key: cord-0313035-05od83aq
authors: Vega, S.; Gomez Blizniak, A.; Theoktisto Ballanis, S.; Cisneros, G.; Villalobos, D.; Armuelles, A. K.; Moreno, L.; Fusumada, F.; Gonzalez, J.; Romero, E.; Torres-Atencio, I.; Cubilla-Batista, I.; Goodridge, A.
title: Clinical characteristics of COVID-19 patients admitted to Intensive Care Unit in Panama during the first pandemic wave admissions in 2020.
date: 2022-05-10
journal: nan
DOI: 10.1101/2022.05.08.22274803
sha: a27141743bb95cf043165d5f46d3dc49efacaf0e
doc_id: 313035
cord_uid: 05od83aq

The severe acute respiratory syndrome Coronavirus 2 (SARS COV-2) caused a global pandemic of COVID-19. Most of people affected are admitted to hospital with various grades of ADRS. A small proportion of these patients requires intensive care unit management and treatment. However not all of them survive. This study aims to describe the epidemiological and clinical characteristics of patients admitted to the intensive care units in Panama main hospital in the first six months of pandemic with available information. Special focus has been oriented to blood and respiratory biomarkers to correlate with survivors and non-survivors. Our results show that patients between 56-75 years old, with hypertension, obesity, and diabetes comorbid conditions are more likely to die in intensive care units. Regarding the PaFi ratio, we observed a greater proportion of non-survivor with values less than 200. The triglycerides, urea nitrogen, creatinine and procalcitonin levels resulted significantly higher in those non survivors. During clinical management, half of patient that were administered Tocilizumab did not survived. These results support the notion that age, comorbidities as well as therapeutic management of patient in intensive care units contribute to the final outcome. We recommend reinforcing patient care strategy, especially in those patients with clinical conditions that favor fatal outcomes.

The severe coronavirus disease by SARS-CoV-2 (COVID-19) outbreak emerged in Wuhan, China in December 2019. In late January 2020, the World Health Organization related to the inhibition of ACE2 by the virus and consequently the systemic failure that induces death [4] .

During the health crisis of COVID-19, the differentiation of seriously ill patients in ARDS is critical for the decision-making of admission and management in intensive care units (ICU). In Panama, cases increased between 25% and 45% daily during the first peak of epidemic. From the experiences of China, Italy, and Spain, we know that up to 20% of positive COVID-19 cases will require hospital care and of this group, 1 in 4 will be severe and require ICU management [5] (Mahase, 2020). At this point in the pandemic, much more is known about the characteristics of the patients, and it is suspected that some of this data may help to predict or anticipate outcomes.

The studies that were carried out in countries such as China, the United States, Italy and Peru found that of the patients who enter ICUs between 68-85% have at least one comorbidity, in addition, the mean age of ICU admission found in different studies has ranged from 53 to 73 years, that being older than 75 years, having a BMI> 40 and being a man are the risk factors associated with severe disease [6] [7] [8] [9] . In Panama, COVID 19 patient 0 was admitted at the beginning of March for suspected Mycoplasma pneumoniae pneumonia, but the COVID-19 diagnostic confirmation was obtained one week later, in post-mortem examination. However, the clinical characteristics of patients admitted to ICU in Panama have not been described yet. Our study aims to conduct an evaluation of the epidemiological and clinical characteristics of patients with COVID-19 admitted to the ICU at the main COVID-19 hospital in Panama during April to September 2020 period (the first six months of admissions in the ICU Dr. Arnulfo Arias Madrid Complex Hospital in Panamá-CHMDrAAM, first wave of our pandemic period with the information we had at that time). 7 (due to missing data, often due to the absence of a family member who could provide us the information or because the patient was not in a clinical condition to answer the questions), among the reported comorbidities, the most prevalent were cardiovascular diseases with 245 (45.7%) subjects from whom 214 (88%) had hypertension. Other comorbidities are listed in Table 2 , where the presence of hypertension, diabetes mellitus and obesity stand out, as the main three. High mortality was observed in the group of diabetic's patients, where 71(59.6%) died. Patients who were admitted with bronchial asthma rapidly worsened and 50% of them died. Two patients admitted with systemic lupus erythematosus and 4 patients with acute renal failure, also died. Table 3 presents the imaging studies performed on the patients as well as some rigorous invasive procedures. All patients were admitted with a chest X-ray with compatible images of acute lung disease due to COVID-19. Of approximately 700 critical care ultrasounds performed on patients with COVID-19 in Panama by the Critical Care Ultrasound Unit (CCUU) leaded by Dr. Gómez, 345 were performed during the first six months of the Pandemic at the CHMDrAAM, of these, 320 were critical care echocardiograms, 21 lung ultrasounds, 3 transcranial Doppler, 1 fast abdominal ultrasound. Chest CT were performed in 3 patients (0.7%) and Chest angio-CT only in 6 patients (1.1%).

