Therapeutic effects of curcumin and piperine combination in critically ill patients with sepsis: a randomized double-blind controlled trial

Abstract

Background

Sepsis, an organ dysfunction caused by deregulated host response to infection, is a major health problem worldwide. Sepsis is associated with high rates of mortality, especially in critically ill patients. Curcumin may improve sepsis through its anti-inflammatory and antioxidant effects. This study aimed to investigate the effects of curcumin-piperine administration in critically ill septic patients.

Method

This double-blind randomized controlled trial (RCT) conducted on 66 patients with sepsis hospitalized in the intensive care unit (ICU). Patients were randomized to either the intervention group receiving two tablets of curcumin-piperine (each containing 500 mg curcuminoids and 5 mg piperine) (n = 33), or the placebo group receiving two matched tablets of placebo (n = 33) daily for 7 consecutive days along with enteral feeding. Clinical, laboratory, and biochemical indices were evaluated before and after the intervention. Statistical analyses were performed based on an intention-to-treat method.

Result

Mortality was observed in 10 patients in the curcumin-piperine group, and 12 patients in the control group. Curcumin-piperine significantly reduced bilirubin-total (P = 0.02), bilirubin-direct (P = 0.02), pH (P < 0.001), C-reactive protein (P = 0.04), erythrocyte sedimentation rate (P < 0.001), and platelet count (P = 0.01) compared with the placebo. A significantly lower reduction was found in red blood cell (P = 0.003), hemoglobin (P = 0.001), and hematocrit (P = 0.002) levels in the intervention vs. placebo group. In addition, mean corpuscular hemoglobin (P < 0.001) and mean corpuscular hemoglobin concentration (P = 0.001) were significantly higher in the intervention vs. placebo group.

Conclusion

Curcumin–piperine supplementation over a short period had beneficial effects on some inflammatory and laboratory indices in critically ill patients with sepsis.

Trial registration

IRCT20150613022681N4; available on:https://en.irct.ir/trial/52661. Registration date: 2021-01-02, 1399/10/13.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-025-08916-5.

Introduction

Sepsis is one of the major life-threatening problems worldwide. About 5.3 million deaths occur due to sepsis annually in the world. However, the real figure could be probably much higher due to scant robust data from low and middle-income countries and inconsistencies in the diagnosis and documentation of sepsis in high-income countries [1].

Sepsis is defined as “a life-threatening organ dysfunction caused by a deregulated host response to infection,” which can lead to tissue and organ damage and ultimately death [2, 3]. Sepsis is one of the main causes of death in critically ill patients admitted to the intensive care unit (ICU), and it is difficult to diagnose because of the presence of several co-morbidities and underlying diseases in these patients [3]. Following infection, the immune cells recognize infectious pathogens, which activate pro- and anti-inflammatory responses, and other immune cells like polymrphonuclear and B cells. These changes lead to the secretion of inflammatory (e.g., interleukin (IL)−1 and tumor necrosis factor (TNF)-α) and anti-inflammatory mediators which are in balance with the body’s normal response to infection. In septic patients, this balance is disturbed [4] and the concentrations of inflammatory mediators rise significantly [5–7]. Moreover, other non-immunological changes in cardiovascular, autonomic, neurological, hormonal, metabolic and clotting pathways have also been observed in the pathophysiology of sepsis [3]. Endothelial damage, tissue edema, hypotension, tissue hypo-perfusion, acute respiratory distress syndrome (ARDS), acute kidney injury, and liver dysfunction are several complications related to sepsis [4]. Management of sepsis is generally based on antibiotic therapy, source control, supportive management, and fluid resuscitation [3, 8, 9]. Despite the advances made in clinical management and treatment of sepsis, the mortality rate is still high [3]. In addition, excessive use of drugs, especially antibiotics, causes many problems and adverse effects including antibiotic resistance [10].

Turmeric, derived from Curcuma longa L. rhizomes, is a widely used spice and natural remedy around the world. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin are major polyphenolic biocomponents of turmeric, which are known as curcuminoids [11]. Curcumin has been shown to possess anti-inflammatory, antioxidant, anti-carcinogenic, anti-diabetic, antibacterial, antiprotozoal, anti-fibrotic, immunomodulatory, anti-pneumonia, anti-septic, antiviral, antifungal, and neuroprotective properties [12–24]. The anti-inflammatory properties of curcumin are exerted through modulation of inflammatory signaling pathways like nuclear factor kappa (NF-kB), activator protein (AP)−1, and Janus kinase/signal transducer and activator of transcription (JAK/STAT), among others [25–28]. Evidences from experimental studies have shown that curcumin can down-regulate the inflammatory transcription factors, cytokines, status of redox, protein kinase, and inflammatory enzymes [26–29]. Results of a systematic review of preclinical studies demonstrated that curcumin has protective effects against inflammation, oxidative stress, and coagulation in sepsis [30, 31]. It has been shown that curcumin is generally safe and tolerable even at doses up to a 8 g per day [32]. However, it has a low oral bioavailability due to low absorption, rapid metabolism, and systemic degradation, which may lead to the attenuation of its therapeutic effects [33]. One of the effective approaches to solve this problem is the use of curcumin in combination with piperine (an alkaloid found in black pepper) as an absorption-enhancing adjuvant. Piperine has been reported to reduce the glucuronidation of curcumin and enhance its bioavailability [33, 34]. In this randomized controlled trial, the effects of curcumin-piperine supplementation in septic patients admitted to ICU were explored.

Materials and methods

According to the approval code “IR.MUI.MED.REC.1399.759,” the research assistant of Isfahan University of Medical Sciences (Biomedical Research Ethics Committee) has supervised and approved the present study. To ensure accuracy, audits were conducted twice during the trial.

