A retrospective cohort study of coagulation function in patients with liver cirrhosis receiving cefoperazone/sulbactam with and without vitamin K1 supplementation

doi:10.21203/rs.3.rs-4275034/v1

Background

Cefoperazone/sulbactam is commonly prescribed for the treatment of infected patients with cirrhosis.

Aim

To investigate the effect of cefoperazone/sulbactam on coagulation in cirrhotic patients and assess the efficacy of vitamin K1 supplementation in preventing cefoperazone/sulbactam-induced coagulation disorders.

Method

This retrospective cohort study compared coagulation function in 217 cirrhotic patients who received Cefoperazone/sulbactam with and without vitamin K1 supplementation (vitamin K1 group, n = 108; non-vitamin K1 group, n = 109).

Results

In the non-vitamin K1 group, the post-treatment prothrombin time (PT) was 16.5 ± 6.5s and the activated partial thromboplastin time (aPTT) was 34.8 ± 9.4s. These were significantly higher than pre-treatment values (PT: 14.6 ± 2.4s, p = 0.005; aPTT: 30.4 ± 5.9s, p < 0.001). In the vitamin K1 group, no differences were observed in PT, thrombin time, or platelet count, except for a slightly elevated post-treatment aPTT (37.0 ± 10.4s) compared to that of pre-treatment (34.4 ± 7.2s, p = 0.033). The vitamin K1 group exhibited a lower risk of PT prolongation (OR: 0.211, 95% CI: 0.047–0.678) and coagulation disorders (OR: 0.257, 95% CI: 0.126–0.499) compared to that of the non-vitamin K1 group. Propensity score matching analysis confirmed a reduced risk in the vitamin K1 group for prolonged PT (OR: 0.128, 95% CI: 0.007–0.754) and coagulation disorders (OR: 0.222, 95% CI: 0.076–0.575). Additionally, the vitamin K1 group exhibited lower incidences of PT prolongation, aPTT prolongation, bleeding, and coagulation dysfunction compared to the non-vitamin K1 group.

Conclusion

Cefoperazone/sulbactam use may be linked to a higher risk of PT prolongation and coagulation disorders in cirrhotic patients. Prophylactic use of vitamin K1 can effectively reduce the risk.

Cefoperazone

sulbactam

Vitamin K1

Coagulation disorder

Liver cirrhosis

Cefoperazone/sulbactam can induce or aggravate coagulation dysfunction in patients with cirrhosis.
Vitamin K1 supplementation is helpful in mitigating the coagulation abnormalities associated with cefoperazone/sulbactam in cirrhotic patients.
Risk stratification is important in identifying patients who would benefit from an intervention.

The liver plays a pivotal role in the hemostatic system by synthetizing and clearing most clotting and fibrinolytic factors [1]; therefore, liver diseases can result in hemostatic defects. Liver cirrhosis is a progressive disease that has a gradual negative impact on coagulation and fibrinolysis. Patients with decompensated liver cirrhosis are susceptible to endotoxemia, which can cause coagulation disorders [2]. Studies have found that cirrhotic patients are more likely to have abnormally prolonged prothrombin time (PT), activated partial thrombin time (aPTT), and thrombin time (TT) [3–4] when compared with non-cirrhotic patients.

Cefoperazone/sulbactam is a combination of cefoperazone and the β-lactamase inhibitor, sulbactam, used at different dosage ratios. This medication is widely used in inpatient settings to treat moderate to severe infectious diseases due to its efficacy and broad-spectrum activity [5]. Cefoperazone/sulbactam is associated with several adverse effects, such as allergic reactions, gastrointestinal reactions, and coagulation disorders which can further lead to bleeding events [6–7]. Compared with other cephalosporins, cefoperazone/sulbactam was found to have a higher risk of coagulopathy [7–8].

Patients with cirrhosis face an infection rate of 32–34%. Cefoperazone/sulbactam is recommended as the initial empirical treatment regimen for cirrhotic patients with infections [9–10]. However, the risk of coagulopathy may be underestimated. Researchers have found that the prophylactic use of vitamin K1 can improve coagulation in patients with hematopoietic stem cell transplantation [11] and in non-bleeding critically ill patients [12]. In addition, vitamin K1 can normalize most of coagulation dysfunctions, induced and aggravated by cefoperazone/sulbactam in emergency department- infected patients [13] and following long-term aspirin use [14]. So far, few data are available regarding whether the use of cefoperazone/sulbactam in cirrhotic patients further exacerbates coagulation abnormalities.This study aimed at evaluating whether cefoperazone/sulbactam use in patients with liver cirrhosis results in a drug-disease interaction that can lead to increased coagulopathy. It also addresses whether vitamin K1 supplementation during cefoperazone/sulbactam treatment of cirrhotic patients with infections could bring coagulation indexes back to normal values.