The main admission diagnoses were pneumonia (96%). All patients required endotracheal intubation upon admission due to the presence of acute respiratory failure indicated by increased respiratory rate and hypoxemia, as well as other laboratory variables detailed in Table 3 . Initial COVID-19 pneumonia, in the majority of patients 531 (96.4%) progressed to ARDS.

The most frequent causes of death in the ICU of the patients in our study were: Multiorgan dysfunction syndrome, followed by acute respiratory distress syndrome secondary to COVID-19 pneumonia, shock of different etiologies (septic, obstructive, cardiogenic and mixed), acute renal failure, refractory pneumothorax complicated by bronchopleural fistula. Table 4 .

Upon admission to the ICU, all patients had received treatment with some antimicrobial, such as azithromycin (79%), hydroxychloroquine (70%) and ivermectin (67%). These three drugs were included in a government authorized kit for early use in COVID-19. Other antibiotics used before admission were ceftriaxone (58%), erythromycin (52%), ampicillin (32%), and ciprofloxacin (28%).

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The copyright holder for this preprint this version posted May 10, 2022. ; https://doi.org/10.1101/2022.05.08.22274803 doi: medRxiv preprint All patients received corticosteroids upon admission, according to local guidelines (some received hydrocortisone, 200 mg daily in case of septic shock, others received dexamethasone 6-10 mg daily. Others received initial bolus prednisone 250 mg, followed by doses of 40-60 mg twice daily for 7-10 days. Table 5 summarizes the medications used in the treatment of the patients. Briefly, 62% of the patients required vasopressors, of which the 51% (275 patients) was norepinephrine. The use of inotropic medications was supported by hemodynamic measurements and echocardiography and was required by 20% of the patients; levosimendan, dobutamine, and milrinone were used. 86% of the patients received anticoagulants, heparin 8% (42) and enoxaparin 78.2% (442). Heparin was used more in the patient with kidney failure. Three biotechnological drugs were included in the treatment. Tocilizumab, in patients with large elevations of IL-6; immunoglobulins and human immunoglobulins enriched with IgM, IgA. Antiparasitic drugs were used at the beginning of the pandemic, also 56% of the patients received hydroxychloroquine (800 mg daily). However, its use began to be reduced due to the presentation of arrhythmias in 22% of the patients (supraventricular tachycardia, atrial arrhythmias, and QT segment prolongation). Ivermectin was used in only 12% of the patients. In none of the patients treated with these drugs we observed benefits inherent to their use.

Blood biomarkers to monitor COVID-19 progression among ICU patients resulted diverse.