All patients or their legal guardians (if the patients were not conscious) gave written informed consent before entering the study. Declaration of Helsinki principles is considered in this study [35]. The protocol of this trial was registered and is available at https://en.irct.ir/trial/52661 (ID: IRCT20150613022681N4).

Trial design

The present study was a double-blind randomized controlled clinical trial that was conducted in the Intensive Care Unit (ICU) of Al-Zahra Hospital, Isfahan, Iran from Feb 2021 to May 2022.

Participants

Inclusion criteria

Patients aged 20–75 years with sepsis hospitalized in the ICU of Al-Zahra Hospital, Isfahan, Iran, who had a normally functioning digestive system and criteria for enteral nutrition, were included in the study. A definitive diagnosis of sepsis was made based on blood culture and confirmation by an ICU expert anesthesiologist and infectious disease expert.

Exclusion criteria

The exclusion criteria included, Patients with BMI <18.5 kg/m²,Inability to receive enteral nutrition in the first 48 h of admission or it was predicted that they would not be able to receive enteral nutrition in the future, history of underlying diseases such as heart disease, diabetes, congenital and immune disorders, kidney and liver failure, and pancreatitis, Patients who were hospitalized in the ICU for less than 48 h and Patients with septic shock or severe sepsis who were expected to die within 12 h after being admitted to the ICU were other exclusion criteria. Patients taking anticoagulants such as heparin, warfarin, aspirin, etc., Pregnant and breastfeeding women, lack of consent of the patient or his legal guardian were also excluded from the trial. Frequent blood collection in patients, creation of infectious processes, diffuse intravascular coagulation [35], and any inflammatory interactions that interfered with the intervention process were other criteria for exclusion. Also, if any side effect was observed after taking the supplement or placebo, the patient was excluded from the study.

After hemodynamic stabilization and resuscitation, the patients were fed enterally using the bolus method for 25 kcal/kg of energy seven times within 24 h (every 3 h from 6:00 to 24:00) when they entered the study.

Interventions

In the intervention group, 2 tablets of curcumin piperine (each tablet contains 500 mg of curcumin and 5 mg of piperine), and in the placebo group, 2 placebo tablets (each tablet contains 500 mg of maltodextrin) daily for 7 consecutive days at 9:00 and 21:00 along with enteral nutrition were received. Tablets were manufactured by Sami-Sabinsa Group Limited (Bangalore, India) labeled A and B for blinding patients and researchers.

All patients received their other usual treatments, and those participating in the present study were only receiving adjuvant treatment.

Sample size

The sample size was calculated by considering the first type error α=0.05 and the second type error β=0.20 with the test power of 80% and the standardized effect size equal to Δ=3 from the following formula based on the CRP index [36]:

$$n=2\left[{\left(Z_{1-a/2},+,Z,1,-,\beta \right)}^2,\times ,S^2\right]/▵2=2\left[{\left(1.96,+,0.84\right)}^2,\times ,{\left(4\right)}^2\right]/{\left(3\right)}^2$$

The sample size in each group was 27 patients. Taking into account the dropout of patients, we considered 33 patients in each group.

Randomization and blinding

After obtaining informed consent from the patients, the randomization process was promptly carried out. Patients were randomized into one of two groups, receiving either curcumin-piperine or placebo, using a block size of four. This process accounted for patients’ age and gender and followed a 1:1 ratio. The randomization was performed through an online random number generator available at the website “https://www.sealedenvelope.com/simple-randomiser/v1/lists”.

The assignment sequences were prepared by an independent statistician, who securely stored them in sealed, opaque envelopes. These envelopes remained unopened until the eligibility criteria for participants were assessed. Throughout the study, both researchers and patients were blinded to the group assignments, ensuring the integrity of the trial until the data analysis was completed.

The patients were randomly assigned to each group, and researchers and patients (or the legal guardians of the patient) were blinded to the study groups. The intervention and placebo tablets were produced by the manufacturer in the same way in terms of shape, color, and smell and were labeled A and B, and their type was not known to the researchers and patients until the final analysis. Therefore, the present study was carried out using a double-blind method.

Outcomes

Primary outcomes

The primary outcomes included clinical variables, C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels.

Clinical parameters such as disease severity were assessed by Acute Physiology and Chronic Health Evaluation II (APACHE II), Nutrition Risk in the Critically Ill (NUTRIC) Score, Sequential Organ Failure Assessment (SOFA) score, and Glasgow Coma Scale/Score (GCS). Other clinical variables investigated included fluid intake, fluid output, and temp.

By following up with patients after the intervention and calling their families, the 28-day mortality rate was collected.

Secondary outcomes

The Chumlea I formula [37] was used to calculate weight and Tarnowski et al.'s equation [38] was used to calculate height, because of limitations in the ICU.

At the beginning and end of the study, five milliliters of blood samples were collected from the patients. The samples were centrifuged, and their serum was separated. Then the serum samples were frozen and stored at − 80 °C.

Laboratory factors including blood urea nitrogen (BUN), serum creatinine (Cr), aspartate aminotransferase [37], alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin-total (BIL-T), bilirubin-direct (BIL-D), albumin, pH, CO₂ pressure, O₂ pressure, BE, O₂ pressure of arterial blood (Po2sat), HCO₃, erythrocyte sedimentation rate (ESR), triglyceride, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), blood glucose (BG), systolic and diastolic blood pressure, sodium, potassium, phosphorus, magnesium, chlorine, and calcium were investigated as the secondary factors.

The investigated blood factors include white blood cell count (WBC), neutrophil, lymphocyte, red blood cell (RBC), hemoglobin, hematocrit, platelet, prothrombin time [32], partial thromboplastin time (PTT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean cell hemoglobin concentration (MCHC).

All clinical, laboratory, and blood variables were examined at the beginning and end of the study (7 days after supplementation).

