Perioperative Analgesia in Crisis Situations: Patient Characteristics in COVID-19 from the PAIN OUT Registry

Abstract

Background: To evaluate analgesic practices in perioperative treatment during the SARS-CoV-2 pandemic; recording parameters collected in the PAIN OUT database, and to compare COVID and no-COVID data. Methods: Data were analyzed for 277 patients (87 COVID-19 confirmed diagnosis and 190 non-COVID): years aged, gender, minutes of surgery duration, Likert Scale punctuation, hours in severe pain, minimum and maximum pain intensity, interference with sleep quality, anxiety, need for help, nausea, drowsiness, itching, dizziness, perception of care, pain relief, participation, satisfaction, and information received. Results: Postoperative mortality 1 month after surgery was recorded at 25.3% in COVID-19. Significant differences were found in postoperative pain intensity (p = 0.019), time with severe pain (p < 0.01), lower sleep quality (p < 0.01), and better outcomes in functional items (p < 0.01); there were more side effects and satisfaction with pain relief (p < 0.01) in COVID-patients than with no COVID-19 patients. Conclusions: In conclusion, COVID-19 patients presented greater intensity and duration of severe postoperative pain, greater somnolence, pruritus, and dizziness, lower physical activity limitation, and higher quality index.

1. Introduction

The coronavirus SARS-CoV-2 was identified as the etiologic agent of a newly emerging clinical picture named COVID-19 (Coronavirus Disease) [1]. This syndrome is characterized by respiratory manifestations from mild cough, asthenia, and fever to severe acute distress syndrome and sepsis. Other less common symptoms are neurological (headache, anosmia, dysgeusia), cardiovascular (thromboembolism, myocarditis, shock), digestive (diarrhea, vomiting), and skin [2]. Despite the limited scientific evidence, an increase in perioperative morbidity and mortality in surgical patients with SARS-CoV-2 infection has been reported [3].

At present, there are no protocols and guidelines for the administration of drugs and non-pharmacological analgesic measures to treat acute postoperative pain in these patients. This is crucial in global crisis, where greater efficiency is required in managing limited resources, using the minimum occupancy of operating rooms and hospital beds [4,5]. The use of opioids and other analgesic drugs could influence the evolution of the syndrome [6], and the lack of pharmacological protocols could favor the appearance of complications and even worsen the opioid crisis [7].

PAIN OUT is an international project for quality improvement in postoperative pain management, registered in ClinicalTrials.gov with code NCT02083835, approved and financed by the European Commission; 7th Framework Program (Grant Agreement no. 223590). This study registered variables of health conditions (cerebrovascular accidents, hypertension, heart disease, diabetes mellitus) and chronic treatments with corticosteroids, NSAIDs, and other medications used in the treatment of pain in surgical patients [8,9].

The main objective was to evaluate analgesic practices in perioperative treatment during the SARS-CoV-2 pandemic. The specific objectives were recording parameters collected in the PAIN OUT database in patients with positive serology to SARS-CoV-2, analgesic treatments, pain intensity, and infection severity data, and comparing them with surgical non-COVID patients.

2. Materials and Methods

2.1. Study Design, Participants, and Registration

A prospective study was approved by the local Ethical Committee on 30 April 2020, with code PI 20-1774 in patients with positive SARS-CoV-2 serology (rapid antibody test or ELISA) or positive naso/oropharyngeal Polymerase Chain Reaction (PCR) swab, undergoing surgery in centers that expressed agreement and signed written informed consent to participation in the study, between 16 June and 20 December 2020, who met the inclusion criteria (more than 18 years aged, scheduled or urgent surgery in the hospitals participating in the study, positive serology for SARS-CoV-2 or positive PCR, with signed consent for entry into the research and do not meet exclusion criteria (no inclusion criteria, no signed study entry consent acceptance, inability to understand the questionnaire: hearing impairment, cognitive dysfunction, not fluent in the language of the questionnaire; and drug addicts)).

2.2. Data Collection

Data were recorded on the comorbidities most frequently associated with expressions of COVID-19 severity and variables collected in the PAIN OUT database and clinical expression data as it recorded the variables summarized in

Table 1. Variables in the study.

