Monthly Archives: December 2024

Does Water Immersion Have a Role in Cord BDNF Levels and Neurological Development of the Baby: A Case Control Study

DOI: 10.31038/IGOJ.2024713

Abstract

Background: Brain-derived neurotrophic factor (BDNF) levels in maternal serum and umbilical cord blood serum samples from women who underwent water immersion during labor and those who gave birth without water immersion were compared.

Objectives: This study aimed to investigate the impact of water immersion on maternal and neonatal serum BDNF levels. A total of 57 pregnant women were included in the study, 32 in the non-water immersion group and 25 in the water immersion group. Serum BDNF levels were measured by ELISA an Enzyme-Linked ImmunoSorbent Assay (ELISA). For comparisons between groups, the independent samples t-test, Mann-Whitney U-test, and Spearman rho correlation test were used.

Results: No differences were observed in age, gravidity, parity, maternal BMI, infant weight, and infant sex (p=0.97, p=0.61, p=0.71, p=0.24, p=0.14, and p=0.88, respectively). There was no difference in maternal serum BDNF levels between the two groups were compared (p=0.152). Cord blood BDNF levels were found to be significantly different in the water immersion group compared to the conventional vaginal delivery group (p=0.03).

Conclusions: The high BDNF levels in the water immersion group suggest that this method may contribute to the neurological development of infants. We believe that water immersion can have a positive effect on the psychology of mothers and their babies.

Keywords

Hydrotherapy, Brain-derived neurotrophic factor, Immersion in water, Neurological development

Introduction

Hydrotherapy and water immersion are long-standing therapeutic techniques used in medicine. Thus, the popularity of this method has increased. Water immersion has become widely used worldwide as a non-pharmacological method for reducing the stress of labor pain [1-3].

Although water birth and hydrotherapy (water immersion or immersion in water) are thought to be similar techniques, they are different. While hydrotherapy is a non-pharmacological method to cope with labor pain, water birth is the use of hydrotherapy in the second stage of labor, and as the delivery takes place in water, it can be accepted as a birth method.

Studies have underscored the drawbacks of water birth, including the risks of maternal and neonatal infections as well as potential respiratory issues for newborns [3]. Water birth performed by skilled obstetric care providers in a hospital setting is a reasonable option for low-risk women and their newborns. In a recent study, the water immersion group demonstrated lower rates of neonatal intensive care, special care nursery admission, and perineal laceration than the control group. Furthermore, this review provides additional information on immersion water [4-6].

The benefits of water immersion for pregnant women are apparent. Owing to the buoyancy of water, hydrotherapy enables pregnant women to move their legs more easily. It has been proposed that water immersion during labor enhances maternal satisfaction and a sense of control [1].

Women who sense control during childbirth tend to have enhanced emotional well-being postnatally [1]. It is also known that immersion in water significantly reduces the anxiety of pregnant women [2]. Some professional associations, such as the Royal College of Obstetricians and Gynecologists and the American College of Nurse-Midwives, support uncomplicated healthy pregnant women having water births [7].

BDNF is a protein belonging to the neurotrophin subfamily that has various effects on the central nervous system. Neurotrophins is a crucial intracellular factor that contributes to the maintenance of neuronal function. BDNF forms neurotrophins, which are very important in protecting the nervous system and neuronal structure. BDNF plays a role in the differentiation of cells into neurons in the neural root during development by preventing neuronal death in cases such as trauma or ischemia in adult brain cells. It contributes significantly to the continuation of their vitality. In addition, BDNF has a significant impact on brain development in the prenatal and postnatal periods [8-10].

BDNF has been studied in mammals, mostly during the prenatal period and neurogenesis phase [8]. This stage is important because although neurogenesis is completed a few days before birth, most neurons in the hippocampus occur after birth [11].

We aimed to investigate the relaxing and pain-reducing effects of water immersion on maternal and infant cord serum BDNF levels.

Methods

Study Design

This prospective case-control observational study was carried out at the Zekai Tahir Burak Women’s Health Education and Research Hospital with the approval of the ethics committee (ethical approval statement: 58/2018) and in accordance with the Helsinki criteria. The women were divided into two groups: the control group consisted of 32 pregnant women who did not receive water immersion during labor and gave birth vaginally, and the case group consisted of 30 women who received water immersion during labor and gave birth vaginally.

Setting

We selected our study patients among full-term pregnant women between 37-40 weeks, hospitalized in the obstetrics clinic for delivery. Our study was conducted over a period of 6 months.

Immersion water was present in the special pools in the delivery room. Attention was paid to the cleaning of the pool. The bathtub was cleaned after each use as part of the precautions taken to prevent infection before immersion. First, the organic waste was removed and prewashed with running water. After preliminary cleaning with detergent and water, drainage pipes were cleaned and treated with chlorine tablets. The cleaning was completed after waiting for a certain period. Materials used in bathtubs, such as thermometers and hand dopplers, are also disinfected by surface disinfectants. After disinfection, cultures were collected from the bathtub surface, pool bottom, drain, and water flow areas. If the culture result is negative, the pregnant woman can be placed in a bathtub. All operations were performed by trained personnel.

Participants

A total of 62 pregnant women between the ages of 18 and 40 years, with pregnancies between 37 and 40 weeks, and who were in active labor during the examination, were included in our study. All pregnant women were in vertex presentation at the examination and had antenatal follow-ups in the maternity polyclinics of the same hospital. The amniotic membrane was observed to be intact during the examination. The exclusion criteria were as follows: pregnant women with a history of cesarean section, chronic disease, malpresentation, ruptured amniotic membrane, high-risk pregnancy, and medical and obstetric risks. Pregnant women with macrosomia fetuses and refugees on ultrasound who also had signs of active infection and fetal distress with bleeding were excluded from the study (Figure 1).

Figure 1: Inclusion and exclusion criterias.

The control group comprised of 32 patients with normal birth pain. No non-pharmacological or pharmacological pain relief methods were applied in this group. Labor was not induced.

Pregnant women in the case group (n=30) with cervical dilatation of 3 cm and 70% were taken to a pool, which had a temperature of 37–37.5⁰C and was wide enough for the woman to move freely. Fetal heart monitoring was performed at regular intervals using Doppler or non-stress tests (NST). The second stage of labor was carried out in a controlled manner outside the water. In both groups, as soon as the baby was born, it was placed on the mother’s womb, the cord was cut, and the delivery of the placenta and membranes was completed.

Venous blood samples were obtained from the mothers after birth. After the cord was clamped, blood samples were collected.

Measurements

Serum samples were separated by centrifugation at 5000 revolutions/min (2236 × g) for 10 min within 15–20 min of blood sampling. They were frozen immediately and stored at -80⁰C until the final analysis.

Serum BDNF levels were measured using an ELISA. The BDNF concentration was determined using the Elab Science Human BDNF ELISA kit (Elabscience Biotechnology Inc., Wuhan, China), which had a sensitivity of 18,75 pg/mL. The sandwich principle was used for the ELISA kit. The micro-ELISA plate provided in this kit was precoated with an antibody specific for human BDNF. Assays were performed according to the manufacturer’s instructions as follows: standards and samples were added to the micro-ELISA plate wells and combined with the specific antibody. Then, a biotinylated detection antibody specific for human BDNF and an avidin-horseradish peroxidase (HRP) conjugate were added to each microplate well and incubated. The free components were then washed away. The substrate solution was then added to each well. The enzyme-substrate reaction was terminated by the addition of a stop solution. The optical density (OD) was measured spectrophotometrically at a wavelength of 450 ± 2 nm. The OD value is proportional to the concentration of human BDNF. Maternal serum and infant cord blood BDNF levels (pg/ml) were recorded.

Bias

The case and control groups were selected from patients with the same characteristics. In contrast, only hydrotherapy was administered in the patient group. Five of the 30 patients in the case group were excluded from the study because their blood samples were damaged during transport. The number of cases had decreased to 25.

Statistical Analyses

Study Size

The mean standard deviation of BDNF in women giving birth in water was predicted to be 1200 ± 290 pg/ml. Thus, the effect size was calculated to be 0.741. With an alpha of 0.05 and power of 0.80, the sample size was determined to be 60 people in total, with at least 30 people in each group.

Variables

After birth, the weight and sex of the infants were recorded. In this study, age, gravidity, parity, BMI, baby weight, baby sex, and BDNF levels were compared between the two groups.