Aim

In this study, we aimed at: (1) Investigating the effect of cefoperazone/sulbactam on coagulation in cirrhotic patients,and (2) Assessing the efficacy of vitamin K1 supplementation in preventing cefoperazone/sulbactam-induced coagulation disorders

Ethics approval

The study was approved (20230601) by the Ethics Review Committee of the Second Affiliated Hospital of Nanchang University. Informed consent was not required for this study due to its anonymous and observational nature.

This retrospective observational study was performed at the Second Affiliated Hospital of Nanchang University in China from July 2018 to June 2022 and included patients with liver cirrhosis who underwent treatment with cefoperazone/sulbactam or cefoperazone/sulbactam combined with vitamin K1. The inclusion criteria for this study were as follows:

diagnosis of cirrhosis;
use cefoperazone/sulbactam and vitamin K1 for 3 consecutive days or more;
available coagulation data;
and aged 18 years or older.

Patients were excluded if they underwent surgery within the 7-day period before cefoperazone/sulbactam therapy until the end of treatment. Patients with bleeding or severe renal disease before treatment were also excluded. For patients who received multiple rounds of antibiotics, only the first round was included. The enrolled patients were divided into non-vitamin K1 group and vitamin K1 group based on whether they received supplementary vitamin K1.

For patient assessment, we collected baseline characteristics, clinical findings, and laboratory results from a retrospective review of the medical records. In addition, detailed information on the use of cephalosporin and vitamin K1(daily dose, duration of treatment, and cumulative dose) was collected. Coagulation tests were performed prior to the initial administration and after the final dose of cefoperazone/sulbactam. Coagulation indexes including PT, aPTT, TT, and platelet count (PLT), were measured utilizing standard techniques.

According to the diagnostic criteria for coagulation dysfunction and literature [7, 14], we considered that coagulation dysfunction occurs if PT, aPTT, or TT increases by 25% from the baseline value after antibiotic treatment, while PLT decrease by 25% from baseline. Bleeding events were defined as occurrences of bleeding events during cefoperazone/sulbactam therapy and within seven days after its discontinuation but not at the time of admission. These bleeding events included hematuria, abdominal wall hematoma, and upper gastrointestinal bleeding [6].

All Statistical analyses were performed using SPSS 22.0 and Python 3.7. Continuous variables were presented as means with standard error (SE). Categorical variables were expressed as counts and percentages. Baseline characteristics were compared between cohorts using the Student's t-test or Mann-Whitney U test. The propensity score matching (PSM) analysis was employed to address differences in characteristics between patients who underwent vitamin K1 supplementation and those who did not. Logistic regression analysis was conducted on the coagulation parameters of both groups. Statistical significance was considered if p < 0.05. The SHapley additive exPlanations (SHAP) values were calculated to determine the contribution of each variable to the performance of the coagulation dysfunction.

For the calculation of the sample size, the coagulation index, prothrombin time (PT), was used as the sample size estimation parameter of this experiment. According to literature [14], we assumed that the mean of PT prolongation was 2s and the standard deviation (SD) was 5s. We selected two independent population means and bilateral contrast, with a α risk of 0.05, a ß risk of 0.20, and a ratio of 1 of the number of subjects between the groups. The required sample size was calculated using independent-samples t-test formulas and the sample size was rounded to 196 patients.

The study comprised three distinct parts. Firstly, we assessed changes in the coagulation index of the cohorts before and after cefoperazone/sulbactam treatment. Secondly, we addressed potential bias in baseline characteristics using PSM analysis between patients who received vitamin K1 intervention and those who did not. Logistic regression analyses were performed for Prolonged PT and aPTT, decreased PLT, and coagulation disorders in both cohorts. Lastly, we utilized SHAP, which provides insights into data interpretation significance of each variable to compute the contribution of each variable to the prediction of coagulation dysfunction [15].

