Does Routine Sedation Influence Anxiety and CRP Levels in Patients Undergoing Elective Coronary Catheterization?

Background. Cardiac catheterization is associated with patient anxiety. Benzodiazepines are often used to relieve anxiety in this setting. The association between anxiety level and C-reactive protein (CRP) remains equivocal. We sought to determine whether anxiety and CRP levels in patients undergoing elective left heart catheterization differ when routine sedation with midazolam is administered. Methods. Patients undergoing elective left heart catheterization were randomly assigned to receive 2 mg of midazolam intravenously or placebo before access insertion in a double-blinded manner. Levels of anxiety were assessed using the State-Trait Anxiety Inventory for Adults (short form) and high-sensitivity CRP at the time of admission and discharge. Surrogate markers for anxiety, such as blood pressure and pulse, were recorded before and after the procedure. Patient-perceived discomfort was measured with a visual analog scale (VAS) on a 0-10 scale. Results. One hundred patients (52 receiving treatment, 48 receiving placebo) participated in the study. Baseline demographic characteristics and previous medical conditions were well balanced between groups. Anxiety level, systolic blood pressure, and diastolic blood pressure were all higher at procedure start than post procedure, but did not differ between the groups. CRP levels were similar at both time points for patients in both groups (0.77 ± 2.53 mg/L pre procedure and 0.70 ± 2.08 mg/L post procedure in the midazolam group vs 0.79 ± 1.39 mg/L pre procedure and 0.83 ± 1.45 mg/L post procedure in the placebo group). Discomfort level assessment was also alike (2.6 ± 2.4 in the treatment group vs 3.4 ± 2.5 in the placebo group; P=.12). Conclusions. Intravenous midazolam administration does not seem to relieve patient discomfort and anxiety nor does it influence CRP level. Therefore, an approach tailored to the patient is advisable.

J INVASIVE CARDIOL 2021;33(12):E993-E997. Epub 2021 November 24.

Key words: anxiety, CRP, elective catheterization, midazolam, sedation

Cardiac catheterization is associated with patient anxiety.¹ Pharmacological and non-pharmacological interventions to ease anxiety have been tested with an excellent safety profile, although with variation in efficacy.^2-6 The use of anesthesia in cardiac procedures seems to vary significantly⁷ and is influenced by geography, culture, hospital policy, and patient preference. Benzodiazepines are often the drug of choice for most cardiologists, followed by opiates or a combination of both.⁸

Anxiety and its associated disorders are common in patients with cardiovascular disease and may significantly influence cardiac health. Anxiety disorders are associated with the onset and progression of cardiac disease, and in many instances have been linked to adverse cardiovascular outcomes, including mortality.^9,10

Both anxiety and anxiety disorders are associated with increased inflammatory markers.⁹ Healthy individuals with elevated anxiety were found to have higher levels of inflammatory and coagulatory markers, including C-reactive protein (CRP).¹¹ Likewise, inflammatory pathways have been linked to the development and progression of cardiac disease.

This study examines whether the routine administration of intravenous midazolam during elective cardiac catheterization influences anxiety, CRP, and patients’ perceived discomfort levels.

Patients. Consecutive patients admitted for elective coronary angiography at Ziv Medical Center in Safed, Israel were enrolled in the study. Patients were excluded for the following reasons: (1) known anxiety disorder; (2) use of benzodiazepines (regularly or frequently ≥2x weekly); (3) known hypersensitivity to benzodiazepines; (4) febrile disease in the week prior to admission or known chronic inflammatory disease; or (5) use of home oxygen therapy. Upon admission and after consent was obtained, patients were asked to complete a questionnaire evaluating the current anxiety level as well as their trait anxiety, the State-Trait Anxiety Inventory (STAI) for adults (20-question “short form”). Venipuncture and complete blood counts, electrolytes, creatinine, blood urea nitrogen, and high-sensitivity CRP were obtained in the usual manner. The study protocol was approved by the medical center’s institutional review board; subsequently, given the choice to register the study in the clinical trials database, we decided to forego this option.