Statistical Methods

Whether the variables with numerical results in the study were normally distributed was examined using the Shapiro–Wilk test and graphs (histogram, boxplot, etc.). Normally distributed variables, such as age, infant weight, and BMI, were compared between the two groups using an independent sample t-test. While performing the independent samples t-test, Levene’s test was used for the equality of variances. The distribution of other numerical variables that did not show a normal distribution was compared between the two independent groups using the Mann-Whitney U test, which is a nonparametric test. Descriptive statistics are given as the mean standard deviation for numerical variables compared with parametric tests and median (min-max) for nonparametric tests. Sex, which is a categorical variable, was compared between the groups using the Pearson Chi-Square test. Yates’ correction was not used, and descriptive statistics for this variable are given as numbers and percentages. The relationships between numerical variables were analyzed using Spearman’s rho correlation coefficients. Statistical significance was set at p < 0.05. Analyses were performed using SPSS IBM Statistics 23.0 Program.

Of the 62 pregnant women included in the study, 32 were in the control group and all were considered suitable until the end of the study. As the serum samples of 30 pregnant women in the case group were collected during transportation, 25 were evaluated.

Results

Descriptive Data

When the demographic data of the two groups were examined, no differences were observed in age, gravidity, parity, maternal BMI, infant weight, and infant sex (p=0.97, p=0.61, p=0.71, p=0.24, p=0.14, p=0.88, respectively) (Table 1).

Table 1: Comparison of demographic characteristics, clinical features and BDNF levels of umbilical cord, and maternal serum between the control and case groups.

Variables

The control group (labor without immersion-no hydrotherapy) The case group (labor immersion in water-hydrotherapy)

P-value t/df/z/x²

Frequency

32

25  

Age (years) Mean ± SD

26 ± 5.5 26 ± 5.8

0.979

t: -0.027

df: 55

Gravida Mean ± SD (Median (Min-Max)

2.03 ± 0.7

2(1-4)

2.16 ± 0.8

2(1-4)

0.613

z: -0.505

Parity Mean ± SD (Median (Min-Max)

0.94 ± 0.6

1(0-2)

1 ± 0.6

1(0-2)

0.711

z: -0.370

BMI kg/m2 Mean ± SD

28.76 ± 4.7

27.49 ± 2.9 0.249

t: 1.166

df: 55

Baby weight kg Mean ± SD

3.304 ± 447 3.460 ± 329

0.149

t: -1.063

df: 55

Baby gender male/female n (%)

Male: 16 (50%)

Female: 16 (50%)

Male: 13 (52%)

Female: 12 (48%)

0.881

x²: 0.022

df: 1

Maternal serum BDNF levels pg/ml Mean ± SD

(Median (Min-Max)

110.07 ± 79.89

85.49(39.16-359.68)

130.83 ± 79.44

113.79(13.90-332.57)

0.152

z: -1.431

Umbilical cord serum BDNF levels pg/ml Mean ± SD

(Median (Min-Max)

160.47 ± 82.31

137.81(66.72-415.49)

226.48 ± 128.44

168.20(84.99-48.204)

0.033* z: -2.127

P-value <0.05 is considered as statistically significant.
BMI: Body mass index; BDNF: Brain derived neurotrophic factor; SD: Standard deviation.Min-Max: Minimal and maximal value.
An independent samples t-test (with t and df) was used to compare age, baby weight, and BMI. While performing the Independent samples t test, Levene’s test was used for equality of variances.
The Mann-Whitney U test (with p and z values) was used to compare gravida, parity, and BDNF.
The Pearson Chi-Square test (with value (x²) and df) was used to compare the gender distribution of babie. Yates’s correction was not us.

Outcome Data

When the maternal serum BDNF levels were analyzed, no statistically significant difference was observed between the two groups (p=0.152). However, cord blood BDNF levels were significantly different between the case group compared with the control group (p=0.03).

Neither maternal serum nor cord serum BDNF values differed according to sex (p=0.861 and p=0.718, respectively). A statistically weak but significant correlation was found between infant weight and maternal serum BDNF level (p=0.004; r=0.371). There was also no relationship between baby weight and cord BDNF level (p=0.642; r=0.063) (Table 2).

Table 2: Maternal and umbilical cord serum BDNF levels acccording to baby gender.

Variables

Female n=28 Male n=29 P-value

Maternal serum BDNF levels pg/ml Mean ± SD

(Median (Min-Max)

126.77 ± 92.05

87.03(39.16-359.68)

111.85 ± 66.38

96.95(13.90-312.64

0.861

z: -0.176

Umbilical cord serum BDNF levels pg/ml Mean ± SD

(Median (Min-Max)

189.94 ± 117.05

191.84 ± 104.02

0.718

z: -0.361

BDNF: Brain Derived Neurotrophic Factor; SD: Standard deviation; Min-Max: Minimal and maximal value.
The Mann-Whitney U test (with p and z values) was used to compare BDNF.

Discussion

Immersion in the waterbirth method provides many benefits in the form of maternal satisfaction, pain control, and easy movement in water. In this method, pain is reduced by hydrotherapy by taking pregnant women into the pool during labor, but birth takes place outside the pool. On the other hand, during a water birth, the pregnant woman is taken into the water during labor, and the birth takes place in the water. Both methods have been found to be beneficial for the emotional comfort of postpartum mothers [1]. However, studies on the neonatal benefits of these methods are limited. There are selected studies on immersion in water and the absence of fetal side effects during birth [4,12].

This study was designed to investigate the potential benefits of water immersion. The advantages of water immersion during labor or birth encompass reduced pain, expanded functional diameter of the true pelvis, improved quality of contractions, heightened release of endorphins, diminished reliance on opiates, increased mobility for the mother, and enhanced positioning during various stages of labor [13]. We aimed to investigate whether hydrotherapy has an increasing effect on maternal and infant cord BDNF values, and whether hydrotherapy has a positive neurohormonal effect. We compared BDNF, a neurotrophic factor in the serum of maternal and infant cord blood, in hydrotherapy and conventional vaginal delivery and found that maternal serum BDNF levels were not different. Although there was no statistical difference between maternal serum BDNFs levels, the mean values in the hydrotherapy group were significantly higher. This may be because of the small sample size. Despite this, cord serum BDNF levels were significantly higher in the hydrotherapy group.

Neurotrophins are important regulators of neural cell survival, development, function and plasticity. Mammals have four neurotrophins that are derived from the same ancestral gene [26]. Neurotrophins support neuron survival and prevent neuron apoptosis [14].

Neurotrophins play an important role in axon growth during development, higher neuronal function, morphologic differentiation, and neurotransmitter expression [15]. Thus, neurotrophins can play an important role in the development of the brain before and after birth. However, data on the presence and effects of neurotrophins in preterm infants are insufficient. BDNF and NT-3 are highly expressed in the cortical and hippocampal structures and have been linked to the survival and function of multiple neuronal populations [16].

BDNF was found to be related to hypoxic-ischemic encephalopathy, mental retardation, and autism in newborns. The importance of BDNF and NT3 in neurodevelopment in the intrauterine period has been emphasized. There is evidence that prenatal or maternal traumatic stress has a significant impact on neurodevelopment. In general, the earlier and more severe the trauma, the more impaired the neurodevelopment [17]. The better the mother’s comfort during delivery, the easier the mother’s adaptation to the mother’s puerperium, and the lower the rate of postpartum depression. Therefore, we believe that immersion in water may be beneficial to neurological development.

BDNF is important in neuronal plasticity [18]. BDNF has mostly been studied in mammals during the prenatal and neurogenesis stages, but relatively less in the postnatal period [8]. This phase is important because, although neurogenesis is completed several days before birth, most neurons in the hippocampus appear after birth [11]. In addition, since BDNF is very important in mammalian adults, our research goal was to investigate whether BDNF changes depending on the mode of delivery.

In the water immersion group, high BDNF levels in the cord blood, but not in the mother’s blood, may contribute positively to the neurological development of the newborn. Moreover, Kodomori et al. showed in their animal study that maternal BDNF contributes to the neurological development of the fetus through uteroplacental passage. In our study, high BDNF levels were detected in the cord blood of rats in the water immersion group. In the perinatal period, the blood-brain barrier is immature because circulating BDNF may reflect the level of BDNF in the central nervous system, and circulating cortical BDNF levels are correlated, as has been reported. Again, in previous studies, conditions such as surgery, stress, birth, and hypotension that cause stress in the central nervous system have been found to cause changes in BDNF release. Accordingly, since hydrotherapy is a less painful and emotional form of delivery, higher BDNF values were obtained in our study group [18-20].