Pain out Questionary
Demographic characteristics: gender, weight, height, country of birth, comorbidities (cancer, renal failure, psychiatric disease, diabetes, arterial hypertension, ischemic heart disease, hematologic disease, digestive disorders such as liver cirrhosis, peptic ulcer, irritable bowel, respiratory disease such as chronic bronchitis, asthma, sleep apnea; fibromyalgia; musculoskeletal systems such as rheumatoid arthritis, fibromyalgia or osteoarthritis; recent surgeries; polytrauma, etc.), pregnancy or lactation; chronic treatments (opioids, corticosteroids, NSAIDs, Cox-inhibitors, acetaminophen, antidepressants, antiepileptics, others)
2. Anesthetic-surgical data of the intervention: premedication (sedatives, analgesics, opioids or others), data of the intervention (surgical procedure, duration of the intervention, anesthetic technique used (general: inhalation or intravenous; regional: epidural, intradural, truncal, or interfascial), analgesics used during the intervention (clonidine, dexamethasone, dexketoprofen, diclofenac, ibuprofen, ketamine, ketoprofen, metamizole, naproxen, nefopam, paracetamol or others), as well as the route of administration and dosage; infiltration of the surgical wound; use of opioid drugs and local anesthetics, route of administration and dosage.
3. Data collected in the post-anesthesia recovery unit: drugs used (non-opioids, opioids), route of administration, and dosage.
4. Medication administered in the hospitalization unit, at least 5 h after the operation and the degree of pain intensity.
5. Pain intensity: the maximum and minimum postoperative pain (according to the NVS scale, or VNPS (where 0 is no pain and 10 is the maximum intensity) endured at the time of data collection, percentage of pain duration of high intensity.
6. Interference of pain with in-bed and out-of-bed activity: deep inspiration, mobility (ambulation, sitting in a chair), time and intensity of sleep, percentage of time up.
7. Psycho-physical repercussions of pain or its treatments: anxiety, need for help, adverse effects (nausea, drowsiness, dizziness, pruritus, others).
8. Perceived quality of analgesic treatment: the possibility of requesting further analgesic treatment, degree of satisfaction with analgesic treatment, quality of the information received about analgesic options, degree of pain relief received, and the possibility of participation in decisions about their treatment.
Clinical expression: Likert severity scale (0–4)
0: asymptomatic patients, 1: uncomplicated disease (local symptoms: sore throat fever, myalgias/arthralgias, ageusia, anosmia, atypical symptoms); 2: mild symptoms: pneumonia confirmed by chest X-ray without signs of severity (SaO2 greater than 90% with FiO2 0.21), CURB65 Scale > 1; or existence of any of the following parameters: age > 65 years, confusion, urea nitrogen > 19 mg/dL or 7 mmol/L, respiratory rate greater than 30/minute); 3: severe pneumonia: more than one organ failure or SaO2 less than 90% on room air or respiratory rate greater than 30 or systolic blood pressure less than 90 mmHg or diastolic blood pressure less than 60 mmHg); 4: respiratory distress, sepsis, or septic shock, defined as respiratory distress by clinical and radiographic findings (bilateral infiltrates) and mild PaO2/FiO2 of 200–300 mmHg, moderate PaO2/FiO2 of 100–200 mmHg or severe PaO2/FiO2 of less than 100 mmHg; sepsis: defined as organ dysfunction and can be identified as an acute change in the SOFA scale >2 points (http://www. samiuc.es/sofa-score/) or a quick SOFA (qSOFA) with 2 of the 3 following clinical variables: Glasgow < 13, systolic pressure < 100 mmHg and respiratory rate > 22/minute. Organ failure may be manifested by the following alterations: acute confusional state, respiratory failure, oliguria, tachycardia, coagulopathy, metabolic acidosis, lactate elevation, and septic shock: arterial hypotension if response to volumetric refill and vasopressors to maintain mean arterial pressure of 65 mmHg and lactate > 2 mmol/L (18 mg/dL) in the absence of hypovolemia.
Microbiological data: results of serological tests, quantification, and/or PCR.

NSAID: Non-Steroidal Anti-Inflammatory Drugs, PCR: Polymerase Chain Reaction, NVS: Numerical Visual Scale, VNPS: Verbal Numerical Pain Scale; Symptomatology: fever, respiratory symptoms (dry or productive cough, sore throat, dyspnea, cold, nasal congestion), fatigue, headache, myalgia, digestive (diarrhea), anosmia, ageusia, or others).