All measurements were carried out at the Al-Zahra Hospital’s laboratory as a routine evaluation using standard kits.

Statistical methods

The intention-to-treat (ITT) principle was used to impute missing values, which were performed in all statistical analyses. SPSS software version 21 and Stata software were used for analysis. To evaluate the normal distribution of variables, the use of the skewness test and Q-Q plot was employed. Mean (standard deviation (SD)) and number (percentage) were the reporting methods used for quantitative and qualitative variables, respectively. The independent-sample t-test and Pearson’s chi-square test were utilized for comparing baseline characteristics of participants among groups when applicable. To determine any differences between the two groups and adjust for baseline values, ANCOVA (analysis of covariance) was utilized. Variables with abnormal distributions were treated using the logarithmic transformation approach. Significance was determined with a p-value < 0.05.

Results

Participants characteristics

The inclusion and exclusion criteria were assessed for 186 patients in all. Among them, 66 patients met the necessary criteria and were included in the study. A total of 33 patients enrolled in the intervention group, and 33 patients participated in the placebo group. In the intervention group, 10 patients, and in the control group, 12 patients died. However, using the ITT method, the analysis was conducted on 66 patients (Fig. 1).

Fig. 1.

CONSORT study flow diagram

The average age of patients in the intervention group was 51.66 ± 19.48 and the placebo group was 61.21 ± 21.52, and there was no significant difference between the two groups (p = 0.06). In terms of gender, there was no significant difference between groups (p = 0.61). As shown in Table 1, at baseline, there was no significant difference between the two groups in other parameters including weight, and calf circumference (Table 1).

Table 1.

Comparison of baseline characteristics between the intervention group (curcumin-piperine) and control group (placebo)

Variables	intervention group (N: 33)	Placebo group (N: 33)	P-value*
Age, years	51.66 ± 19.48	61.21 ± 21.52	0.06
Female, n (%)	15 (45.5%)	13 (39.4%)	0.61
Exp	10 (30.3%)	12 (36.4%)	0.60
Weight (kg)	74.09 ± 12.39	76.57 ± 10.56	0.38
Calf circumference (cm)	32.16 ± 4.84	30.95 ± 5.34	0.33

Data are shown as means ± standard deviation or frequencies (percentage)

^*P-values were obtained from the chi-square (χ²) test or independent sample T-test

The effects of curcumin-piperine on clinical variables

None of the clinical factors including APACHE II, NUTRIC, SOFA, GCS, fluid intake, fluid output, and temp had significant changes in the comparison between groups.

Fluid intake in the curcumin-piperine group was significantly reduced compared to baseline (− 340.28 ± 916.56; P-value: 0.04). Also, a significant decrease in fluid output was observed in the intervention group compared to the baseline (− 441.01 ± 863.95; P-value: 0.006).

In addition, there was a significant decrease in Temp in the intervention group compared to the baseline (− 0.26 ± 0.56; P-value: 0.01) (Table 2).

Table 2.

Monitoring clinical variables in the intervention group (curcumin-piperine) and control group (placebo) at baseline and end of the trial (day 7)

Variables	Group	Before intervention	After intervention	P-value**	Mean changes	Mean difference ± SE (95% confidence interval for difference)	p-valuea
APACHE II	Curcumin	14.75 ± 4.67	14.90 ± 4.93	0.78	0.14 ± 2.98	− 1.01 ± 0.78 (− 2.58,0.54)	0.19
	Placebo	17.72 ± 5.03	18.45 ± 5.25	0.16	0.72 ± 2.95
	P-value*	0.01	0.006	-	-
NUTRIC	Curcumin	4.09 ± 1.64	4.06 ± 1.75	0.86	− 0.02 ± 0.77	− 0.14 ± 0.21 (− 0.57, 0.27)	0.49
	Placebo	5.03 ± 1.70	5.09 ± 1.75	0.67	0.06 ± 0.82
	P-value	0.02	0.02	-	-
SOFA	Curcumin	5.87 ± 2.30	6.08 ± 2.77	0.48	0.20 ± 1.70	− 0.32 ± 0.41 (− 1.15, 0.50)	0.43
	Placebo	6.21 ± 2.04	6.67 ± 1.99	0.08	0.46 ± 1.47
	P-value	0.53	0.58	-	-
GCS	Curcumin	10.48 ± 3.28	9.89 ± 3.40	0.17	− 0.58 ± 2.40	0.16 ± 0.51 (− 0.85, 1.18)	0.74
	Placebo	8.93 ± 3.43	8.42 ± 3.49	0.05	− 0.51 ± 1.48
	P-value	0.06	0.08	-	-
Fluid intake	Curcumin	3246.66 ± 1119.78	2906.38 ± 1084.500	0.04	− 340.28 ± 916.56	− 127.22 ± 203.51 (− 534.35, 280.11)	0.53
	Placebo	3035.90 ± 935.87	2893.98 ± 906.40	0.31	− 141.92 ± 793.44
	P-value	0.41	0.96	-	-
Fluid output	Curcumin	2603.32 ± 1292.94	2162.31 ± 711.29	0.006	− 441.01 ± 863.95	− 369.02 ± 193.98 (− 757.18, 19.14)	0.06
	Placebo	2766.42 ± 1213.74	2534.50 ± 977.20	0.28	− 231.91 ± 1234.60
	P-value	0.59	0.08	-	-
Temp	Curcumin	37.63 ± 0.72	37.36 ± 0.50	0.01	− 0.26 ± 0.56	− 0.09 ± 0.14 (− 0.38, 0.18)	0.49
	Placebo	37.10 ± 0.90	37.31 ± 0.58	0.20	0.21 ± 0.96
	P-value	0.01	0.74	-	-

Data are shown as means ± standard deviation

Abbreviations APACHE II Acute Physiology and Chronic Health Evaluation II, NUTRIC Nutrition Risk in Critically Ill, SOFA Sequential Organ Failure Assessment, GCS Glasgow Coma Scale