A total of 217 cirrhotic patients were eligible for inclusion criteria, with 109 non-vitamin K1 users and 108 vitamin K1 users. All patients received anti-infection treatment consisting of 3g cefoperazone/sulbactam q8h to q12h. Vitamin K1 doses ranged from 10 to 30mg, with 20 mg the most used dose (64/108, 59.3%). Patient baseline characteristics, before and after PSM, are presented in Table 1. Prior to PSM, demographics, type of infections, concomitant medications, duration of antibiotic treatment, and concomitant diseases, except for tumors, were comparable between the two groups. However, patients who received prophylactic vitamin K1 had laboratory results characterized by higher baseline levels of PT, aPTT, TT, and bilirubin compared with to those in patients without prophylaxis. After PSM, the aforementioned indicators were well balanced, resulting in 60 patients in each group.

Table 1. Baseline characteristics of patients before and after PSM

Characteristic	Before PSM		After PSM
Characteristic	Non-vitamin K1 group(n=109)	Vitamin K1 group(n=108)	Non-vitamin K1 group(n=60)	Vitamin K1group(n=60)
Sex (%)
Male	77(70.6)	77(71.3)	40(66.7)	45(75.0)
Female	32(29.4)	31(28.7)	20(33.3)	15(25.0)
Age (%)
18~44	17(15.6)	21(19.4)	10(16.7)	6(10.0)
45~64	55(50.5)	64(59.3)	36(60.0)	37(61.7)
≥65	37(33.9)	23(21.3)	14(23.3)	17(28.3)
Type of infections (%)
Intra-abdominal infection	90(82.6)	91(84.3)	48(80.0)	52(86.7)
Respiratory infections	16(14.7)	16(14.8)	12(20.0)	7(11.7)
Other	3(2.8)	1(0.9)	0(0.0)	1(1.7)
Initial laboratory results, mean±SD
Total bilirubin, umol/L	70.3±77.6	169.0±159.7**	87.0±84.4	90.7±89.5
PT,s	14.6±2.4	16.6±3.2**	15.3±2.4	15.2±2.0
aPTT,s	30.4±5.9	34.4±7.2**	31.9±6.5	31.8±5.5
TT,s	19.1±2.7	20.7±4.2**	19.4±3.1	19.5±2.8
Medical history, n (%)
Malignant tumor	39(35.8)	18(16.7)**	15(25.0)	14(23.3)
Diabetes mellitus	12(11.0)	18(16.7)	10(16.7)	11(18.3)
Hepatic encephalopathy	7(6.4)	12(11.1)	4(6.7)	5(8.3)
Concomitant medications, n (%)
Statins	19(17.4)	11(10.2)	8(13.3)	7(11.7)
Other antibiotics	12(11.0)	10(9.3)	7(11.7)	6(10.0)
PPIs	25(22.9)	36(33.3)	16(26.7)	14(23.3)
Total duration of cefoperazone/sulbactam, n (%)
3~7	74(67.9)	60(55.6)	39(65.0)	33(55.0)
7~14	27(24.8)	36(33.3)	17(28.3)	22(36.7)
＞14	8(7.3)	12(11.1)	4(6.7)	5(8.3)

Data presented as mean±SD or percentage. PT=prothrombin Time;aPTT= activated partial thromboplastin time;TT=thrombin time;PPIs =indicates proton pump inhibitors. *p < .05. **p < .01.

Based on the results presented in Table 2, no significant difference was observed in PLT and TT before and after treatment in the non-vitamin K1 group. However, the mean PT was 16.5s (SD 6.5), and the aPTT was 34.8s (SD 9.4) after cefoperazone/sulbactam treatment. These values were significantly higher than the PT of 14.6s (SD 2.4, p = 0.005) and aPTT of 30.4s (SD 5.9, p < 0.001) before cefoperazone/sulbactam treatment. In the vitamin K1 group, no statistically significant differences in PT, PLT, and TT before and after treatment, except for a slight increase in aPTT after treatment (37.0 ± 10.4s) compared with that of the pretreatment baseline measurement (34.4 ± 7.2s, p = 0.033).

