functional impairment was absent or mild in 253 of 280 (90%), and risk factors for brain abscess included immunocompromise in 95 of 287 (33%), dental infection in 68 of 287 (24%), and ear-nose-throat infection in 33 of 287 (12%). Overall, a neurological deficit was present in 246 of 276 (86%) and in combination with headache and fever in 64 of 287 (22%). Identified microorganisms were primarily the Streptococcus anginosus group, Fusobacterium, Actinomyces, and Aggregatibacter spp., and 117 of 287 (41%) were polymicrobial. Unfavorable outcome occurred in 92 of 246 (37%) at 6 months after discharge and was associated with antibiotics before neurosurgery (RR, 3.28; 95% CI, 1.53-7.04), rupture (RR, 1.89; 95% CI, 1.34-2.65), and immunocompromise (RR, 1.80; 95% CI, 1.29-2.51), but not with specific targeted antibiotic regimens. Identified dental infection was associated with favorable prognosis (RR, 0.58; 95% CI, .36-.93).Conclusions Brain abscess due to oral cavity bacteria often occurred in previously healthy individuals without predisposing dental infections. Important risk factors for unfavorable outcome were rupture and immunocompromise. However, outcome was not associated with specific antibiotic regimens supporting carbapenem-sparing strategies. Brain abscess due to oral cavity bacteria often occurs in healthy individuals for unknown reasons with high risks of unfavorable outcome. Important prognostic factors include rupture of brain abscess and immunocompromise. Targeted antibiotic regimen was not associated with outcome.

Background: Knowledge regarding CNS pharmacokinetics of moxifloxacin is limited, with unknown consequences for patients with meningitis caused by bacteria resistant to beta-lactams or caused by TB. Objective: (i) To develop a novel porcine model for continuous investigation of moxifloxacin concentrations within brain extracellular fluid (ECF), CSF and plasma using microdialysis, and (ii) to compare these findings to the pharmacokinetic/pharmacodynamic (PK/PD) target against TB. Methods Six female pigs received an intravenous single dose of moxifloxacin (6 mg/kg) similar to the current oral treatment against TB. Subsequently, moxifloxacin concentrations were determined by microdialysis within five compartments: brain ECF (cortical and subcortical) and CSF (ventricular, cisternal and lumbar) for the following 8 hours. Data were compared to simultaneously obtained plasma samples. Chemical analysis was performed by high pressure liquid chromatography with mass spectrometry. The applied PK/PD target was defined as a maximum drug concentration (C-max):MIC ratio >8. Results: We present a novel porcine model for continuous in vivo CNS pharmacokinetics for moxifloxacin. C-max and AUC0-8h within brain ECF were significantly lower compared to plasma and lumbar CSF, but insignificantly different compared to ventricular and cisternal CSF. Unbound C-max:MIC ratio across all investigated compartments ranged from 1.9 to 4.3. Conclusion: A single dose of weight-adjusted moxifloxacin administered intravenously did not achieve adequate target site concentrations within the uninflamed porcine brain ECF and CSF to reach the applied TB CNS target.

The use of pigs as an experimental animal model is especially relevant in neuroscience research, as the porcine and human central nervous systems (CNS) share many important functional and architectural properties. Consequently, pigs are expected to have an increasingly important role in future research on various neurological diseases. Here, a method to perform an anterior craniectomy through the porcine frontal bone is described. After a midline incision and subsequent exposure of the porcine frontal bone, anatomical landmarks are used to ensure the optimal location of the craniectomy. By careful and gradual thinning of the frontal bone with a rounded drill, a rectangular opening to the dura mater and underlying cerebral hemispheres is achieved. The presented method requires certain surgical materials, including a pneumatic high-speed drill, and some degree of surgical experience. Potential complications include unintended lesions of the dura mater or dorsal sagittal sinus. However, the method is simple, time-efficient, and offers a high degree of reproducibility for researchers. If performed correctly, the technique exposes a large portion of the unaffected pig brain for various neuromonitoring or analyses.