We also investigated the relationship between infant weight and BDNF levels and found only a weak link between maternal serum BDNF levels and infant weight. All the infants included in this study were term. In a recent animal experimental study [21], the relationship between infant sex and BDNF was investigated, and it was shown that BDNF content increased in the brains of both male and female rat pups 0 h after hypoxia and 4 h in serum; however, only males had increased brain BDNF levels 4 h after hypoxia. When we investigated the relationship between baby sex and BDNF levels, we did not find any difference in BDNF levels between the sexes. This may be due to the small number of patients. As this subject has been extensively researched and the importance of BDNF and other neurohormones is increasing, more long-term studies are needed.

Recent studies have investigated the use of serum BDNF levels in Alzheimer’s disease and as a biomarker of schizophrenia and depression. We aimed to examine serum BDNF levels because we believe that hydrotherapy has positive effects on maternal psychology and protects against the development of postpartum depression. As hydrotherapy has positive effects on maternal psychology and postpartum depression, we examined serum values [21-23].

Neurotrophic factors play crucial roles in neuroprotection. Neurotrophins promote survival and reduce apoptosis in many populations of neurons [14].

Limitations of the Study

The small number of participants in our study and the fact that we did not follow mothers and babies in the long term may be a limitation of our study.

Conclusions

In light of these studies, the neuroprotective effects of neurotrophins, especially BDNF, including anti-apoptotic axonal development of neurons, neurodevelopmental effects that have healing effects in some neurodegenerative diseases, and their positive effects in diseases such as autism and mental retardation, have increased the importance of BDNF in recent years. The relationship between BDNF, other delivery modes, and hydrotherapy has not been previously studied. Although we have shown in our study that hydrotherapy delivery may have a positive effect on BDNF levels, we believe that immersion in water contributes to the development of neurons in newborns by increasing BDNF levels. We hope that our study will encourage future research on this very important subject and will shed light on future studies on this very important subject.

Declarations

  1. Conflict of interest: Not applicable
  2. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
  3. Ethical approval: Ethical approval was received from the Zekai Tahir Burak Women’s Health Education and Research Hospital with the approval of the ethics committee (ethical approval statement: 58/2018).
  4. Consent to Participate: All participants provided written informed consent prior to their participation in the study in accordance with the tenets of the Declaration of Helsinki.
  5. Authors’ Contributions:
    Conceptualization: Rahime Bedir Findik
    Investigation: Rahime Bedir Findik, Ozlem Uzunlar, Esin Merve Erol Koc
    Methodology: Rahime Bedir Findik, Ozlem Uzunlar
    Resources: Rahime Bedik Findik, Ozlem Uzunlar, Esin Merve Erol Koc
    Validation: Rahime Bedir Findik, Ozlem Uzunlar
    Supervision: Yaprak Ustun
    Writing – original draft: Rahime Bedir Findik, Ozlem Uzunlar
    Writing – review & editing: Rahime Bedir Findik, Ozlem Uzunlar
    Formal analysis: Jale Karakaya, Gulsen Yilmaz, Fatma Meric Yilmaz Mert
    All authors have read and agreed to the submitted version of the manuscript.
    1. Data availability: Data are however available from the authors upon reasonable request and with permission from [third party name].

    Abbreviations

    BDNF: Brain-Derived Neurotrophic Factor; ELISA: Enzyme- Linked ImmunoSorbent Assay; OD: The Optical Density

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Evaluation of In Vitro Cell Viability and Cytokine Production by Mesenchymal Stem Cells Exposed to the Homeopathic Medicine Matricaria chamomilla D3

DOI: 10.31038/IJVB.2024823

Abstract

Chamomilla has long been recognized in traditional medicine for its established uses in herbal medicine and homeopathy. It is commonly recommended for treating respiratory, hepatic, gastrointestinal, and mental disorders. Additionally, it exhibits sedative, antiseptic, antiemetic, and anti-inflammatory properties and is frequently used to address issues related to teething in young patients. Despite its widespread use, scientific validation is essential to enhance the credibility of this medicine. In vitro studies offer a valuable approach for assessing the impact of homeopathic medicines on cellular functions, including cytotoxicity and cytokine secretion. Cell viability is typically evaluated through assays such as MTT, which measures cellular metabolic activity and provides insight into the proportion of viable cells following exposure to specific compounds. In the case of mesenchymal stem cells (MSCs) exposed to Matricaria chamomilla D3, the goal is to determine whether the homeopathic remedy affects cell survival or induces cytotoxicity. MSCs are known for secreting various cytokines that regulate inflammatory responses and promote tissue regeneration. Exposure to Matricaria chamomilla D3 may influence cytokine secretion, potentially altering the inflammatory response. This study evaluated the in vitro toxicity of injectable Chamomilla D3 in human mesenchymal stem cells, along with its potential anti-inflammatory effects, as evidenced by the reduction in the pro-inflammatory cytokine IL-8. The findings suggest that homeopathic Chamomilla D3 exhibits in vitro anti-inflammatory activity.

Keywords

Homeopathy, Vegetal, Complementary medicine

Introduction

Matricaria chamomilla, also known as chamomile, is a globally distributed plant [2]. It has a rich history in herbal medicine and homeopathy, with indications for treating various diseases [1]. Matricaria chamomilla is a versatile plant with multiple uses in folk medicine. It treats respiratory, hepatic, gastrointestinal, and mental alterations like stress and anxiety. It is also used as a sedative, antiseptic, and antiemetic, among others reported.

The phytochemistry, biological, and pharmacological properties of Matricaria chamomilla extracts are extensively characterized and systematically documented within herbal medicine. Its phytochemical composition encompasses over 120 bioactive compounds, including essential oils, terpenoids, and phenolic substances such as phenolic acids, flavonoids, and coumarins. These compounds impart a range of well-documented activities, including antioxidant, antibacterial, antifungal, antiparasitic, insecticidal, antidiabetic, anticancer, anti-inflammatory, antidepressant, antipyretic, anti-allergic, and analgesic effects [3].

According to the Homeopathic Medical Material, Matricaria chamomilla is indicated for various clinical manifestations such as irritability and hypersensitivity. Additionally, it may be relevant for treating otitis and diarrhea, especially in children, and for conditions associated with teething and gastrointestinal disturbances [4]. described effects such as anti-inflammatory and antispasmodic activities, among others, that support alleviating clinical symptoms. These effects may significantly improve the previously mentioned signs and symptoms [5].

The present study aimed to evaluate the anti-inflammatory activity of Matricaria chamomilla prepared according to the homeopathic pharmacopeia, specifically at a D3 potency and a concentration of 8 µL/mL. This evaluation focused on releasing the inflammatory cytokine Interleukin 8 (IL-8) and assessed the viability of healthy mesenchymal stem cells exposed to the medicine Matricaria chamomilla.

Materials and Methods

MTT Assay

The injectable homeopathic medicinal product Chamomilla D3 was tested on human mesenchymal stem cells (MSC) by the MTT test at a concentration of 8 µL/mL. Cell culture was performed in 75 cm2 flasks until reaching 80% confluence. Human mesenchymal stem cells in culture were trypsinized and distributed in a 96-well plate. After this process, the cells were incubated for 24 hours at 37°C in a 5% CO₂ environment. The test substance was prepared at 8 µL/mL and distributed into the designated wells. After 24-hour incubation, the culture medium was withdrawn and discarded. A volume of 50 μL of medium supplemented with 20% FBS was added, followed by 50 μL of medium containing the diluted test substance. The cells were incubated for an additional 48 hours in a CO₂ incubator, maintained at 5% CO₂ and a temperature of 37°C. After this period, the treatment medium was discarded, and 100 µL of the MTT solution was added to each well. The plate was covered with aluminum foil and incubated for 4 hours in an oven. Subsequently, MTT was removed, and 100 µL of DMSO was added to each well. The optical density was measured at 570 nm ± 10 nm using a plate reader. After this assay, the cytokine levels released upon exposure to the medicine were measured.