Table 2

Comparison of coagulation indexes of the 2 groups of patients before and after treatment with antibiotics
Variable	Group	n	Overview	Before treatment	After treatment	T	p
PT(± SD), sec	Non-vitamin K1 group	218	15.5 ± 4.9	14.6 ± 2.4	16.5 ± 6.5	-2.866	0.005**
PT(± SD), sec	Vitamin K1 group	216	16.5 ± 3.6	16.6 ± 3.3	16.4 ± 3.9	0.427	0.670
aPTT(± SD), sec	Non-vitamin K1 group	218	32.6 ± 8.1	30.4 ± 5.9	34.8 ± 9.4	-4.149	< 0.001**
aPTT(± SD), sec	Vitamin K1 group	216	35.4 ± 9.0	34.4 ± 7.2	37.0 ± 10.4	-2.144	0.033*
TT(± SD), sec	Non-vitamin K1 group	218	18.8 ± 2.6	19.1 ± 2.7	18.5 ± 2.4	1.707	0.089
TT(± SD), sec	Vitamin K1 group	216	20.7 ± 3.9	20.7 ± 4.2	20.6 ± 3.7	0.179	0.858
PLT(± SD), 10⁹/L	Non-vitaminK1 group	218	110.6 ± 78.3	110.8 ± 74.9	110.4 ± 81.6	0.039	0.969
PLT(± SD), 10⁹/L	Vitamin K1 group	216	16.5 ± 3.6	16.6 ± 3.2	16.4 ± 3.9	0.427	0.670
Data presented as mean ± SD. PT = prothrombin Time;aPTT = activated partial thromboplastin time;TT = thrombin time;PLT = platelet. p < .05. *p < .01.

Table 3 presents an overview of the proportion of coagulation disorders within the study populations. Overall, the vitamin K1 group exhibited slightly higher rates of decreased PLT (8.3% vs. 6.4%) and TT prolongation (3.7% vs. 3.7%) compared to the non-vitamin K1 group. Conversely, the vitamin K1 group demonstrated lower proportions of PT prolongation (2.8% vs. 8.3%), aPTT prolongation (9.3% vs. 22.0%), bleeding events (0.9% vs. 6.4%), and coagulation disorders (12.9% vs. 36.7%) following cefoperazone/sulbactam treatment.

Table 3

Summary of coagulation disorders in the full cohort after treatment with antibiotics
Variable	Non-vitamin K1 group, No. (%) (n = 109)	Vitamin K1 group,No. (%) (n = 108)
PT prolongation	9(8.3)	3(2.8)
aPTT prolongation	24(22.0)	10(9.3)
TT prolongation	4(3.7)	4(3.7)
Coagulation disorders	40(36.7)	14(12.9)
Decreased in platelet count	7(6.4)	9(8.3)
Bleeding	7(6.4)	1(0.9)
Data presented as percentage. PT = prothrombin time;aPTT = activated partial thromboplastin time; TT = thrombin time

Prior to PSM for baseline characteristics, the study included 217 patients. The vitamin K1 group exhibited a decreased risk of PT prolongation (odds ratio [OR]: 0.211, 95% confidence interval [CI]: 0.047–0.678) and coagulation disorders (OR: 0.257, 95% CI: 0.126–0.499) compared with the non-vitamin K1 group. However, no significant differences in PLT (OR: 1.067, 95% CI: 0.563–2.023) and aPTT (OR: 0.485, 95% CI: 0.227–0.997) were observed between the two groups (Table 4).

Table 4

Comparison of patient coagulation markers before and after PSM
PT prolongation (OR:95%CI)		Coagulation disorders (OR:95%CI)		Decreased in PLT (OR:95%CI)		aPTT prolongation (OR:95%CI)
Before PSM	After PSM	Before PSM	After PSM	Before PSM	After PSM	Before PSM	After PSM
0.211 (0.047,0.678)	0.128 (0.007,0.754)	0.257 (0.126,0.499)	0.222 (0.076,0.575)	1.067 (0.563,2.023)	0.556 (0.204,1.438)	0.485 (0.227,0.997)	0.364 (0.109,1.056)
PT = prothrombin time;Coagulation disorders was defned as PT, aPTT, or TT increases by 25% from the baseline value after antibiotic treatment, while PLT decrease by 25% from baseline;aPTT = activated partial thromboplastin time; PSM = propensity score matching

After PSM for baseline characteristics, the cohort included 120 patients. A lower risk of PT prolongation (OR: 0.128, 95% CI: 0.007–0.754) and coagulation disorders (OR: 0.222, 95% CI: 0.076–0.575) were observed in the vitamin K1 group compared with those in the non-vitamin K1. However, no significant differences in PLT (OR: 0.556, 95% CI: 0.204–1.438) and aPTT (OR: 0.364, 95% CI: 0.109–1.056) (Table 4) were observed between the two groups. In conclusion, the pre- and post-PSM data analysis provides evidence that vitamin K1 supplementation can reduce the risk of PT prolongation and coagulation disorders induced by cefoperazone/sulbactam.