^*P-values were obtained from independent sample T-test

**paired-sample T-test, and

^aanalysis of covariance (ANCOVA) with the adjustment for baseline values

The effects of curcumin-piperine on laboratory variables

In addition, the between-group analysis indicated that differences between the curcumin piperine group and control group were significant for CRP (− 17.48 ± 27.21 vs. − 1.49 ± 39.83; P-value: 0.04) and ESR (− 34.29 ± 37.36 vs. − 2.02 ± 34.76; P-value: < 0.001) with mean differences ± SE (95% CI for difference) being − 13.12 ± 6.49 (− 26.11, − 0.12) and − 27.91 ± 7.50 (− 42.93, − 12.89), respectively. The CRP and ESR levels decreased by 30.81% and 40.36% in the intervention group, compared to decreases of 3.15% and 2.71% in the control group, resulting in a 27.66% and 37.65% greater reduction in the intervention group, respectively.

Changes in BIL-T (− 0.23 ± 1.06 vs. 0.05 ± 0.16; P-value: 0.02) and BIL-D (− 0.12 ± 0.66 vs. 0.02 ± 0.07; P-value: 0.02) were significant compared to placebo, with mean differences ± SE (95% CI for difference) for BIL-T and BIL-D being − 0.11 ± 0.04 (− 0.20, − 0.01) and − 0.04 ± 0.01 (− 0.08, − 0.005), respectively. Changes in pH were significant compared with placebo (−0.001 ± 0.08 vs. 0.23 ± 0.20; P-value: < 0.001).

Other laboratory factors including BUN, creatinine, AST, ALT, ALP, LDH, albumin, CO₂ pressure, O₂ pressure, BE, O₂ pressure of arterial blood, HCO₃, triglyceride, cholesterol, HDL, LDL, BG, systolic and diastolic blood pressure, sodium, potassium, phosphorus, magnesium, chlorine, and calcium did not change significantly compared to the placebo (Table 3).

Table 3.

Monitoring laboratory variables in the intervention group (curcumin-piperine) and control group (placebo) at baseline and end of the trial (day 7)