Cytokine Dosing

After reaching cellular confluence, cultured human mesenchymal stem cells were subjected to trypsinization and plated in 96-well plates. After 24 hours of incubation at 37°C with 5% CO₂, the culture medium was removed, and the wells were washed with PBS. Subsequently, 200 μg/mL of LPS (lipopolysaccharides from *Escherichia coli* O55: B5 – Sigma Aldrich), diluted in an antibiotic-free medium, was added in wells of positive control group and treatment group. Negative control group did not receive LPS, only culture medium. A subsequent incubation was performed for an additional 24 hours. Following the induction period of cellular inflammation with LPS, the medium was removed from the plate, and the wells were washed with PBS. The medicine was added at a final concentration of 8 μL/mL in treatment group. In negative and positive control groups, culture medium was added. The plate was then incubated for 24 hours under the previously described conditions.

After the treatment period, the supernatant was removed, and serum-free culture medium was added for 24 hours. The supernatant was collected for IL-8 analysis. IL-8 levels were measured using flow cytometry with the FACS VIA BD™ cytometer.

Results and Discussion

The present study assessed the cytotoxicity of the injectable homeopathic medicine Chamomilla D3 in human mesenchymal stem cells. The analysis revealed that, at the tested concentration, the material exhibited no cytotoxic potential (Table 1 and Figure 1).

Table 1: Cell viability obtained from the control and treated groups (Chamomilla 8 μl/mL) after MTT testing.

Cell viability(%)

Control

Chamomilla 8µl/mL
94

93

101

93
102

95

Figure 1: Cell viability (%) of the control and treated groups (Chamomilla 8 μl/mL): ns = no statistical difference.

Following the initial analysis, the release of the inflammation marker IL-8 by MSCs was evaluated both in response to LPS exposure and after treatment with the medicine. It was observed that LPS induced the release of IL-8, demonstrating its effectiveness in stimulating inflammation within the cell culture environment (see Figure 2). Additionally, cells previously “inflamed” by LPS were subsequently “treated” with the homeopathic medicine Chamomilla D3. The results demonstrated a significant reduction in the inflammation marker IL-8 following treatment. A similar pattern was observed in the control group, which consisted of cells maintained in a culture medium without LPS induction or Chamomilla D3 treatment (see Figure 2).

Figure 2: The results of the cytokine dosage test are presented in pg/mL for the following groups: the control group without LPS addition, the control group with LPS addition, and the treated group with Chamomilla at 8 μl/mL.

Homeopathy is frequently investigated due to its low likelihood of toxicity and minimal risk of causing side effects. According to Millstine [6], homeopathy can benefit the treatment of specific clinical conditions by potentially providing symptom relief.

Homeopathic Chamomilla is known for its anti-inflammatory effects, which can aid in treating various conditions [10]. Studies have demonstrated that the compounds in Chamomilla, such as flavonoids and terpenoids, possess properties that aid in reducing inflammation and alleviating related symptoms. As noted by Amsterdam [7], Chamomilla is also recognized for its calming and relaxing effects, which can contribute to alleviating stress and anxiety – factors often associated with inflammatory processes in the body.

Furthermore, regarding the anti-inflammatory properties of homeopathic Chamomilla, this article supports and validates the study by Scabello and Gardin [8], which examines injectable dynamized medicines available in Brazil. The authors noted that Chamomilla harmonizes the excessive action of the soul organization over the vital force, particularly within the digestive and menstrual spheres, and addresses general inflammation, per the principles of Anthroposophical Medicine.

In the homeopathic form, Chamomilla was identified as one of the ten most frequently used medicines for treating migraines, as highlighted and reviewed by Santos. Migraines are types of headaches that impair the patient’s quality of life.

Another property attributed to a medicine based on Matricaria chamomilla is its relaxation and analgesic effects. These effects were demonstrated in the study by Jyothis [9], which experimentally evaluated its impact on the central nervous system. As a result, a significant reduction in locomotor activity was observed, indicating muscle relaxation, analgesic effects, and anticonvulsant activity. Pinto [12] also reported relaxation effects in animals subjected to stress and depression.

The antibacterial and fungicidal actions of Matricaria chamomilla were emphasized in the study by, which explored its various aspects and properties. The study noted that its compounds impart sedative attributes, support digestion, and exhibit antimicrobial effects against bacteria and fungi [13].

Conclusion

The present study demonstrated the low in vitro toxicity of injectable Chamomilla D3 in human mesenchymal stem cells. Additionally, it suggested a potential anti-inflammatory action, as evidenced by a reduction in the levels of the pro-inflammatory cytokine IL-8. However, further studies are needed to confirm the homeopathic indications of its compounds in their homeopathic form and establish Chamomilla‘s in vivo anti-inflammatory activity.

References

  1. Reis LS, Pardo PE, Oba E, Kronka Sdo N, Frazatti-Gallina NM (2006) Matricaria chamomilla CH12 decreases handling stress in Nelore calves. J Vet Sci. [crossref]
  2. El Mihyaoui A, Esteves da Silva JCG, Charfi S, Candela Castillo ME, Lamarti A, Arnao MB (2022) Chamomile (Matricaria chamomilla L.): A Review of Ethnomedicinal Use, Phytochemistry and Pharmacological Uses. Life (Basel) [crossref]
  3. Santos ARF, da C, Cruz JH, de A, Guênes GMT, Oliveira Filho A Ade, Alves M ASG (2020) Matricaria chamomilla L: pharmacological properties. Archives Of Health Investigation, 8(12)
  4. Lathoud JA (2017) Studies of Homeopathic Materia Medica. Ed. Organon. 3rd edition. Sao Paulo.
  5. Fernanda Michel Tavares CANTO(a) Oswaldo de Castro COSTA NETO(a) Jéssica Muniz LOUREIRO(a) Guido Artemio MARAÑÓN-VÁSQUEZ(a) Daniele Masterson Tavares Pereira FERREIRA(b) Lucianne Cople MAIA(a) Matheus Melo PITHON(c) (2022) Efficacy of treatments used to relieve signs and symptoms associated with teething: a systematic review. Oral Res. [crossref]
  6. Millstine D (2023, December) Homeopathy. MSD Manual.
  7. Amsterdam JD, Li Y, Soeller I, Rockwell K, Mao JJ, Shults J (2009) A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder. J Clin Psychopharmacol. [crossref]
  8. Scabello RT, Gardin NE (2015) Potentized injectable medicines available in Brazil: indications based on homotoxicology and possibilities of use according to anthroposophic medicine. Arte Med Ampl
  9. JYOTHIS, AB Ram. A Study on Analgesic activity of Matricaria chamomilla.
  10. Srivastava JK, Shankar E, Gupta S (2010) Chamomile: A herbal medicine of the past with bright future. Mol Med Report. [crossref]
  11. Amsterdam JD, Li Y, Soeller I, Rockwell K, Mao JJ, Shults J (2009) A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder. J Clin Psychopharmacol.
  12. Pinto SAG, Bohland E, de Paula Coelho C, de Azevedo Morgulis MSF, Bonamin LV (2008) An animal model for the study of Chamomilla in stress and depression: pilot study. Homeopathy [crossref]
  13. Singh O, Khanam Z, Misra N, Srivastava MK (2011) Chamomile (Matricaria chamomilla L.): an overview. Pharmacognosy Reviews.

Existential Communication – Old Wine in New Skins?

DOI: 10.31038/PSYJ.2024644

Abstract

Background: The term existential communication did not emerge but recently in medical terminology. It refers to doctor-patient-communication comprising issues of mortality, fragility of human being, and associated rational and emotional coping.

Objective and methods: A literature search the term existential communication was carried out in PubMed. Moreover, from the results and the author`s long background of facilitating “breaking-bad-news” workshops for oncologists, features of an existential communication are demonstrated.

Results: A PubMed search resulted in only 8 papers from the last decade explicitly using the term existential communication. Hundreds of papers used existential in various other attributions – from existential aspects to existential yearnings. The term existential was rooted in various directions of predominantly German existential philosophy, which after National-Socialism resonated in the USA and catalyzed pioneering strategies of psycho- oncological support. Some training programs for existential communication have been established and share the principles of breaking-bad-news communication.