Studies on brain abscess are hampered by single-centre design with limited sample size and incomplete follow-up. Thus, robust analyses on clinical prognostic factors remain scarce. This Danish nationwide, population-based cohort study included clinical details of all adults (≥18 years) diagnosed with brain abscess in the Danish National Patient Registry from 2007 through 2014 and the prospective clinical database of the Danish Study Group of Infections of the Brain covering all Danish departments of infectious diseases from 2015 through 2020. All patients were followed for 6 months after discharge. Prognostic factors for mortality at 6 months after discharge were examined by adjusted modified Poisson regression to compute relative risks with 95% confidence intervals (CI). Among 485 identified cases, the median age was 59 years [interquartile range (IQR 48-67)] and 167 (34%) were female. The incidence of brain abscess increased from 0.4 in 2007 to 0.8 per 100 000 adults in 2020. Immuno-compromise was prevalent in 192/485 (40%) and the clinical presentation was predominated by neurological deficits 396/485 (82%), headache 270/411 (66%), and fever 208/382 (54%). The median time from admission until first brain imaging was 4.8 h (IQR 1.4-27). Underlying conditions included dental infections 91/485 (19%) and ear, nose and throat infections 67/485 (14%), and the most frequent pathogens were oral cavity bacteria (59%), Staphylococcus aureus (6%), and Enterobacteriaceae (3%). Neurosurgical interventions comprised aspiration 356/485 (73%) or excision 7/485 (1%) and was preceded by antibiotics in 377/459 (82%). Fatal outcome increased from 29/485 (6%) at discharge to 56/485 (12%) 6 months thereafter. Adjusted relative risks for mortality at 6 months after discharge was 3.48 (95% CI 1.92-6.34) for intraventricular rupture, 2.84 (95% CI 1.45-5.56) for immunocompromise, 2.18 (95% CI 1.21-3.91) for age >65 years, 1.81 (95% CI 1.00-3.28) for abscess diameter >3 cm, and 0.31 (95% CI 0.16-0.61) for oral cavity bacteria as causative pathogen. Sex, neurosurgical treatment, antibiotics before neurosurgery, and corticosteroids were not associated with mortality. This study suggests that prevention of rupture of brain abscess is crucial. Yet, antibiotics may be withheld until neurosurgery, if planned within a reasonable time period (e.g. 24 h), in some clinically stable patients. Adjunctive corticosteroids for symptomatic perifocal brain oedema was not associated with increased mortality.

Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials. Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load. Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group (P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log10 copies/mL (p <0·05) and -0·82 log10 in the placebo group (P <0·05). Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001200-42.

BACKGROUND Venous thromboembolism (VTE) is a potentially fatal complication of SARS-CoV-2 infection and thromboprophylaxis should be balanced against risk of bleeding. This study aimed to examine risks of VTE and major bleeding in hospitalized and community-managed SARS-CoV-2 patients compared with control populations. METHODS Using nationwide population-based registries, 30-day risks of VTE and major bleeding in SARS-CoV-2 positive patients were compared with those of SARS-CoV-2 test-negative patients and with an external cohort of influenza patients. Medical records of all COVID-19 patients at six departments of infectious diseases in Denmark were reviewed in detail. RESULTS The overall 30-day risk of VTE was 0.4% (40/9,460) among SARS-CoV-2 patients (16% hospitalized), 0.3% (649/226,510) among SARS-CoV-2 negative subjects (12% hospitalized), and 1.0% (158/16,281) among influenza patients (59% hospitalized). VTE risks were higher and comparable in hospitalized SARS-CoV-2 positive (1.5%), SARS-CoV-2 negative (1.8%), and influenza patients (1.5%). Diagnosis of major bleeding was registered in 0.5% (47/9,460) of all SARS-CoV-2 positive individuals and in 2.3% of those hospitalized. Medical record review of 582 hospitalized SARS-CoV-2 patients observed VTE in 4% (19/450) and major bleeding in 0.4% (2/450) of ward patients, of whom 31% received thromboprophylaxis. Among intensive care patients (100% received thromboprophylaxis), risks were 7% (9/132) for VTE and 11% (15/132) for major bleeding. CONCLUSIONS Among people with SARS-CoV-2 infection in a population-based setting, VTE risks were low to moderate and were not substantially increased compared with SARS-CoV-2 test-negative and influenza patients. Risk of severe bleeding was low for ward patients, but mirrored VTE risk in the intensive care setting.