Variables	Group	Before intervention	After intervention	P-value**	Mean changes	Mean difference ± SE (95% confidence interval for difference)	P-valuea
BUN	Curcumin	21.90 ± 11.02	20.74 ± 11.47	0.26	− 1.16 ± 5.94	− 0.84 ± 1.97 (− 4.8, 3.10)	0.66
	Placebo	23.66 ± 12.93	22.75 ± 10.86	0.60	− 0.91 ± 10.14
	P-value*	0.55	0.46	-	-
Cr	Curcumin	1.29 ± 1.24	1.29 ± 1.36	0.93	− 0.002 ± 0.19	− 0.08 ± 0.07 (− 0.23, 0.07)	0.29
	Placebo	1.10 ± 0.65	1.16 ± 0.82	0.42	0.05 ± 0.39
	P-value	0.45	0.64	-	-
AST	Curcumin	56.84 ± 117.60	45.29 ± 54.28	0.50	− 11.55 ± 98.54	9.93 ± 9.75 (− 9.57, 29.44)	0.31
	Placebo	52.90 ± 73.00	34.96 ± 32.38	0.09	− 17.94 ± 59.41
	P-value	0.87	0.35	-	-
ALT	Curcumin	29.54 ± 22.34	30.13 ± 18.91	0.80	0.58 ± 13.40	− 17.04 ± 22.02 (− 61.11, 27.02)	0.44
	Placebo	58.93 ± 107.56	67.08 ± 138.41	0.69	8.14 ± 119.35
	P-value	0.13	0.13	-	-
ALP	Curcumin	216.28 ± 104.62	198.50 ± 75.55	0.05	− 17.78 ± 50.93	− 11.29 ± 15.07 (− 41.45, 18.87)	0.45
	Placebo	276.69 ± 197.53	251.91 ± 160.06	0.12	− 24.77 ± 89.20
	P-value	0.12	0.0.09	-	-
BIL-T	Curcumin	1.15 ± 2.69	0.92 ± 1.65	0.22	− 0.23 ± 1.06	− 0.11 ± 0.04 (− 0.20, − 0.01)	0.02
	Placebo	0.69 ± 0.24	0.74 ± 0.29	0.09	0.05 ± 0.16
	P-value	0.33	0.54	-	-
BIL-D	Curcumin	0.51 ± 1.54	0.38 ± 0.88	0.28	− 0.12 ± 0.66	− 0.04 ± 0.01 (− 0.08, − 0.005)	0.02
	Placebo	0.26 ± 0.09	0.28 ± 0.10	0.11	0.02 ± 0.07
	P-value	0.35	0.50	-	-
LDH	Curcumin	560.40 ± 142.16	503.70 ± 122.92	< 0.001	− 56.70 ± 81.17	− 55.01 ± 31.17 (− 117.39, 7.36)	0.08
	Placebo	520.43 ± 198.93	526.70 ± 208.14	0.82	6.26 ± 160.11
	P-value	0.35	0.58	-	-
Alb	Curcumin	2.89 ± 0.61	2.93 ± 0.69	0.58	0.04 ± 0.42	0.17 ± 0.10 (− 0.03, 0.37	0.10
	Placebo	2.63 ± 0.47	2.56 ± 0.46	0.28	− 0.06 ± 0.36
	P-value	0.05	0.01	-	-
pH	Curcumin	7.40 ± 0.07	7.40 ± 0.08	0.93	− 0.001 ± 0.08	− 0.27 ± 0.03 (− 0.34, − 0.19)	< 0.001
	Placebo	7.43 ± 0.06	7.66 ± 0.18	< 0.001	0.23 ± 0.20
	P-value	0.17	< 0.001	-	-
pCO2	Curcumin	41.36 ± 13.41	41.44 ± 6.64	0.97	0.08 ± 13.17	− 0.92 ± 2.10 (− 5.13, 3.28)	0.66
	Placebo	41.14 ± 11.45	42.24 ± 10.92	0.50	1.09 ± 9.22
	P-value	0.94	0.72	-	-
Po2	Curcumin	77.59 ± 31.95	80.24 ± 29.29	0.68	2.65 ± 37.53	− 6.52 ± 6.63 (− 19.79, 6.75)	0.33
	Placebo	76.81 ± 22.85	86.15 ± 21.78	0.06	9.34 ± 27.55
	P-value	0.90	0.35	-	-
BE	Curcumin	0.39 ± 5.91	0.29 ± 4.94	0.92	− 0.10 ± 6.30	− 0.66 ± 1.14 (− 2.94, 1.61)	0.56
	Placebo	2.37 ± 7.99	1.65 ± 5.08	0.49	− 0.72 ± 5.90
	P-value	0.25	0.27	-	-
Po2sat	Curcumin	88.85 ± 13.20	88.13 ± 9.82	0.62	− 0.72 ± 8.47	− 2.37 ± 1.83 (− 6.03, 1.28)	0.2
	Placebo	89.37 ± 14.22	90.71 ± 13.38	0.32	1.33 ± 7.68
	P-value	0.87	0.37	-	-
HCO3	Curcumin	23.69 ± 6.79	23.75 ± 5.90	0.94	0.06 ± 5.51	− 0.84 ± 1.09 (− 3.04,1.35)	0.44
	Placebo	25.14 ± 7.71	25.38 ± 5.84	0.77	0.24 ± 4.80
	P-value	0.42	0.26	-	-
CRP	Curcumin	56.73 ± 34.61	39.25 ± 19.29	0.001	− 17.48 ± 27.21	− 13.12 ± 6.49 (− 26.11, − 0.12)	0.04
	Placebo	50.45 ± 43.38	48.86 ± 35.90	0.83	− 1.49 ± 39.83
	P-value	0.51	0.17	-	-
ESR	Curcumin	84.96 ± 41.65	50.67 ± 26.54	< 0.001	− 34.29 ± 37.36	− 27.91 ± 7.5 (− 42.93, − 12.89)	< 0.001
	Placebo	74.30 ± 37.69	72.28 ± 38.79	0.74	− 2.02 ± 34.76
	P-value	0.28	0.01	-	-
TG	Curcumin	130.90 ± 48.22	124.89 ± 36.88	0.22	− 6.01 ± 27.92	− 21.14 ± 12.59 (− 46.34, 4.05)	0.09
	Placebo	143.63 ± 50.39	154.48 ± 77.35	0.32	10.84 ± 62.64
	P-value	0.29	0.05	-	-
CHOL	Curcumin	125.42 ± 38.26	119.92 ± 39.49	0.01	− 5.50 ± 12.58	− 3.77 ± 5.64 (− 15.07, 7.52)	0.50
	Placebo	123.48 ± 47.85	121.74 ± 48.09	0.72	− 1.74 ± 28.25
	P-value	0.85	0.86	-	-
HDL	Curcumin	33.12 ± 9.62	32.12 ± 6.47	0.23	− 0.99 ± 4.76	− 0.65 ± 1.37 (− 3.41, 2.10)	0.63
	Placebo	32.84 ± 11.14	32.56 ± 9.00	0.84	− 0.27 ± 8.29
	P-value	0.91	0.81	-	-
LDL	Curcumin	61.03 ± 21.33	57.47 ± 21.30	0.03	− 3.55 ± 9.21	− 0.23 ± 3.91 (− 8.07, 7.60)	0.95
	Placebo	67.36 ± 29.43	63.46 ± 32.76	0.24	− 3.90 ± 18.85
	P-value	0.32	0.38	-	-
BS	Curcumin	143.24 ± 68.50	124.45 ± 42.35	0.01	− 18.78 ± 41.15	5.47 ± 7.96 (− 10.45, 21.41)	0.49
	Placebo	130.39 ± 41.72	113.39 ± 36.76	0.03	− 16.99 ± 44.99
	P-value	0.36	0.26	-	-
SBP	Curcumin	129.31 ± 15.86	124.52 ± 12.40	0.02	− 4.79 ± 11.81	1.03 ± 3.69 (− 6.35, 8.41)	0.78
	Placebo	127.50 ± 25.79	123.20 ± 16.37	0.40	− 4.29 ± 29.07
	P-value	0.73	0.71	-	-
DBP	Curcumin	76.42 ± 12.38	73.61 ± 9.61	0.18	− 2.80 ± 11.79	1.66 ± 2.68 (− 3.71, 7.04)	0.53
	Placebo	79.42 ± 13.19	73.31 ± 13.05	0.01	− 6.10 ± 13.19
	P-value	0.34	0.91	-	-
Na	Curcumin	139.51 ± 3.16	137.54 ± 2.89	0.008	− 1.96 ± 4.01	− 1.08 ± 0.95 (− 2.99, 0.81)	0.25
	Placebo	139.81 ± 4.61	138.66 ± 4.49	0.19	− 1.15 ± 5.05
	P-value	0.75	0.23	-	-
K	Curcumin	4.03 ± 0.51	3.99 ± 0.51	0.68	− 0.03 ± 0.43	− 10.37 ± 9.64 (− 29.68, 8.93)	0.28
	Placebo	3.97 ± 0.52	4.08 ± 0.51	0.23	0.11 ± 0.54
	P-value	0.65	0.48	-	-
Ph	Curcumin	2.70 ± 0.85	2.59 ± 0.86	0.20	− 0.10 ± 0.47	− 0.17 ± 0.13 (− 0.43, 0.09)	0.20
	Placebo	2.63 ± 0.53	2.69 ± 0.69	0.51	0.05 ± 0.52
	P-value	0.69	0.60	-	-
Mg	Curcumin	1.76 ± 0.28	1.96 ± 0.18	< 0.001	0.19 ± 0.27	0.06 ± 0.04 (− 0.02, 0.15)	0.18
	Placebo	1.98 ± 0.32	1.94 ± 0.15	0.51	− 0.03 ± 0.31
	P-value	0.006	0.66	-	-
Cl	Curcumin	107.39 ± 5.43	106.72 ± 3.90	0.54	− 0.66 ± 6.18	− 0.25 ± 1.27 (− 2.80, 2.28)	0.84
	Placebo	107.00 ± 7.02	106.84 ± 6.22	0.89	− 0.15 ± 6.66
	P-value	0.8	0.92	-	-
Ca	Curcumin	8.01 ± 0.81	8.10 ± 0.77	0.42	0.08 ± 0.62	0.22 ± 0.12 (− 0.03, 0.47)	0.08
	Placebo	8.24 ± 0.65	8.03 ± 0.50	0.01	− 0.21 ± 0.47
	P-value	0.19	0.69	-	-