The SHAP model was utilized to determine the importance of each variable for coagulation disorders and identify the positive and negative relationships between these predictors and the target outcome [15–16]. The study involved the analysis of 217 cirrhotic patients. According to the SHAP summary plot, higher SHAP values of a feature were associated with a greater likelihood of coagulation disorders. The treatment group exhibited the strongest predictive value across all prediction horizons, closely followed by baseline aPTT, baseline TT, liver function (Child-Pugh classification), age factor, and total duration of antibiotic treatment (Fig. 2).

In this retrospective cohort study, we found potential associations between cefoperazone/sulbactam treatment and higher risks of PT prolongations, aPTT prolongations, coagulation disorders, and bleeding. However, no significant associations were observed with higher risks of decreased PLT and TT prolongations. Furthermore, the results of logistic regression analysis, performed before and after PSM in the two groups, consistently showed that vitamin K1 supplementation reduces the risks of PT prolongation and coagulation dysfunction induced by cefoperazone/sulbactam. Additionally, we documented a total of eight bleeding events, with seven occurring in the non-vitamin K1 group. These bleeding events were observed in patients with coagulation disorders, reinforcing the notion that coagulation disorders may contribute to major bleeding [6].

A retrospective study by Wu et al. also reported that cefoperazone/sulbactam causes significant prolongation of PT and aPTT but not TT in patients with long-term aspirin use. These observations can be attributed to the cefoperazone/sulbactam interference with vitamin K metabolism and synthesis, leading to the disruption in the synthesis of various vitamin K-dependent coagulation factors, while having no impact on fibrinogen synthesis and secretion. However, unlike our study, they also found that patients experienced a significant decrease in platelet count following cefoperazone/sulbactam treatment, which might be related to aspirin-induced platelet apoptosis [14]. Furthermore, the concurrent use of cefoperazone/sulbactam and aspirin might enhance the therapeutic effect of aspirin by regulating aspirin's pharmacokinetic [17].

Cefoperazone can induce hypoprothrombinemia, but the mechanism is not fully understood. Some experts proposed that the main cause is associated with cefoperazone’s N-methyltetrazolium sulfide (NMTT) side chain interfering with vitamin K1 metabolism. Two potential mechanisms have been suggested:1) it can inhibit vitamin K1-dependent gamma-carboxylation of glutamic acid, thereby inhibiting K1 epoxide reductase; and 2) because the drug is mainly excreted through the biliary tract, and therefore, can inhibit vitamin K1-producing intestinal microflora [8].However, when comparing with other cephalosporins with NMTT or even cefoperazone-tazobactam, cefoperazone/sulbactam was found to have a higher risk of coagulopathy[7–8]. This suggests that sulbactam may intensify cefoperazone’s effect on coagulation function [7]. A study on the PK/PD of cefoperazone/sulbactam in cirrhotic patients showed that the total clearance of cefoperazone was often decreased in cirrhotic patients [10], which would theoretically exacerbate vitamin K1 deficiency. Based on this pathogenic mechanism, vitamin K1 supplementation has been suggested as a resolution [18]. In the present study, the SHAP method revealed 17 predictors of coagulation dysfunction, with “drugs” identified as the most important predictor variables and vitamin K1 supplementation having a negative impact, pushing the prediction towards normal coagulation function, which further verified this hypothesis.

The Child-Pugh score is widely used to assess the severity of cirrhosis in patients [19]. In our study, the SHAP method revealed that Child-Pugh C had a positive impact and pushed the prediction towards abnormal coagulation function, which is consistent with our findings from multivariate analysis within the vitamin K1 group (Child-Pugh C: OR = 17.931, 95% CI: 1.646-342.818, P = 0.03; Supplementary Table S1). This observation aligns with previous studies, such as the one conducted by Penget al., where they observed gradual prolongation of PT and aPTT and an increase in the Child-Pugh score (P < 0.01) [3]. Additionally, Liet et al. also found that hemostatic parameters, including PT, INR, aPTT, and TT, gradually increased with the increase of Child-Pugh score [2].