Conclusion: Existential communication describes more precisely than end-of-life (EOL) discussion a long-standing and teachable medical task which must not be neglected without compromising high quality patient care, in particular in oncology and palliative medicine. Existential communication is prerequisite to avoid burdening patients with very advanced cancers with futile tumor-specific treatments and detrimental adverse-effects. Existential communication is important for patients but may foster a deeper professional satisfaction of health care professionals (HCP).

Keywords

Medical communication, Cancer, Psycho-oncology palliative care, Spirituality end-of-life discussion

Im existentiellen Bereich sind Wahrheit und Kommunikation dasselbe.

In the existential realm truth and communication are identical (translation HK) Hannah Arendt, 1957 [1]

Introduction

Originally the term existential communication has been a central concept of the existential philosophy of Karl Jaspers (1883-1969) [2], a renowned German philosopher and psychiatrist. Nearly a century ago, he coined existential communication for a uniquely dyadic and non-hierarchical communication which enables both interlocutors to evolve their distinctive personhood, their existence. The term opposed the Daseins-communication (communication of being) of daily life inclusive clinical practice. Thus, Jaspers` philosophical construct of existential communication was not established for clinical practice and consequently did not enter medical terminology. Hence, in 1969 Swiss- American psychiatrist Elisabeth Kübler-Ross could finish her landmark book On death And Dying [3] without using the term existential, even if her end-of-life conversations with patients doubtlessly meet today´s understanding of existential communication. Neither can be found the term existential in Cicely Saunders paramount book of palliative medicine of 1978 [4]. However, this book outlined her concept of total pain, which soon should shape the understanding of palliative care of the World Health Organization (WHO) [5] and of international and national palliative care societies [6]. Since then, state-of-the-art care of patients with life-threatening disease embraces a spiritual dimension. Almost simultaneously with the term spiritual the term existential emerged in the Anglo-American medical literature, though. Unlike existential communication the single term existential had entered psychiatric literature of German language already in the first half of the 20th century. The German philosopher Martin Heidegger (1889- 1976) had influenced the psychiatric and respective psychotherapeutic Daseins-Analysis of Ludwig Binswanger [7] and Medard Boss [8], both Swiss psychiatrists and psycho-analysts. Moreover, Viktor Frankl, an Austrian psychiatrist of Vienna, who had established his scientific reputation with innovative concepts of care for suicidal individuals and patients with depression, i.e. patients facing an existential crisis, had outlined his Existence-analysis and Logotherapy since the mid- thirties [9]. But during the Nazi-Era humanistic psychiatric patient care influenced by psychoanalysis and existential philosophy was eradicated in Nazi-dominated Europe and many of the most eminent representatives of German oncology and psychiatry – for being Jews – were forced to emigrate or into murderous concentration camps. In regard to their Nazi-collaboration German medical organizations put under taboo and discouraged any deeper reflection of existential philosophical issues like responsibility, guilt, and shame after the defeat of the Nazi-regime for more than one generation. However, US-American psychiatrists explicitly referring to the above mentioned European philosophers and clinicians soon should introduce the term existential into a now Anglo-American medical literature. Viktor Frankl, who had survived four concentration camps, took an important role for this transatlantic loop of the term existential. He refined his meaning-centered Logotherapy and Existence-analysis reflecting his years of existential threat and the murdering of his family in concentration camps. Initially his concept did not resonate much in the scientific community of post war Austria and Germany, but he gained recognition as a visiting professor at Harvard and other US- universities and with the English translation [10] of his post war book, which has been sold in millions of copies. In a 1991 survey Man’s Search for Meaning was rated one of the ten most influential books in the US. Independently, Stanford psychiatrist Irvin Yalom developed his very influential Existential Psychotherapy [11] leaning on Viennese psycho- analytic concepts and European pre-war existential philosophy. Yalom´s resources-centered therapeutic approach has been modified for psycho- oncological support for patients with cancer: at Stanford psychiatrist David Spiegel established his Supportive-Expressive Psychotherapy [12,13], while William Breitbart – a child of Holocaust survivors, and explicitly referring to Viktor Frankl – developed his Meaning-Centered Psychotherapy [14] at New York´s Sloan-Kettering Cancer Center. Spiritual, existential and finally existential communication had entered literature of oncology and palliative medicine, even if the conceptual understanding of different authors diverge [15].

Methods and Materials

A literature search was conducted in Pubmed (accessed June 21,2024) using the search term existential communication which resulted in 834 references. These comprised both papers using the combined term or just the single term existential or communication. Thus, many references dealt with the vast fund of medical communication which was considered helpful for outlining principles of existential communication. Moreover, the author returned to his extensive experience from facilitating workshops for clinicians on “breaking-bad-news” [16] where modules of communication on death and dying and associated emotions regularly were appreciated most by the participants.

Results

The term existential communication emerged in medical literature only a decade ago and of the 834 references only 6 papers had existential communication in their titles, with 5 of them affiliated with the Denish University of Odense [17-22]. In addition, 2 papers used the term (or modified as existential conversation [23]) in their abstracts or texts [24]. Hundreds of papers employed existential attributively to describe illness experiences, suffering, crisis, loss, shock, aspects of relationships and core values, feelings of guilt, isolation, and yearning (Table 1).

Table 1: Attributive use of existential in medical literature.

existential anxiety

e. conflicts

e. guilt

e. outcome

e. struggle

e. aspects

e. constructs

e. impact

e. pain

e. suffering

e. beliefs

e. crisis

e. uncertainty

e. perspective

e. support

e. burden

e. decision making

e. insight

e. intervention

e. problems

e. survivorship

e. terror

e. care

e. determinator

e. isolation

e. quality

e. thoughts

e. challenges

e. dimension

e. issues

e. questions

e. threat

e. circumstances

e. distress

e. loneliness

e. reactions

e. values

e. communication

e. encounter

e. loss

e. relation

e. vulnerability

e. concern

e. experience

e. meaning

e. rupture

e. well-being

e. condition

e. fear

e. needs

e. shock

e. yearnings

The term existential is embedded into two concurrent concepts. The European Association of Palliative Care (EAPC) und papers adopting its definition use spiritual as a meta-concept which includes existential [6]. Irvin Yalom`s Existential Psychotherapy considers existential as overarching concept, though, which comprises spiritual and religious issues [11]. In the same manner Scandinavian study groups understand existential as a meta-concept, which includes spiritual issues [20]. They are backed by a sample survey of the Denish population, which showed that “the existential” serves well as an overarching construct potentially including secular, spiritual and religious domains of meaning [25]. Moreover, general practitioners of the secular Denish society felt more at ease with the term existential in comparison to spiritual. However, the structural differences of both meta-concepts do not interfere much in actual communication with severely ill patients, and both meta- concepts sometimes may be found in parallel use by the same authors, or existential, spiritual and religious aspects are pragmatically put side by side on a same level [20,26].

Elise Tarbi`s study group at Boston`s Dana-Farber Cancer Institute defines existential communication “as any discussion concerned with confronting mortality and the fragility of existence; in particular, relating to major themes of (1) time as a pressing boundary; (2) maintaining a coherent self; and (3) connecting with others” [24]. This definition is compatible with the one used by the Denish study group at Odense University: “a metaconcept that includes communication about broad existential aspects and potentially, but not mandatorily, communication about spiritual and religious aspects [20].

Why Existential Communication?

In oncological and palliative care existential communication means communication in and about an existential crisis. Coping with a crisis situation depends on communication. Thus, existential communication features both a diagnostic and a therapeutical dimension [27]. The concept of total pain [4] already underscores the importance of giving attention to existential suffering for adequate symptom control [24,28] and quality of life. Otherwise patients might run the risk of being labeled as “difficult” by medical care providers. Breitbart pointed out that he teaches his trainees that “whenever they encounter an angry patient with advanced cancer think existential guilt […]Anger and anxiety have the same etymological roots, and in fact angry typically comes from fear. The fear of loss; loss of love, hope, life. [..]. Clinically I see Existential Guilt manifest as either depression, shame, anger, or intense death anxiety” [29].