Data are shown as means ± standard deviation

Abbreviations CBC complete blood count, K potassium, Ca calcium, Na sodium, Mg magnesium, ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, BG blood glucose, ALB albumin, BUN blood urea nitrogen, Cr serum creatinine, BIL-T bilirubin total, BIL-D bilirubin direct, LDH lactate dehydrogenase, CRP C-reactive protein

^*P-values were obtained from independent sample T-test

**paired-sample T-test, and

^aanalysis of covariance (ANCOVA) with the adjustment for baseline values

The effects of curcumin-piperine on blood variables

A significant lower reduction was found in RBC (− 0.08 ± 0.43 vs. − 0.23 ± 0.48; P-value: 0.003), Hb (− 0.33 ± 1.41 vs. − 0.78 ± 1.49; P-value: 0.001) and Hct (− 0.90 ± 3.57 vs. − 1.88 ± 4.38; P-value: 0.002) levels in the intervention group in comparison to the placebo group, with mean differences ± SE (95% CI for difference) being 0.26 ± 0.08 (0.09, 0.44), 0.90 ± 0.27 (0.36, 1.44), and 2.21 ± 0.69 (0.81, 3.60). respectively.

Also, a significant increase was observed in the two factors MCH (0.63 ± 1.66 vs. − 0.46 ± 1.35; P-value: < 0.001) and MCHC (0.48 ± 1.76 vs. − 9.39 ± 50.14; P-value: 0.001) compared to placebo, with mean differences ± SE (95% CI for difference) being 1.39 ± 0.34 (0.71, 2.07) and 1.74 ± 0.49 (0.75, 2.74), respectively.

Compared to the control group, the curcumin-piperine group showed a decrease in platelet levels (− 27,510.11 ± 84,490.48 vs. 45,002.73 ± 132,978.48; P-value: 0.01) with mean differences ± SE (95% CI for difference) − 59,378.63 ± 23,910.37 (− 107,223.18, − 11,534.09). However, there were no significant changes in other blood variables when compared to the placebo (Table 4).

Table 4.

Monitoring blood variables in the intervention group (curcumin-piperine) and control group (placebo) at baseline and end of the trial (day 7)

Variables	Group	Before intervention	After intervention	P-value**	Mean changes	Mean difference ± SE (95% confidence interval for difference)	P-valuea
WBC	Curcumin	8169.09 ± 4470.82	8043.86 ± 3598.57	0.85	− 125.22 ± 3835.78	289.32 ± 860.39 (− 1432.31, 2010.96)	0.73
	Placebo	8779.69 ± 5758.32	8134.50 ± 5180.84	0.34	− 645.19 ± 3891.95
	P-value*	0.63	0.93	-	-
Neutrophil	Curcumin	74.04 ± 10.83	75.23 ± 11.33	0.55	1.19 ± 11.48	1.66 ± 2.76 (− 3.86, 7.19)	0.54
	Placebo	75.83 ± 13.87	75.03 ± 16.39	0.65	− 0.79 ± 10.12
	P-value	0.56	0.95	-	-
Lymphocyte	Curcumin	15.74 ± 7.90	15.68 ± 9.71	0.97	− 0.06 ± 9.47	− 3.33 ± 3.66 (− 10.66, 3.98)	0.36
	Placebo	19.41 ± 13.83	18.61 ± 16.75	0.72	− 0.79 ± 12.75
	P-value	0.19	0.38	-	-
RBC	Curcumin	3.62 ± 0.53	3.53 ± 0.35	0.24	− 0.08 ± 0.43	0.26 ± 0.08 (0.09, 0.44)	0.003
	Placebo	3.43 ± 0.58	3.20 ± 0.44	0.01	− 0.23 ± 0.48
	P-value	0.16	0.001	-	-
Hb	Curcumin	10.89 ± 2.04	10.55 ± 1.28	0.18	− 0.33 ± 1.41	0.90 ± 0.27 (0.36, 1.44)	0.001
	Placebo	10.13 ± 1.77	9.35 ± 1.39	0.005	− 0.78 ± 1.49
	P-value	0.11	0.001	-	-
Hct	Curcumin	32.92 ± 5.40	32.02 ± 3.19	0.15	− 0.90 ± 3.57	2.21 ± 0.69 (0.81, 3.60)	0.002
	Placebo	30.97 ± 5.30	29.08 ± 3.78	0.01	− 1.88 ± 4.38
	P-value	0.14	0.001	-	-
MCV	Curcumin	87.08 ± 13.49	88.23 ± 4.46	0.54	1.15 ± 10.85	0.40 ± 0.84 (− 1.27, 2.08)	0.63
	Placebo	88.31 ± 4.12	88.19 ± 3.91	0.78	− 0.12 ± 2.62
	P-value	0.61	0.96	-	-
MCH	Curcumin	29.44 ± 2.54	30.08 ± 2.13	0.03	0.63 ± 1.66	1.39 ± 0.34 (0.71, 2.07)	< 0.001
	Placebo	28.82 ± 2.18	28.36 ± 1.89	0.05	− 0.46 ± 1.35
	P-value	0.19	< 0.001	-	-
MCHC	Curcumin	32.86 ± 1.56	33.34 ± 1.42	0.12	0.48 ± 1.76	1.74 ± 0.49 (0.75, 2.74)	0.001
	Placebo	41.12 ± 50.25	31.73 ± 2.25	0.29	− 9.39 ± 50.14
	P-value	0.34	0.001	-	-
PLT	Curcumin	241,030.30 ± 118,041.43	213,520.19 ± 100,796.42	0.07	− 27,510.11 ± 84,490.48	− 59,378.63 ± 23,910.37 (− 107,223.18, − 11,534.09)	0.01
	Placebo	209,212.12 ± 109,426.27	254,214.85 ± 97,418.58	0.06	45,002.73 ± 132,978.48
	P-value	0.26	0.1	-	-
PT	Curcumin	15.91 ± 1.89	15.42 ± 1.88	0.05	− 0.48 ± 1.38	0.23 ± 0.33 (− 0.43, 0.91)	0.48
	Placebo	14.53 ± 4.30	14.31 ± 2.95	0.54	− 0.21 ± 2.01
	P-value	0.09	0.07	-	-
PTT	Curcumin	42.51 ± 12.91	40.01 ± 7.07	0.14	− 2.49 ± 9.61	− 3.77 ± 2.59 (− 8.97, 1.43)	0.15
	Placebo	39.61 ± 15.64	41.56 ± 18.33	0.34	1.94 ± 11.79
	P-value	0.41	0.65	-	-