.

In all cases, the delivery of the questionnaires to the patients and the entry of the data in the database designed for the study were carried out by researchers outside the healthcare personnel responsible for the patient’s care. Data were collected at three points in time: in the immediate postoperative period (in the first 24 h after the end of the operation and at least 6 h later), 1 week, and 1 month after the operation.

2.3. Sample Size and Statistically Analysis

Finally, statistical analysis was conducted on all the data collected in the study. To define the continuous variables, the mean was used as a measure of central tendency and the standard deviation was used as a measure of dispersion. The Shapiro–Wilk test was applied to demonstrate the tendency of a normal distribution in the quantitative and qualitative variables according to their frequency distribution.

The sample size was calculated, taking into account a population of 1006 people with laboratory COVID-19 diagnostic and surgical indication, a margin of error of 10%, and a confidence interval of 95%, obtaining a result of 88 patients. This sample size determined a power greater than 80% for the majority of outcomes when compared with the control population (n = 190).

The association of qualitative variables was analyzed using Pearson’s Chi-square test. If the number of cells with expected values less than 5 was greater than 20%, Fisher’s exact test or the likelihood ratio test for variables with more than two categories was used. Significant values were considered in the case of p-values ≤ 0.05.

In case of correlation between postoperative pain intensity, certain drugs recorded, and disease evolution data, Fisher’s exact test was used, after designing the necessary 2 × 2 contingency tables. The statistical data analysis was performed by applying descriptive statistics using the SPSS vs. 22 statistical packages for Windows.

3. Results

During the study period, 22,135 patients were assisted in hospital centres; 10,702 of them were diagnosed as COVID-19 patients, and 2980 (27.84%) of them were scheduled for surgery. Their age was 64.77 ± 21.10 (0–105) years, and the gender distribution was predominantly female (1934 patients) (54.9%). A COVID-19 or a compatible clinic attended to the majority (88.63%) of patients (9485), but only 1006 cases had a laboratory-confirmed diagnosis (10.61%). A mortality rate of 24.1% (2575 cases) was recorded.

A total of 2425 surgical patients had undergone procedures included in the PAIN OUT database (

Table 2. Number of patients analyzed in the study and the percentage, with respect to the total number of patients requiring hospital admission.

Types of Surgery	Frequency	Percentage of Incomes
Vascular surgeries	131	0.6
Cardiac surgery	25	0.1
General and digestive surgery	960	4.3
Pediatric surgery	23	0.1
Plastic surgery	73	0.3
Thoracic surgery	59	0.3
Neurosurgery	162	0.7
Otorhinolaryngology	214	1.0
Orthopedics	524	2.4
Urology	264	1.2
Total	2435	11

).

After crossing the databases of hospitalized patients and the patients undergoing surgeries studied in PAIN OUT study, only 604 met the study criteria; only 41 patients had a laboratory-confirmed diagnosis of COVID-19 disease (6.8%), 143 (23.7%) presented compatible symptoms, and there was no information on 387 patients (64.1%). Only 33 patients (5.5%) had laboratory confirmation of being free of SARS-CoV-2.

Data from 277 patients registered in the PAIN OUT database were analyzed during the study period; 87 of them received a clinical/radiological or microbiological diagnosis of COVID-19. The sample population was 67.55 ± 15.714 (27–97) years aged; with predominance of the male gender (47 men and 40 women). The data that could be obtained from the PAIN OUT study questionnaire were analyzed (

Table 3. Characteristics of patients undergoing surgery with clinical suspicion of COVID-19 disease.

Variables	Minimum	Maximum	Median	Standard Deviation
Duration (min)	33	600	200.7	118.6
Age (years)	27	97	67.6	15.7
Likert Scale (0–4)	0	4	1.6	1.5
Time in severe pain (h)	0	15	4.6	3.2
Minimum pain intensity (EVA Scale)	0	6	1.1	1.6
Maximum pain intensity (EVA Scale)	0	9	5.7	2.2
Interference of pain with movement in bed (0–10)	0	7	2.3	2.4
Time to get out of bed (h)	0	8	3.7	2.4
Exacerbation of pain with cough (0–10)	0	7	3.6	1.7
Interference with sleep quality (0–10)	0	8	4.4	2.9
Out-of-bed activities (0–10)	0	5	1.9	1.8
Anxiety (0–10)	0	10	4.8	3.2
Need for help (0–10)	0	10	3.8	3.1
Nausea (0–10)	0	9	1.7	2.5
Drowsiness (0–10)	0	9	3.7	2.7
Itching (0–10)	0	9	2.8	2.1
Dizziness (0–10)	0	8	3.8	2.3
Perception of care (10–100)	10	100	51.7	28.3
Pain relief (0–10)	2	10	6.6	2.5
Participation (0–10)	2	10	7.3	2.9
Satisfaction (0–100)	50	100	79.8	17.5
Information received (0–100)	50	100	81.7	17.6