Procedure. Participating patients were randomly divided into 2 groups: (1) patients in the treatment group, who received 2 mg of midazolam; and (2) patients in the control group, who received a placebo. Patient demographic data were recorded in the catheterization laboratory. Both the study drug and placebo were prepared by the medical center’s pharmacy staff in identical 5 mL syringes filled with either 2 mg/2 mL midazolam or 2 mL 0.9% sodium chloride. Participating patients and medical staff were blinded to the treatment arm. Patient randomization was carried out using sealed envelopes containing a piece of paper marked with either “A” or “B” by the pharmacy staff before drug preparation. Syringes were marked according to treatment arm with “A” or “B.” Upon preparing and draping the wrist for access insertion, the study drug/placebo was administered by the nurse. The patient’s vital signs, including blood pressure, heart rate, and oxygen saturation, were recorded throughout the procedure as required by hospital protocol for all patients receiving sedation or anesthesia. All technical procedural aspects, including catheters, balloons, stents, and given drugs, were at the operator’s discretion. Operators were free to add any chosen drug (including midazolam or opiates) if deemed necessary during catheterization.

The following day, before discharge, the patient’s anxiety level was assessed again with the STAI inventory and blood was drawn for CRP measurement. Moreover, patients were asked to rate their procedure-related discomfort with a visual analog scale (VAS) on a 0 to 10 scale, with 0 corresponding to “no discomfort” and 10 to “extreme pain and discomfort.”

Statistical analysis. Descriptive statistics for the study population are presented as mean ± standard deviation for continuous variables and number (%) for categorical variables. All statistical tests were considered statistically significant when the P-value was <.05. Data analyses were performed using Statistical Package for Social Sciences, version 24 (IBM Corporation).

One hundred patients (52 in the treatment group and 48 in the control group) were recruited. Baseline demographic characteristics, including age, gender, body mass index, and previous medical conditions, were well balanced between groups (Table 1). All procedures were performed transradially. The indication for angiography was either evaluation of anginal symptoms or the completion of full revascularization (staged percutaneous intervention). Most procedures did not include coronary intervention (71% in the treatment group vs 63% in the control group; P=non-significant).

Anxiety levels and vital signs, including systolic, diastolic and, mean blood pressure, were all higher pre procedure than post procedure (Table 2). No significant difference was seen between the treatment and control groups. Patient heart rates in both groups were higher upon completion of angiography, with no differences between the groups. High-sensitivity CRP levels were overall low and did not differ pre/post procedure or between the treatment and control groups (Table 2).

The mean trait anxiety was similar for both groups (17.4 ± 4.8 in the treatment group vs 16.8 ± 5.2 in the control group; P=.54). As expected, anxiety levels were significantly higher in both groups before angiography (19.2 ± 6.1 in the treatment group vs 19.0 ± 6.6 in the control group; P=.90) than post procedure (15.8 ± 5.8 in the treatment group vs 15.9 ± 6.1 in the control group; P=.93), but no effect was noticed that could be attributed to midazolam treatment (Table 3). Furthermore, the patient-perceived level of discomfort/pain was low and similar between the 2 groups (2.6 ± 2.4 in the treatment group vs 3.4 ± 2.5 in the control group; P=.12). Interestingly, anxiety levels were similar in the subgroup of patients who had an angiogram before the index procedure, or myocardial infarction, compared with naïve patients (Table 4). None of the patients required additional sedation/analgesia following the administration of the study drug or placebo.

Our findings show that routine administration of intravenous midazolam did not influence patients’ anxiety levels. Moreover, CRP levels and patient discomfort were not influenced by the drug administration.