Patients with advanced cancer usually want to talk about existential issues with their doctors. But doctors often fail to recognize these wishes or feel time pressured or incompetent for a sensitive wording or consider these issues too private to address. Moreover, physicians with their training in the biomedical approach often focus on obtaining objective measures and fixing a problem. Confronted with problems that cannot be measured objectively and with no direct solutions at hand this approach is bound to reach deadlock [26]. On the other hand, HCPs who engage in communication about existential issues report higher professional meaning and satisfaction and personal depth. Early communication on death and dying with patients with advanced oncological diseases entails less futile and costly oncological treatments and detrimental adverse effects in the weeks before death. These patients have a better quality of life, spend fewer days in a hospital, are less frequently admitted to intensive care units and have a higher chance to die outside a hospital [30]. As the percentage of patients receiving futile oncological treatment in the last weeks of their life did not diminish in the last decade eminent US- American cancer centers pleaded for a better training of oncologists to communicate with patients on existential issues [31].

Principles and Practice of Existential Communication

Existential issues like finitude, mortality and meaning of life cannot be solved but require an individual positioning, acceptance and maybe a possible reevaluation. Patients with life-threatening illness may have a lot of physical and psychosocial problems, but in contrast, they share their existential condition with their HCPs – even if the latter sense less urgency for grappling with their existential issues. Thus, doctors and nurses, wo feel confident in providing medical expertise or advice, generally feel far more challenged when a patient addresses existential suffering. It is beneficial for HCP-teams to reflect personal values and existential beliefs. As a matter of fact, doctors who have been confronted with existential threats in their biography tend to be more attentive to their patients` existential concerns [2]. Spiegel`s concept of “detoxifying dying” in group therapy constructively confronts one´s own mortality when faced with death or imminent loss and can be helpful for HCP-teams [12]. Communication is not an end in itself. Medical communication should be beneficial in coping with severe illness: patients should experience: (1) a sense of resonance – having been seen, heard and understood; (2) a “solidarity of mortals” – an empathetic relationship respecting the remaining autonomy and dignity; (3) hope – an expectation that in severe illness and even with facing death positive experiences may be possible [27]. For Suchman “the feeling of being understood by another person is intrinsically therapeutic: it bridges the isolation of illness and restores the sense of connectedness that patients need to feel whole.” [32] Quite often physicians neglect the crucial elements of establishing a therapeutic relationship: respectful greeting, eye contact, attention and showing interest and empathy. Connection will fail, if doctors just have eye contact with the display of their digital tools for timesaving and simultaneous documentation of patient information. Empathy is not identical with professional friendliness.

As soon as a patient gets informed about a life-threatening disease existential issues intermingle with questions about therapeutic options and treatment schedules: “How much time will I have left? “Why me?” “I am trapped in a black pit”, “I can´t be a burden for my family”, or “oh gosh, that´s the end!” During the last three decades very useful protocols for “breaking bad news” communication have been evaluated, even if lack of adherence to them still is a problem in clinical reality [33,34]. Existential topics are rarely expressed explicitly in palliative care conversations [21]. They often sprinkle patient-caregiver contacts for physical or psycho-social symptom assessment, medical or nursing procedures, or are woven within practical conversations during medical rounds. Statements like “It´s enough!”, “please give me something to die” deal with death, others with issues of justice and guilt: “Why do I have to suffer like this?” Issues of existential loss – loss of self-esteem and identity – emerge in sighs like “I am just a burden”, “This isn´t me anymore!” Again, as in “breaking-bad-news” communications, it is of paramount importance for HCPs not only to grasp the literal content of those statements but also to identify and to primarily address their implicit and dominant emotional contents: uncertainty, fear, despair, anger, shame, feelings of worthlessness. That is how emotional resonance is achieved [16,32,35]. A clinical snippet may demonstrate this approach:

Patient: “This is no life any more.”

Physician responding to the literal message:

Oh no, we do everything to help you, you can rely on our palliative care expertise.Physician responding to the emotional message:

“You are really despaired.” Pause, and when the patient confirms non-verbally (nod, eye contact):

Please tell me what is haunting you most?

The response to the literal message implicitly devaluates the present illness experience while dodging the emotional issue as a “empathetic terminator” [32]. To minimize a risk of rebuff patients weave existential cues within conversations during medical care or nursing procedures. They sound the openness of HPCs for existential communications [22]. This may be underlined by another clinical snippet:

A 67-year-old woman presenting with ascites was diagnosed with advanced ovarian cancer. She is scheduled for a diagnostic laparotomy. When the experienced anesthesiologist sees her the day before surgery to explain his procedure he is puzzled by the welcome statement of that friendly lady: “I wonder about my future?” The senior doctor hesitates, then answers: “In my opinion, people don´t reflect enough about death.” The patient is startled. She just answers to the technical questions relevant for adequate anesthesia. She is too upset to sleep during the night before surgery.

The patient´s statement “I wonder about my future” doubtlessly is a distinct existential cue. The doctor perceives the emotional message of fear of death. He could address this emotion by labeling it: “Are you afraid to die soon?” However, the doctor flinched from dealing with the emotional issue und took refuge to a rational comment, schoolmasterly dodging the patient´s existential distress. Every existential crisis is charged with unpleasant emotions. Therefore, physicians may be tempted to side-step these emotions by moving quickly to the field of professional action competence with comments, giving advice, or hurriedly suggesting solutions. But it is crucial to take up the patients´ emotional cues first in order to advance to an existential communication. Moreover, HCPs should keep in mind that strong emotions hamper cognitive information processing. Nevertheless, before engaging in an existential communication HCPs should clarify, whether there are any interfering uncontrolled physical symptoms such as pain, thirst, or an urge to urinate. The above snippet demonstrates: Existential clues often hit the HCPs by surprise. They have to decide whether momentarily engaging in an existential communication is a feasible or wise option. Anyway the HCP should signify having registered the cue, maybe – concerning the above snippet by commenting: “That´s an important issue for you, but it makes sense to wait for the results of tomorrow`s operation.Or the consultant may request the patient´s consent to inform his responsible physician about a desire for a deeper communication, or may ask permission to pass a more specific religious topic to a chaplain.

Tarbi found that conversations with more discussion of prognosis also contained more discussion of existential topics [24]. But without showing a lack of courteous manners doctors often focused on strictly medical facts, failing to notice or ignoring the patient´s existential illness experience and strife for meaning and validation. “Courteous but not curious” is Agledahl`s [36] summary of analysis of doctor- patient encounters in a Norwegian teaching hospital. Whether patients open up to share their existential thoughts heavily depends on non-verbal and sensory elements of an encounter: whether a HCP is perceived both physically and relationally present. “The bodily sensation of presence and sensing seems to precede the verbal dimension of spiritual care and communication […] The patients use a sort of decoding in which they try to sense and decipher whether they will be accommodated, if they initiate a conversation about spiritual matters” [37]. Reciprocally HCPs have to decode the patients` non- verbal cues and keep in mind the most important principles of medical communication: (1) active listening – learning the illness experience; (2) asking questions – showing interest, and encouraging a narrative and its clarification; (3) perception – what and how does the patient communicate verbally and non-verbally. It is important to recognize that a patient is the single expert of his illness experience which he might share by answering to questions like:

“What burdens you most?”

“If you ponder on your illness, how much time do you think you have got to live?”

“When thoughts of death and dying come to your mind, do they cause fear or anxiety?”

“When you think about the rest of your life, what matters most for you?”

“Do you have a specific event or goal you would like to live?”

“When you think back, what did help you most in coping with your disease?”

“When you reflect on your life, what makes you really proud?”

I encourage this kind of “empathetic curiosity” which had been lacking in Agledahl`s study of patient-doctor encounters [36]. Addressing tabooed or anxiety-ridden issues reduces anxiety. Moreover, a simultaneous validation of coping efforts will diminish a patient´s sense of helplessness, hopelessness, and isolation and restore a sense of agency in spite of an advanced disease. Meanwhile, useful concepts of existential communication have been established [18,20,22]. In addition, established guidelines for “breaking bad news” in medicine and reviewed programs of communication skills training in oncology [34] comprise the principles of existential communication.