).

Postoperative mortality 1 month after surgery was recorded in 22 patients (25.3%). The surgeries were as follows: tracheotomy in 11 patients, right colectomy (2), femoral osteosynthesis (2), thoracoscopy (1), surgical wound dehiscence (1), radical hysterectomy (1), femoral-popliteal bypass (1), pectoral hematoma (1), sigmoidectomy (1), and intestinal resection and anastomosis (1). All of them presented confirmed COVID-19.

General anesthesia was more frequently used (67 cases, 77%) versus regional (18 cases, 20.7%) or sedation (2 cases, 2.3%).

Symptoms compatible with COVID appeared in only 21 cases (24.1%). In 54 cases (62.1%), after a negative preoperative PCR test, laboratory results were positive during postoperative admission.

Of the 87 patients studied, 61 (70.1%) had risk factors included in the PAIN OUT study. There were 4 cases of depression (4.6%), 3 strokes (3.4%), 11 dyslipidemia (12.6%), 13 arterial hypertension (14.9%), 8 alcoholism (9.2%), 2 psychiatric diseases (2.3%), 8 type 2 diabetes (9.2%), 1 asthma (1.1%), 3 irritable bowel syndrome (3.4%), 10 cancer (11.5%), 2 coronary heart disease (2.3%), 2 patients with cirrhosis (2.3%), 2 osteoporosis (2.3%), 7 renal failure (8%), 4 anemia (4.6%), 10 atrial fibrillation (11.5%), 4 pulmonary thromboembolism (PTE) (4.6%), 3 deep vein thrombosis (DVT) (3.4%), 3 obesity (3.4%), 10 smokers (11.5%), and 9 former smokers (10.3%).

Regarding chronic treatments, 2 patients were taking corticosteroids (2.3%) and 38 (43.7%) were taking opioids/IECAs or NSAIDs.

Data from 190 no-COVID-19 surgical patients registered in the PAIN OUT database were compared with the 87 COVID-19 patients operated on during the study period.

General anesthesia was the most frequently used technique in COVID-19 (77% of cases) versus locoregional anesthesia in no-COVID (56%). The differences were significant with p ≤ 0.01.

There were no significant differences in gender between groups, with a greater predominance of the male sex in COVID (54%) compared to no-COVID (50.2%).

Comorbidities were higher in COVID (69%) than in no-COVID (32.1%), with a statistical significance of p ≤ 0.001. Risk factor differences related to the occurrence of chronic pain appeared significant (p ≤ 0.05) in alcoholism (higher in COVID), inflammatory bowel disease (higher in COVID), renal failure (higher in COVID), and obesity (higher in no-COVID).

The chronic drug treatments associated with increased incidence or severity of SARS-CoV-2 infection, including opioids, angiotensin-converting enzyme inhibitors, and nonsteroidal anti-inflammatory drugs (NSAID), were found in 26 (29.9%) of the patients studied.

The enrollment of patients on chronic opioid therapy was significantly higher (p = 0.001) in no-COVID base (20%) versus COVID (4.6%). The most commonly used were transdermal fentanyl or oral morphine.

NSAIDs were used in higher proportion (p ≤ 0.001) in no-COVID (57.3%) than in COVID (17.2%).

Angiotensin inhibitors were used in 10.3% of COVID-19 patient cases (

Table 4. Correlation in risk factors between COVID and no-COVID patients. Significant differences. The PAIN OUT registry collects other data from surgical patients that did not show significant differences (arterial hypertension, psychiatric diseases, diabetes, asthma, oncology pathology, chronic bronchitis, coronary artery disease, chronic corticosteroid therapy, fibromyalgia, peptic ulcus, cirrhosis, rheumatoid arthritis, osteoporosis, renal failure (dialysis), anemia, non-smokers, atrial fibrillation, pulmonary thromboembolism, deep vein thrombosis, or obesity). p value was considered significant to p ≤ 0.05 and β ≥ 0.08 power values.