Several options for reducing patient anxiety exist, including pharmacological and non-pharmacological approaches. Although non-pharmacological techniques are efficient,² they cannot be implemented ad hoc and are therefore of limited value in a catheterization laboratory setting. Therefore, the use of drugs, mainly benzodiazepines and opiates, is often the preferred option for many operators.

Previous studies have evaluated the efficacy of midazolam as a means to reduce anxiety. While most studies demonstrated an excellent safety profile,^12,13 the efficacy of midazolam at reducing anxiety and discomfort was moderate, as not all patients experienced relief despite the drug therapy.^3,4,14 Moreover, benzodiazepines were administered for reducing anxiety while using one of a variety of protocols (eg, intravenous vs oral; solely or in combination with other drugs) and the studies examined several different endpoints (anxiety level, discomfort level, or pain). Even when anxiety was measured, different questionnaires were used. It appears that there is no uniform, generally accepted method for the measurement of anxiety level in this setting. We used the STAI for adults due to its extensive use as a research tool, including the assessment of environmental stress in the setting of medical procedures.¹⁵ For practical reasons only, the inventory’s short version was chosen. Taken together, the wide heterogeneity in study design, drug application, tools of anxiety assessment, and other factors hinder the option of drawing a clear conclusion from previous works.

The timing and mode of drug application in our work (before access insertion and intravenous use) represent common practices in many institutions and were previously tested in a large-scale randomized trial.⁸ The rapid onset of drug action enables operators to “eyeball” patient anxiety level just before the procedure begins and, if deemed necessary, administer drugs. Although the primary outcome of the above-mentioned work was radial artery spasm, procedure-related patient discomfort was also reported. The use of the VAS scale, as well as timing (next morning), were similar in both studies. Nevertheless, we could not demonstrate a drug-related improvement in discomfort. The difference may be related to their use of a drug combination that included fentanyl and its analgesic properties, leading to overall improved patient experience with the procedure. Similar to this trial and previous studies, no intervention due to respiratory depression was required in any of the patients receiving the drug, strengthening previous experience related to drug safety.

Anxiety is a common finding among patients with cardiovascular disease, not only in the setting of coronary artery disease but also among patients with heart failure, cardioverter defibrillators, and those awaiting cardiac surgery.⁹ Inflammatory pathways play a significant role in the development of cardiac atherosclerosis and cardiac diseases. Several mediators, such as CRP, interleukins 1 and 6, and tumor necrosis factor-alpha, have all been linked to the development of these lethal illnesses.^16,17 Likewise, the same mediators associated with the inflammatory process that leads to cardiovascular disease are elevated in people with anxiety or anxiety disorders.^11,18,19 Therefore, addressing anxiety can theoretically be a novel approach for future therapy in those suffering from atherosclerosis.

Our findings did not demonstrate a significant change in CPR levels between patients receiving either midazolam or placebo. CRP levels were overall low in both groups before and after the procedure and anxiety levels were not reduced once the procedure was completed. Therefore, it seems that CRP cannot mirror anxiety levels in the setting of acute, procedure-related anxiety, unlike CRP levels in those having anxiety or anxiety disorder as a stable or chronic condition. Alternatively, the lack of change in CRP in both study groups may indicate the futility of midazolam in easing anxiety.

Study limitations. The main limitations of our study lie in its small, unpowered sample size and its single-center design. Nevertheless, lack of clear benefit at reducing anxiety with benzodiazepines was demonstrated in previous studies and therefore it is questionable whether large-scale trials will have different results. The measured CRP values in our work were low overall and variation between groups was minimal. If true anxiety-related CRP variation does exist, future large-volume trials will be needed to demonstrate such small variations.

Intravenous midazolam administration, although safe, does not seem to relieve patient discomfort and anxiety or influence CRP levels. Therefore, an approach tailored to the patient rather than routine use of midazolam is advisable.

Acknowledgments. We would like to thank our medical center pharmacy staff for their help in patient randomization and drug preparation, and the catheterization laboratory technicians and nurses for drug application and documentation of all procedural data.

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