Background. Venous thromboembolism (VTE) is a potentially fatal complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and thromboprophylaxis should be balanced against risk of bleeding. This study examined risks of VTE and major bleeding in hospitalized and community-managed SARS-CoV-2 patients compared with control populations. Methods. Using nationwide population-based registries, 30-day risks of VTE and major bleeding in SARS-CoV-2 positive patients were compared with those of SARS-CoV-2 test-negative patients and with an external cohort of influenza patients. Medical records of all COVID-19 patients at 6 departments of infectious diseases in Denmark were reviewed in detail. Results. The overall 30-day risk of VTE was 0.4% (40/9460) among SARS-CoV-2 patients (16% hospitalized), 0.3% (649/226 510) among SARS-CoV-2 negative subjects (12% hospitalized), and 1.0% (158/16 281) among influenza patients (59% hospitalized). VTE risks were higher and comparable in hospitalized SARS-CoV-2 positive (1.5%), SARS-CoV-2 negative (1.8%), and influenza patients (1.5%). Diagnosis of major bleeding was registered in 0.5% (47/9460) of all SARS-CoV-2 positive individuals and in 2.3% of those hospitalized. Medical record review of 582 hospitalized SARS-CoV-2 patients observed VTE in 4% (19/450) and major bleeding in 0.4% (2/450) of ward patients, of whom 31% received thromboprophylaxis. Among intensive care patients (100% received thromboprophylaxis), risks were 7% (9/132) for VTE and 11% (15/132) for major bleeding. Conclusions. Among people with SARS-CoV-2 infection in a population-based setting, VTE risks were low to moderate and were not substantially increased compared with SARS-CoV-2 test-negative and influenza patients. Risk of severe bleeding was low for ward patients, but mirrored VTE risk in the intensive care setting.