	COVID-19 (%)	Non COVID-19 (%)	p Value	β Power
Alcoholism	9.2	0.9	0.01	0.874
Type 2 diabetes	9.2	0.9	0.01	0.874
Inlammatory bowel disease	3.4	0	0.02	0.115
Renal insufficiency	8	2.8	0.057	0.497
Smokers	11.5	2.9	0.045	0.777
Obesity	3.4	15.1	0.005	0.868

).

As for chronic analgesic medication, 29.9 percent of the patients studied were found to be on chronic analgesics treatment; most of them in NSAIDs therapies (

Table 5. Percentage of patients on chronic analgesic medication. p value was considered significant to p ≤ 0.05 and β ≥ 0.08 power values.

Analgesics	COVID-19 (%)	Non COVID-19 (%)	p	β
Opioids	4.6	20	0.001	0.957
NSAIDs	17.2	57.3	<0.001	0.999

). Significant differences were found between COVID and non-COVID patients, both in the use of opioids and NSAIDs.

4. Discussion

An increase of 5% in the number of surgical procedures performed worldwide has been observed annually, along with an increase in the complexity of these procedures and patients’ comorbidities. Nevertheless, between 30–80% of patients experience moderate to severe acute postoperative pain (APP) after the first 24 h postoperatively, despite better pathophysiological knowledge, the use of new techniques and analgesic drugs, the publication of new guidelines, and the creation of Acute Pain Units (APU) [10].

Surgical activity had to be interrupted due to the extraordinary demand for medical care caused by the pandemic. In Leon and Castille, in Spain, 22,135 patients were attended, and 10,702 (48.35%) required hospital admission. This resulted in an overload of the hospital system. Only 2980 were operated on. This would equal less than one-tenth of the usual surgical activity [11]. COVID-19 has led to cancellations of elective surgery and changes in treatment options, reducing surgical activity in the World [12].

In our work, 9425 (81%) of the hospitalized patients were attended by COVID-19 or a compatible clinic, but only 1006 of them (13.5%) presented conclusive laboratory tests (PCR tests or serology). This fact is confirmed by Arevalo-Rodriguez’s article, where they included 34 studies enrolling 12,057 COVID-19 confirmed cases. The findings reinforce the need for repeated testing in patients suspected of SARS-CoV-2 infection given that up to 54% of COVID-19 patients may have an initial false-negative RT-PCR [13].

A mortality rate of 24.1% was very high, but these data are in line with published mortality data for 2020 in Spain [14,15]; and Kivrak’s study, which found postoperative mortality of 25.3% 1 month after surgery in COVID-19 patients [16] and a 30-day postoperative complications rate [17]. In contrast, retrospective studies such as Mavrothalassitis’ concluded that outcomes of patients undergoing surgery and 30-day mortality after surgery were not compromised [18].

Acute postoperative pain is a common clinical condition requiring an evidence-based, planned, and multimodal approach [19].

General anesthesia was the most frequently used technique in COVID-19 patients (77% of cases) versus loco-regional anesthesia and analgesia techniques (56%), despite recommendations of various scientific societies to avoid aerosol-generating procedures, such as intubation or airway management maneuvers and preservation of respiratory function with regional anesthesia techniques [20,21,22,23]. After a review of the evidence, the American Pain Society formulated recommendations for postoperative pain management, including preoperative education, perioperative pain management planning, use of different pharmacological and nonpharmacological modalities, organizational policies, and transition to outpatient care [24,25].

In addition, several publications have demonstrated the presence of thrombopenia in COVID-19 patients, and therefore, the possible contraindication to regional blockades [26,27,28] limits its use.

Of the patients studied, 70.1% had risk factors related to the severity of COVID or increased postoperative pain intensity listed in the PAIN OUT database, the most frequent being hypertension (14.9%), dyslipidemia (12.6%), atrial fibrillation (11.5%), smokers (11.5%), and former smokers (10.3%). All of them associated were with high mortality [24]. This finding could be because, at the time of the study, surgical patients were only operated on if their lives were in danger, especially COVID-19 patients, to avoid risks of infection.