Data are shown as means ± standard deviation

Abbreviations WBC white blood cell count, RBC red blood cell, PLT platelet, Hb hemoglobin, Hct hematocrit, PT prothrombin time, PTT partial thromboplastin time

^*P-values were obtained from independent sample T-test

**paired-sample T-test, and

^aanalysis of covariance (ANCOVA) with the adjustment for baseline values

No adverse events were observed in none of the groups, and both curcumin, piperine, and placebo tablets were safe (Table 4).

Discussion

To the best of our knowledge, only scant data is available on the effects of curcumin–piperine supplements on monitoring laboratory variables and clinical outcomes in critically ill patients with sepsis. In this trial, 66 patients were randomized, and all completed the trial and were included in the analyses. After 7 days of taking 1000 mg/day curcuminoids plus 10 mg piperine supplements in this trial, the patients experienced a significant change in laboratory variables including CRP and ESR, BIL, and pH (Fig. 2). However, this supplement no significant difference was observed in clinical variables, including APACHE II, NUTRIC, SOFA, GCS, fluid intake and output, and temperature, between the studied groups.

Fig. 2.

Effects of curcumin-piperine supplementation in ICU patients with sepsis in the present study

Consistent with our findings, several prior studies have demonstrated the anti-inflammatory properties of curcuminoids [30]. A recent systematic review and meta-analysis of 13 randomized controlled trials (involving 785 participants) with intervention durations ranging from 4 to 12 weeks revealed that curcuminoids supplementation significantly improved inflammatory markers (TNF-α and CRP) levels [39]. In a similar meta-analysis conducted on 15 RCTs, supplementation with curcuminoids significantly decreased the levels of hs-CRP and IL-6 in patients diagnosed with metabolic syndrome, type 2 diabetes mellitus, hyperlipidemia, and obesity [40]. In a RCT, 160 mg/day nano-curcumin supplementation for 10 days significantly decreased ESR and IL-8 in sepsis patients [41]. Another recent RCT found that curcumin-piperine supplementation significantly decreased CRP in COVID-19 patients admitted to the ICU at the same dose used in this study [42]. Furthermore, in contrast to earlier studies, Silva et al. [43] reported that curcumin supplementation (1000 mg/day for 1 month) did not significantly improve the inflammatory and oxidative stress indices in HIV-infected patients. Systemic inflammation, a contributing factor in sepsis, is accompanied by the production of a wide range of pro-inflammatory cytokines [44, 45]. Curcuminoids can regulate the production of pro-inflammatory cytokines through several suggested mechanisms. Studies have demonstrated that reducing LPS-induced inflammation can be achieved by inhibiting the phosphorylation of inhibitory-κB kinase (IKKs), Akt, and c-Jun N-terminal kinase (JNK), KBa (IkBa), NF-κB, and p38 mitogen-activated protein kinase pathways. Curcumin prevents NF-κB activation by preventing IκB phosphorylation and nuclear translocation. This phytochemical can also bind to the TNF-α receptor, thereby reducing TNF-α’s inflammatory effects [30, 46–48].

In the current study, temperature was significantly decreased in the intervention group compared to the baseline after 7 days of intervention. Our findings are consistent with the results obtained by Feng et al. [49], who reported that curcumin supplementation significantly reduced PRV infection-induced body temperature, slow growth, and microglial activation in rats after 24 h of infection.