In our study, the SHAP analysis revealed that the daily dose of cefoperazone/sulbactam had little predictive value for clotting abnormalities, which is consistent with our multivariate analysis results within the vitamin K1 group (T/X2 = 0.309, P = 0.579, Supplementary Table S1). This finding may be explained by the previous study of Dong Y et al., which reported no significant difference in the Cmin content of cefoperazone between the two administration regimens of 3g q8h and 3g q12h in patients with liver cirrhosis. This outcome may be related to the increase of creatinine clearance through high frequency administration [10]. On the other hand, the SHAP analysis revealed the total duration of antibiotic ranked 6th in the list of influencing factors and showed some value in predicting coagulation abnormalities.

In previous studies, various recommendations have been made regarding the dosage of vitamin K1 for prophylaxis. Wu et al. suggested a subcutaneous injection of 10 mg of vitamin K1 before each dose of cefoperazone/sulbactam, while Hunt et al. recommended a weekly dose of 10 mg for critical care patients at risk of bleeding [20]. However, none of these studies have explored the association between the drug dose of vitamin K1 and its impact on coagulation. In our study, the vitamin K1 group received daily subcutaneous injections of vitamin K1 ranging from 10 mg to 30 mg for more than 48 hours. The SHAP analysis indicated that the total duration and daily dose of vitamin K1 ranked 12th and 17th, respectively, in the list of influencing factors, suggesting limited predictive value in assessing coagulation abnormalities. Considering the potential risk of serious adverse reactions associated with higher doses of vitamin K1, such as severe allergic reactions, cardiovascular system damage, and respiratory system damage [21], we recommend a daily prophylactic dose of 10 mg of vitamin K1.

In this novel retrospective analysis, we investigated the impact of cefoperazone/sulbactam on coagulation in patients with liver cirrhosis, while also exploring the potential improvement in coagulation function through vitamin K1 prophylaxis. To mitigate the influence of confounding factors, we utilized PSM to balance baseline characteristics, resulting in 60 patients in each group. Additionally, we established an association between the daily dose and course of cefoperazone/sulbactam, vitamin K1 supplementation, and coagulation, which compensated the shortcomings of the previous study [14]. We also employed the SHAP model to ascertain the importance of each predictor variable in coagulation disorders. Despite these valuable findings, several limitations must be acknowledged. Firstly, this study was conducted at a single center, potentially limiting the generalizability of our findings. Secondly, the sample size was modest. These limitations highlight the need for future studies with larger sample sizes and a multi-center approach to bolster the robustness of our conclusions.

Our study emphasizes the frequent occurrence of coagulation dysfunction in liver cirrhosis patients treated with cefoperazone/sulbactam. Clinicians should exercise caution, particularly in patients classified as Child-Pugh C. Our investigation also identified prolonged antibiotic courses, concomitant use of anticoagulants, and diabetic complications as risk factors for cefoperazone/sulbactam-induced coagulation dysfunction. Moreover, our findings demonstrate that prophylactic vitamin K1 supplementation effectively ameliorates most of the abnormalities in blood coagulation parameters, associated with cefoperazone/sulbactam treatment in liver cirrhosis patients. Based on these results, we recommend that patients, especially those with identified risk factors, receive vitamin K1 supplementation when undergoing cefoperazone/sulbactam treatment. These measures can contribute to the management and prevention of coagulation dysfunction in cirrhosis patients.

Conflicts of interest

No conflicts of interest have been declared.

Funding

This study was supported by the Jiangxi Province Natural Science Foundation of China (Grant No. 20212BAB206054).

Acknowledgements

The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn) for the expert linguistic services provided.

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Supplementarytable1.docx

A retrospective cohort study of coagulation function in patients with liver cirrhosis receiving cefoperazone/sulbactam with and without vitamin K1 supplementation

Status:

Journal Publication

Version 1

Abstract

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Impact of findings on practice statements

Introduction

Aim

Ethics approval

Method

Results

Discussion

Conclusion

Declarations