This finding could explain the high mortality recorded, in line with Silvapulle’s article, that recommended hospitalized or persistent symptoms patients undergo targeted organ-specific assessment using a combination of echocardiography, lung function tests, and biomarkers to provide quantitative estimation of perioperative risk [29]. Such information is crucial for the complex surgical decision-making and counseling of patients presenting with positive SARS-CoV-2 infection status. Further studies are required to understand the impact of new variants, large-scale vaccination, and new therapeutics on the postoperative outcomes of COVID-19 patients [30].

Higher rates of mortality and postoperative complications, especially thromboembolic events, have been significantly proven, among patients with perioperative SARS-CoV-2 infection compared with patients without SARS-CoV-2 infection. Moreover, matched SARS-CoV-2—infected patients had a higher risk of mortality even if they were asymptomatic at presentation [31].

Symptoms compatible with COVID-19 appeared in only 24.1% of patients, but in 62.1% of them, after a negative preoperative PCR test, the laboratory result was positive during postoperative admission. This could be explained by the low negative PCR predictive value, to which we must add asymptomatic patient contacts with not diagnosed COVID-19. These results agree with Rose’s article, which concluded that nucleic acid amplification confirmation is crucial. However, nucleic acid amplification in active COVID-19 infections unnecessarily can make testing cost-efficient [32].

The mortality rate that was registered was high but similar to other registries in critical patients [33] and the excess mortality rate due to the COVID-19 pandemic [34]. The difference between excess mortality and reported COVID-19 deaths might be a function of underdiagnosis due to insufficient testing, reporting challenges, or higher-than-expected mortality from other diseases due to pandemic-related changes in behaviors or reduced access to health care or other essential services.

The presence of certain risk factors such as age (younger than 54 years), preoperative pain in the surgical area, female gender, duration of surgery longer than 90 min, preoperative opioid administration, anxiety, and the need for help with pain have been associated with a higher frequency and longer time of severe postoperative pain and the need for more analgesic treatment [35]. Stamenkovic’s study demonstrated that a small set of evidence-based interventions is associated with improved outcomes in perioperative pain. The interventions were a full daily dose of one to two nonopioid analgesics (eg, paracetamol and nonsteroidal anti-inflammatory drugs), at least one type of local/regional anesthesia, pain assessment by staff, and offering patients information about pain management [8].

Clinicians are now equipped with an armamentarium of therapies based on high-quality evidence to manage COVID-19 patients: anti-inflammatory agents, antivirals, antithrombotics, therapies for acute hypoxaemic respiratory failure, anti-SARS-CoV-2 (neutralizing) antibody therapies, modulators of the renin-angiotensin-aldosterone system, EK1C4, resveratrol, melatonin, and vitamins [36,37].

In this study, only 43.7% of patients were on opioids, angiotensin inhibitors, and non-steroidal anti-inflammatory drugs treatment; and 2.3% were treated with corticosteroids.

The study’s main limitation is that the suspicion and diagnosis of the COVID disease were difficult at the moment the study was done. Proof of this is the large number of errata published in the original studies on this topic. Currently, the most sensitive test is PCR of gold or nasopharyngeal exudate, although the false negative rate is high and depends on numerous factors. On the other hand, the study has the limitations inherent to the PAIN OUT study: Several factors are involved in the appearance of postoperative pain (included in the study variables), and it is difficult to establish homogeneous groups for comparison; each center collects and analyzes its data using different statistical analysis methods. The high mortality recorded prevents extrapolation of the results to other COVID-19 patients with fewer preoperative risk factors.

In conclusion, despite the high percentage of patients with risk factors for developing severe postoperative pain, no special analgesic measures were applied. A large improvement margin is demonstrated in tracking of current guidelines for acute postoperative pain management, such as multimodal perioperative analgesic strategies and patient information. It was found that there was a greater intensity and duration of severe postoperative pain, greater somnolence, pruritus, and dizziness in COVID-19 patients. The limitation of physical activity was lower and the perceived higher quality index than in non-COVID patients.

The individualized study of the patients and the severity of the disease establishes the probability of postoperative complications in COVID-19 patients. Pain control must also take into account the variability among surgical patients.