Conclusion

The recent term existential communication with its secular roots and associations excellently describes a long standing medical task which is crucial for state-of-the art patient care, especially in oncology and palliative medicine. In contrast to the common term end-of-life discussion existential communication semantically does not focus on the end of life but also on the life before. Existential communication also deals with maybe lifelong individual values and resources which impact treatment decisions. But on disease progression of advanced cancer oncologists often “skip over discussions of prognosis and jump to offering a new line of therapy” [31]. They struggle with “taking away hope” [38]. feel uncomfortable with existential issues, and biasedly believe that additional treatment will benefit the patient. That is why existential communications are to be actively scheduled in patient care and are particularly crucial when disease-modifying treatment is stopped. Existential issues of remaining life time and anxiety or confusion surrounding dying regularly emerge at this phase of an illness trajectory. At the same time therapeutic responsibility often changes which may structurally augment the patient´s suffering of having to leave behind loved ones. A patient`s complicit encouragement of his oncologist to offer additional treatment sometimes is motivated by the patient´s fear that otherwise his medical life-line will be cut. Therefore, an early integration of palliative care specialists into the oncological care team is important. Moreover, patients may feel very relieved when oncologists empathetically explain, that with stopping a futile treatment survival will not be shorter but quality of life will be better because adverse effects will cease.

Acknowledgment

The author thanks Matthias Demandt, MD,. for constructive comments on early versions of the manuscript

Competing Interest

The author declares that he has no competing interests.

Funding Information

The author did not receive external funding.

The author did not receive external assistance with data collection, analysis, and manuscript preparation

Ethical Declaration

This study did not involve human participants or animal subjects.

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Tobacco Pandemic: Challenges and Responses

DOI: 10.31038/CST.2024943

Abstract

Smoking is the leading cause of preventable death worldwide. Its toxicity affects every organ. It is a risk factor or aggravating cause of many diseases: cancer, chronic obstructive pulmonary disease, cardiovascular disease, diabetes, HIV infection and tuberculosis, and is a major source of environmental pollution. The socio-economic costs of smoking, already exorbitant, are likely to become unsustainable by 2050 for all countries, particularly low- and middle-income countries. Twenty years after the adoption and implementation of the WHO Framework Convention on Tobacco Control (FCTC), this article aims to take stock of the situation regarding tobacco use and tobacco control. All countries and international health agencies must be involved in the fight against the tobacco pandemic. It is more important than ever to strengthen tobacco control policies, particularly by helping people to stop smoking, to curb the pandemic and its devastating consequences.

Keywords

Smoking, Smoking-related diseases, Tobacco control, Smoking cessation, Public-health

Introduction

Currently more than 20% of the world’s population were smokers. Smoking remains a global health issue despite the gradual reduction in its prevalence. It is responsible for more than 8 million deaths a year worldwide [1]. The toxicity of tobacco products affects every organ in the body, and it is a direct cause, adjuvant and aggravating factor in many diseases: cancer, cardiovascular disease, chronic obstructive pulmonary disease (COPD), diabetes, HIV infection, tuberculosis, environmental health risks, all of which affect all countries, particularly low- and middle-income countries [2]. The prevalence and mortality of these diseases are set to rise sharply by 2050, entailing very high socio- economic costs. Twenty years after the adoption and implementation of the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC), this article takes stock of the impact of this pandemic and the state of tobacco control, highlighting the necessity to intensify efforts to combat smoking.

Smoking: A Preventable Killer

Smoking is a chronic disease causing many illnesses. It is the leading preventable cause of death. Smoking cessation is associated with an improvement in life expectancy and quality of life, the greater the earlier the cessation, but even after the age of 60 it is associated with an increase in life expectancy [3].

Cancer

In 2022, there will be 20 million new cases and 9.7 million deaths from cancer. It is estimated that there will be more than 35 million new cases of cancer in 2050, an increase of 77% compared with 2022, particularly in low- and middle-income countries, where cancer mortality will double [4].

Smoking is associated with an increased risk of most cancers.The harmful effects of smoking are exacerbated by other factors (alcohol abuse, malnutrition, viral infections, air pollution) [3,4]. Smoking is the main cause of lung cancer (12.4% of all new cancer cases and 18.7% of all cancer deaths). The prevalence of this cancer is increasing in all countries and its incidence could rise by 47% between 2020 and 2040 [4].

The risk of cancer decreases with the length of time smokers have quit [3]. In Korea, a retrospective cohort study of 3 million smokers aged 30 years and older showed that the risk of cancer decreased after 10 years of smoking cessation (HR=0.83 ; 95% CI: 0.80-0.86) compared with continued smoking. The reduction in the risk of lung cancer is more pronounced for quitting before the age of 50 (HR=0.43; 95% CI: 0.35-0.53) compared with quitting at the age of 50 or older (HR=0.61 ; 95% CI: 0.56-0.66). Smoking cessation also reduces the risk of perioperative complications from excisional surgery and the risk of recurrence after cure, it increases life expectancy and quality of life in patients treated for cancer [5].

Cardiovascular Disease

Nearly two million deaths per year are attributable to smoking- related cardiovascular diseases, and the socioeconomic costs of these diseases will rise sharply by 2050 [6].

In high-income countries, tobacco-related cardiovascular mortality is tending to decrease among men, but is increasing among women. In France, for example, the incidence of myocardial infarction before the age of 65 increased by 50% in women (16% in men) between 2005 and 2014. For the same level of smoking, women have a 25% higher risk of coronary heart disease than men [7]. Almost 75% of deaths from cardiovascular disease occur in developing countries, where people have less access to primary health care, screening and early treatment of these diseases.

Mortality from coronary heart disease is reduced by 35% after 2 to 4 years of smoking cessation and by 50% after 10 years. Smoking cessation helps prevent coronary heart disease in young people, where smoking is the main cause. Quitting also reduces the risk of death or reintervention after coronary artery bypass graft surgery or angioplasty, stroke, abdominal aortic aneurysm and obliterative arteritis of the lower limbs [3,7].

Chronic Obstructive Pulmonary Disease

COPD is the fourth leading cause of death worldwide (4.7% of annual mortality), affecting 10.3% of the world’s population, and its prevalence is expected to increase by more than 20% by 2050 [6]. The socioeconomic costs of smoking are increasing, particularly in low- and middle-income countries [8].

Tobacco smoke is the main risk factor for COPD, and women are more susceptible than men [9]. Smoking accelerates the decline in lung function, which is a source of disability. It increases the frequency of exacerbations, leading to death and hospitalisation, and the development of cardiovascular, metabolic and cancer-related comorbidities [9].

Stopping smoking is associated with a reduction in patient-reported symptoms of chronic bronchitis within one to two months. It slows the decline in lung function (FEV1) in COPD patients and reduces the risk of respiratory infections, exacerbations, hospitalisations, death and smoking-related co-morbidities [3,9].

Diabetes

In 2021, 10.5% of adults aged 19-75 worldwide had diabetes mellitus; 90% of them lived in an emerging country. Diabetes will cause 6.7 million deaths. By 2045, 12.2% of adults will have diabetes, and the explosion in the number of cases, in which smoking is a key factor, will place a socioeconomic burden on all countries [10]. The prevalence of smoking is 20.8% in patients with type 2 diabetes and 10-30% in those with type 1 diabetes [11].

Smoking increases insulin resistance, the risk of prediabetes and diabetes in the general population, and gestational diabetes. Diabetic smokers have a 48% excess risk of premature death from all causes and a 36% excess risk of cardiovascular mortality. Smoking increases the risk of macroangiopathy and microangiopathy, hospitalisation for infections, cancer and depression [10,11].

In people with diabetes, smoking cessation reduces the risk of premature mortality, cardiovascular disease and progression of microangiopathy lesions. It also reduces the risk of cancer, hospitalisation for infections and maternal-foetal complications in gestational diabetes. Finally, it facilitates glycaemic control and reduces symptoms of anxiety and depression [11].

HIV Infection

Worldwide, 39 million people are living with HIV ; 630,000 die and 1.3 million are newly infected each year [12]. Antiretroviral therapy (ART) has significantly reduced AIDS-related mortality, but the proportion of deaths from non-AIDS-related causes has increased, mainly due to smoking, which is twice as common as in the general population [13].

HIV-infected smokers have lower CD4 cell counts, higher HIV viral loads and lower self-reported quality of life than HIV-positive non-smokers. Their risk of dying from cardiovascular disease, cancer or bacterial pneumonia is twice as high and with equivalent ART, smokers have a life expectancy 12 years less than non-smokers. [14].

Smoking cessation among people living with HIV is associated with a reduction in all-cause and smoking-related mortality compared with compared with continuous smokers. Stopping smoking reduces the risk of cardiovascular disease, bacterial pneumonia, COPD and cancer, especially lung cancer [13]. WHO recommends that smoking cessation interventions be integrated into HIV care [12].