In this study, no significant difference in the APACHE II and NUTRIC scores between the groups, though a significant reduction in these scores was observed in the intervention group. It appears that improved APACHE II components and decreased inflammatory biomarkers (IL-6 and TNF-α) following curcumin supplementation might have significantly reduced APACHE II and NUTRIC scores. Consistent with our findings, a recent clinical trial found that the APACHE Il score did not change between the study groups after 10 days of nano-curcumin supplementation in ICU-admitted patients with sepsis [41]. On the contrary, Zahedi et al. found that APACHE II and NUTRIC scores were significantly improved following curcuminoids supplementation (500 mg/day for 7 days) compared with placebo in critically ill patients with traumatic brain injury. In contrast to this research, one study found that a 10-day intervention with 160 mg of nano-curcumin administered via a nasogastric tube twice a day significantly improved the SOFA score in critically sepsis patients with sepsis [41].

In the current study, curcumin-piperine supplementation significantly increased RBC, Hb, Hct, MCH, and MCHC, while significantly reducing platelet count compared with the placebo group. Previous clinical research has indicated that hematological parameters have a significant impact on the prognosis of patients with sepsis. In addition, in a study by Panahi et al. [50], curcumin (500 mg per 12 h) was used for 9 weeks in cancer patients. The results did not show any significant difference between the groups at the end of the trial. However, during the trial, significant differences were observed in Hb and HCT. In cases of sepsis, platelet count serves as a valuable diagnostic and prognostic biomarker. In agreement with our findings, Naeini and co-workers reported that nano-curcumin supplementation significantly changed platelet counts in patients with sepsis in a 10-day double-blind placebo-controlled trial [50]. It has been postulated that curcumin improves hematological indices by stimulating leucocytosis and erythropoiesis, upregulating antioxidant enzymes, inhibiting lipid peroxidation, and modulating immune system activity [51].

The observed reduction in platelet counts and improvement in RBC, hemoglobin, and hematocrit levels can be attributed to the distinct mechanisms of curcumin-piperine supplementation. Curcumin's anti-inflammatory properties are well-documented, including its ability to modulate signaling pathways such as NF-κB, JAK/STAT, and MAPK, which contribute to the reduction of systemic inflammation and associated platelet activation [30, 48]. Lower platelet counts in sepsis patients may reflect decreased activation in response to curcumin's anti-inflammatory effects. On the other hand, curcumin has shown potential in supporting erythropoiesis through upregulation of antioxidant enzymes, inhibition of lipid peroxidation, and modulation of immune responses. These mechanisms may help stabilize and improve hematological indices like RBC and hemoglobin levels. Additionally, the antioxidative effects of curcumin could further reduce oxidative stress in erythrocytes, contributing to their improved functionality and survival [50, 51]. Thus, the dual impacts—anti-inflammatory effects reducing platelet counts and hematopoietic stimulation improving RBC-related markers—highlight the multifaceted actions of curcumin-piperine in critically ill patients.

No adverse effects were reported after curcumin–piperine supplementation in this study, which further confirms the safety and tolerability of this phytochemical. Curcumin has a limited oral bioavailability, which is partly because of its lipophilic nature and low solubility in water. High doses of curcumin result in low serum levels due to poor absorption, rapid metabolism, and elimination. Researchers have attempted to increase curcumin’s bioavailability using adjuvants like piperine, quercetin, and genistein [52]. In this regard, in a study by Shoba et al., the authors demonstrated that with the administration of curcumin alone (2 g/day), the levels of curcumin in their blood were either undetectable or very low. Coadministration of curcumin with piperine was shown to significantly enhance the bioavailability of the former [53]. This study utilized piperine, administered in a small amount, specifically 1% of the curcumin dose, to enhance the bioavailability of curcumin, as previously demonstrated [53, 54]. This dose of piperine is not expected to exert pharmacological effects considering the findings of previous trials comparing curcumin–piperine combination versus piperine alone [55, 56].

The current study utilized stratified permuted block randomization and a double-blind, placebo-controlled methodology, which strengthened the validity of results. Nevertheless, some limitations must be considered. These include the relatively small sample size and short follow-up duration. Furthermore, assessment of mortality was not the primary outcome which calls for additional larger studies to look at the impact of curcumin-piperine combination on the sepsis-related death rate. In addition, patients with comorbidities (e.g., diabetes) were excluded, thus reducing the generalizability of the findings. Of course, this led to an increased homogeneity and reduced confounding in the study population, thus making the results more reliable and robust.

Finally, the present study only involved a single dosage and any potential dose–response association remains to be explored.

Conclusion

The study findings showed that curcumin-piperine supplementation over a short period of time had a beneficial effect on inflammatory biomarkers such as CRP and ESR, as well as laboratory variables such as BIL, pH, Hb, Hct, MCH, MCHC, and platelet levels. However, further trials with larger and longer interventions and dose-ranging studies are required to confirm the beneficial effect of curcumin-piperine on sepsis patients.

Authors’ contributions

Study design: B.A, N.Kh, S.Ab, Z.I, A.S, A.M, M.B. Data gathering: B.A, N.Kh, E.H, S.Ab, S.A, Z,K. Sh.H. Statistical analysis: M.BP, S.A, Z,K. Sh.H, Z.I, A.S, M.B. Drafting the manuscript: B.A, N.Kh, M.BP, E.H, S.A, Z,K. Sh.H. Critically revised the manuscript: S.Ab, Z.I, A.S, A.M, M.B. All authors have read and approved the final manuscript before submission.

Funding

This study has been approved and funded by Isfahan University of Medical Sciences with grant number 199375.

Data availability

The data that support the findings of this study are available from the corresponding author (MB) upon reasonable request.

Declarations

Ethics approval and consent to participate

All participants provided informed written consent. The study procedure was performed according to CONSORT 2010 checklist. The study protocol was ethically approved by the local Ethics Committee of Isfahan University of Medical Sciences (Ethical code: IR.MUI.MED.REC.1399.759).

Consent for publication

All authors approved the final version of the manuscript and agreed for all aspects of the work to be published.

Competing interests

Anju Majeed is the Group Executive Chairperson of Sami-Sabinsa Group Limited. The other authors have nothing to disclose.