Importance:Coagulopathy may deter physicians from performing a lumbar puncture.Objective:To determine the risk of spinal hematoma after lumbar puncture in patients with and without coagulopathy.Design, Setting, and Participants:Danish nationwide, population-based cohort study using medical registries to identify persons who underwent lumbar puncture and had cerebrospinal fluid analysis (January 1, 2008-December 31, 2018; followed up through October 30, 2019). Coagulopathy was defined as platelets lower than 150 × 109/L, international normalized ratio (INR) greater than 1.4, or activated partial thromboplastin time (APTT) longer than 39 seconds.Exposures:Coagulopathy at the time of lumbar puncture.Main Outcomes and Measures:Thirty-day risk of spinal hematoma. Risks were provided as numbers and percentages with 95% CIs. Secondary analyses included risks of traumatic lumbar puncture (>300 × 106 erythrocytes/L after excluding patients diagnosed with subarachnoid hemorrhage). Adjusted hazard rate ratios (HRs) were computed using Cox regression models.Results:A total of 83 711 individual lumbar punctures were identified among 64 730 persons (51% female; median age, 43 years [interquartile range, 22-62 years]) at the time of the procedure. Thrombocytopenia was present in 7875 patients (9%), high INR levels in 1393 (2%), and prolonged APTT in 2604 (3%). Follow-up was complete for more than 99% of the study participants. Overall, spinal hematoma occurred within 30 days for 99 of 49 526 patients (0.20%; 95% CI, 0.16%-0.24%) without coagulopathy vs 24 of 10 371 patients (0.23%; 95% CI, 0.15%-0.34%) with coagulopathy. Independent risk factors for spinal hematoma were male sex (adjusted hazard ratio [HR], 1.72; 95% CI, 1.15-2.56), those aged 41 through 60 years (adjusted HR, 1.96; 95% CI, 1.01-3.81) and those aged 61 through 80 years (adjusted HR, 2.20; 95% CI, 1.12-4.33). Risks did not increase significantly according to overall severity of coagulopathy, in subgroup analyses of severity of coagulopathy by pediatric specialty or medical indication (infection, neurological condition, and hematological malignancy), nor by cumulative number of procedures. Traumatic lumbar punctures occurred more frequently among patients with INR levels of 1.5 to 2.0 (36.8%; 95% CI, 33.3%-40.4%), 2.1 to 2.5 (43.7%; 95% CI, 35.8%-51.8%), and 2.6 to 3.0 (41.9% 95% CI 30.5-53.9) vs those with normal INR (28.2%; 95% CI, 27.7%-28.75%). Traumatic spinal tap occurred more often in patients with an APTT of 40 to 60 seconds (26.3%; 95% CI, 24.2%-28.5%) vs those with normal APTT (21.3%; 95% CI, 20.6%-21.9%) yielding a risk difference of 5.1% (95% CI, 2.9%-7.2%).Conclusions and Relevance:In this Danish cohort study, risk of spinal hematoma following lumbar puncture was 0.20% among patients without coagulopathy and 0.23% among those with coagulopathy. Although these findings may inform decision-making about lumbar puncture by describing rates in this sample, the observed rates may reflect bias due to physicians selecting relatively low-risk patients for lumbar puncture.

Background: Risk of spinal haematoma following lumbar puncture in patients with abnormal coagulation status remains unclear and may deter physicians from performing the procedure. Methods: We accessed nationwide, population-based medical registries to examine the risk of spinal haematoma in patients with coagulopathy (thrombocytopenia 1·4, or activated partial thromboplastin time [APTT] >39 seconds) at time of lumbar puncture in Denmark from 2008 to 2019. Next, we reviewed the medical records of all such patients in North Denmark Region from 1998 through 2018. Risks are provided as counts and percentages with 95% confidence intervals (CI). Adjusted hazard rate ratios (HRRs) were computed using Cox regression models. Findings: Using medical registries, we identified 83,711 lumbar punctures in 64,730 individuals. At time of the procedure, thrombocytopenia was present in 7,875 patients, high INR in 1,393 patients, and prolonged APTT in 2,604 patients. Spinal haematoma occurred within 30 days in 143/83,711 lumbar punctures yielding an overall risk of 0·17% (95% 0·14-0·20) compared with 0-0·33% among patients with coagulopathy. Independent risk factors for spinal haematoma were male sex (HRR 1·75 [95% 1·18-2·61]) and age group 61-80 years (HRR 2·41 [95% 1·20-4·84]). Results remained unchanged in subgroup analyses by paediatric specialty, medical indication, and cumulative number of procedures. Overall risk of traumatic lumbar puncture (>300 x 106 erythrocytes /L) was 27·8% and was increased in some subgroups of patients with coagulopathy (range 22·6-44·0%). Medical record review of 1,694 lumbar punctures in patients with coagulopathy uncovered one case (0·06%) of spinal haematoma in a thrombocytopenic patient. Interpretation: Risk of spinal haematoma after lumbar puncture is small and without substantial increases among patients with coagulopathy. These results offer clinicians a firm basis to proceed with a lumbar puncture, if needed, regardless of coagulopathy in patients with serious medical conditions. Funding Statement: None. Declaration of Interests: All authors declare no conflicts of interests. Ethics Approval Statement: The study was approved by the legal representatives of North Denmark Region (2018-45) and the Danish Board of Health (3-3013-2477/1).