Tuberculosis

In 2023, tuberculosis (TB) was no longer among the top ten causes of death worldwide, but it still caused 1.3 million deaths. Nearly 8 million new cases of TB were diagnosed: 410,000 people developed a multidrug resistant or resistant to rifampicin TB [15].

More than 80% of TB case and 90% of TB deaths occur in developing countries. The main drivers of the TB epidemic are the spread of HIV and drug-resistant TB, but smoking is responsible for 17.6% of TB case and 15.2% of deaths in high-burden countries [16]. Smoking, whether active or passive, triples the risk of tuberculosis infection and disease, particularly severe and infectious lung disease, forms resistant to anti-tuberculosis drugs, mortality and disease recurrence, and treatment failure [16].

Smoking cessation among smokers with TB is associated with better treatment adherence, higher cure rates, lower mortality and fewer relapses [16]. WHO recommends that TB and tobacco control should be tackled simultaneously to end the TB epidemic, which is one of the United Nations Sustainable Development Goals [17].

Environmental Health Risks

The WHO estimates that 12.6 million deaths worldwide (23% of all deaths) are attributable to the environment; 75% of pollution-related deaths occur in developing countries. Every year, tobacco production, processing and transport emit 84 million tonnes of CO2, contributing to global warming [18].

Air pollution and passive smoking are responsible for 35% of all cases of bronchopulmonary disease worldwide [18] Cigarette smoking produces toxic substances in mainstream smoke (inhaled by the smoker), second-hand smoke (burning of the glowing end of the cigarette), third-hand smoke (deposition of tobacco residue on surfaces) and cigarette butts [19].

The toxic gases and particles produced (polycyclic aromatic hydrocarbons (PAHs), nitrosamines, aldehydes, ketones, alcohols, phenols, PM2.5 and PM10 microparticles) cause lung cancer, COPD, respiratory infections and allergies, as well as cardiovascular, metabolic (type 2 diabetes, thyroid dysfunction), intestinal and mental diseases [20]. These facts are a justification for tobacco control and smoking cessation.

Tobacco Control and Smoking Cessation

Financial Implications of Smoking

A report from the World Health Organization (WHO) estimates that the annual economic cost of smoking worldwide, including health expenditure, lost productivity, is approximately $1.4 trillion (1.8% of the annual global gross domestic product) and in the USA, the economic cost of smoking is nearly $300 billion a year. [20]. Of this amount, 40% affects developing countries. In France, despite a decline in smoking prevalence, the social cost of smoking is estimated at €156 billion annually, representing an annual cost of €2,300 per inhabitant, regardless of smoking status [21]. In Belgium, this cost reaches €20 billion per year and €2,000 per inhabitant per year [22].

Globally, at least 70% of tobacco consumption occurs in low- and middle-income countries. In addition to the morbidity and mortality associated with tobacco use, the cultivation, processing, and disposal of tobacco products pose environmental risks, including atmospheric pollution, global warming, and changes to ecosystems. These challenges impede the economic development of these countries.

Modalities of Tobacco Control

All forms of tobacco use are detrimental to health and well- being. Only a comprehensive, global approach to tobacco control, encompassing regulation of production, marketing and smoking cessation, can effectively safeguard individuals and the environment from the adverse effects of tobacco use.

The WHO Framework Convention on Tobacco Control (FCTC) – A Legal Framework for Tobacco Control

Adopted in 2003 and implemented in 2005, it has been ratified by 183 countries, representing 90% of the world’s population [21]. Its objectives are “to protect present and future generations from the health, social, environmental and economic consequences of tobacco use and exposure to tobacco smoke by providing a framework for the implementation of tobacco control measures by Parties at the national, regional and international levels, with a view to achieving sustained and substantial reductions in the prevalence of tobacco use and exposure to tobacco smoke”.

It has led to the implementation of tobacco control measures: (1) demand reduction (increasing tobacco price and restricting its availability, banning all forms of tobacco advertising, informing and warning the public, providing cessation services); (2) supply reduction (combating illicit trade, banning sales to minors, unit sales, vending machines); (3) evaluation, scientific and technical cooperation on tobacco control.

These measures have already led to a reduction in the prevalence of smoking worldwide, but the devastating effects will only be felt in the long term.

Strengthening Tobacco Control

Tobacco control needs to be continuously strengthened to meet new challenges [1]. For example, banning the sale of all new tobacco products (nicotine pearls and pouchs, disposable vaping products and non-tobacco flavors, the use of menthol) and restricting the places where tobacco is consumed (health units, urban and outdoor areas) will make it possible to reduce the trade and consumption of tobacco. Plain packaging must become the rule, the sale of tobacco products must be strictly regulated and fighting illicit trafficking must be stepped up. Finally, the policy of increasing tobacco prices must be pursued relentlessly. Taken together, these measures will denormalize the image of smokers and smoking [18,21].

The Protection of Young People is a Priority

Smoking often starts in adolescence, and young people are a prime target for the tobacco industry. Their brains are more vulnerable to the effects of psychoactive substances such as nicotine. The prevalence of smoking peaks between the ages of 25 and 35, and tobacco addiction makes it difficult to quit [1].

The promotion of a tobacco-free lifestyle from an early age is based on: (1) the strict application of tobacco control measures (regular and consistent increases in tobacco prices, bans on the sale of tobacco to minors and on new tobacco products: nicotine pearls and pouchs, disposable vaping devices, smoke-free schools, universities and transport); (2) parental information and smoke-free homes; (3) educational initiatives in schools aimed at strengthening young people’s psychosocial skills and critical thinking are effective [24]. All these measures contribute denormalizing tobacco use, preventing smoking and, more generally, addictive behaviour [24,25].

Various actors are involved in preventing smoking (tobacco, cancer, respiratory associations, etc.). In 2024, the theme of World No Tobacco Day was ‘Protecting children from tobacco industry interference’, which raised awareness of the tobacco industry’s harmful influence on young people [26]. Many countries are working towards a ‘tobacco-free adult generation’ in the next decade [22].

Helping People to Stop Smoking

Strategies to Help People Quit

The provision of smoking cessation services is explicitly included in the FCTC (Art. 14) [23]. Smoking cessation is the only way to reduce the morbidity and mortality associated with tobacco use.

Smoking cessation is part of the treatment of diseases related to tobacco use. Health professionals must be involved in this intervention, using evidence-based non-medication strategies (counselling to quit, cognitive behavioral therapy) [26] and medication strategies (nicotine replacement therapy, bupropion, varenicline) [28].

Medications to help people stop smoking are not widely available in low- and middle-income countries because of their high cost and the lack of trained prescribers. Only a public health framework that takes into account the specific characteristics of these countries and based on the denormalization of smoking, the training of health professionals in smoking cessation and the provision of smoking cessation medications by international health authorities, will enable them to implement effective tobacco control [29].

Strategies for Harm Reduction?

There is no threshold of consumption below which smoking is safe [30]. However, can strategies be proposed to reduce risks and harms associated with smoking?

Tobacco companies offer products that deliver nicotine without burning tobacco (heated tobacco, snus, nicotine pearls and pouchs), promising an alternative to traditional cigarettes. These products may reduce the harmful effects associated with smoke inhalation (lung cancer, COPD), but they maintain nicotine dependence, they are not free of toxicity and therefore not credible proposals [31].

The electronic cigarette (e-cig.) vaporizes a nicotine-containing liquid that is much less toxic than tobacco smoke, making it a potential tool for reducing the risks of smoking when used exclusively, although there are uncertainties about the safety of long-term use. Recent studies [28,32] show that e-cig. can help people to quit smoking; further studies are needed to determine whether this benefit applies to smokers in developing countries [33]. The increasing use of e-cigarettes by young people, especially disposable (puff) and high-nicotine devices (JUUL), could lead to nicotine addiction and subsequent cigarette smoking [34], which has led many countries [35] and the WHO to propose measures to prevent e-cig. use by young people [36].

Conclusion

Twenty years after the implementation of the FCTC, every country in the world is affected by the tobacco pandemic, the leading cause of preventable death. Tobacco control in all its forms remains a major public health challenge because of its health, socioeconomic and environmental consequences. More than ever, health professionals need to be involved in smoking prevention initiatives and in helping people to quit.

Contribution to the Article

All authors contributed to the writing and correction of this article.

Conflict of Interest

The authors declare that they have no conflict of interest.

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