Blood biomarker upon admission to ICU including glycemia, urea nitrogen, creatinine as well as C-reactive protein (CRP) D-dimer, ferritin, Interleukin 6, troponin and procalcitonin and others are shown in table 6. For example, we noted that COVID-19 patients withhold an average CRP level of 123.97 UI (SD 93.41 UI). Whereas Procalcitonin was elevated in most patients admitted to ICU (mean 4.43, range 0.02 -160). Only in a few cases (30%) could it be correlated with the presence of concomitant bacterial infection. Regarding the blood cell parameters, we observed that 69% of ICU newly admitted patients had lymphocyte-predominant leukocytosis. When comparing the blood biomarkers between survivors and non survivors, we noted an overall increase of blood biomarker levels. Table   7 show the different blood biomarker level between survivors and non-survivors after ICU admission.

Dyslipidemia promotes endothelial dysfunction and activation, which leads to an increase in pro-inflammatory cytokines such as interleukin 1 among others and the formation of . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 10, 2022. ; https://doi.org/10.1101/2022.05.08.22274803 doi: medRxiv preprint reactive oxygen species [10, 11] . This cytokine increase could exacerbate a systemic inflammatory response in those with chronic diseases or even those who do not present them [12] [13] [14] . Once hypertriglyceridemia was defined according to the cut-off point of our laboratory as values > 150 mg/dl in blood, of the 324 patients who underwent a lipid profile in these first sixth months, we observed a higher mortality in those who presented levels > 150, being 39.2% (127) of the non-survivor's vs 24.7% (80) of the survivors. As for those with levels <150, the observed mortality was similar in both 18.8% (61) survivors vs 17.3%

(56) of non-survivors. Although we observe a higher mortality in patients with triglyceride levels > 150 mg/dl, we cannot establish a direct correlation with the level of severity of the disease.

The cytokine profile was also studied. We noted that most patients admitted to ICU (81.1%) presented high values of IL-6 (mean 248, range 1.15 -1620.0). IL-6 determination was used as an indicator to use Tocilizumab. Among those patients that received Tocilizumab, we noted that levels of IL-6 resulted higher in patients that did not survive at 

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The copyright holder for this preprint this version posted May 10, 2022. ; https://doi.org/10.1101/2022.05.08.22274803 doi: medRxiv preprint 1 0 COVID-19 turned into the major public health threat during the 2020-2021 period. Here we aimed to describe the clinical and epidemiological characteristics of COVID-19 patients admitted to the ICU at the main COVID 19 hospital in Panama during the first pandemic wave during April to September 2020 period. We found that survival from COVID-19 is highly dependent on the presence of comorbidities and a worse biomarker profile of each patient.

High mortality rate was due to uncontrolled ARDS al ICU´s worldwide. In August 1967, Dr.

David Ashbaugh, together with Boyd Bigelow, Thomas Petty, and Bernard Levin, described for the first time in 12 patients a syndrome characterized by hypoxemia, tachypnea, and decreased lung compliance that did not respond to conventional methods of oxygen therapy. The syndrome resembles that observed in childhood distress syndrome, which presents hyaline membranes and atelectasis, which is why it is called Adult Acute Respiratory Syndrome, mentioning in turn the possible beneficial impact of the use of PEEP (positive pressure at the end of expiration) and corticosteroids as adjunctive therapy in fat embolism and viral pneumonia [15, 16] . Patients with ARDS associated with COVID-19 have a form of injury that, in many respects, is like that of those with ARDS not related to COVID-19, presenting a reduction in lung compliance and that together with an increase in D-dimer concentrations have high mortality rates.

Pathophysiologically, ARDS is characterized by acute and diffuse inflammatory damage to the capillary-alveolar barrier known as diffuse alveolar damage (DAD), which is associated with increased vascular permeability, as well as reduced compliance and tissue size. The clinical management of COVID-19 patient have been outlined. In our study, the patients received mechanical ventilation therapy according to current guidelines for the . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We use low Vt (tidal volume), moderate levels of PEEP (positive end-expiratory pressure), low DP (driving pressure) and low PP (plateau pressure). Such approach was like those used by others previously [6, 29] . On the other hand, several drugs were used at the beginning of the pandemic to try to save the lives of our patients based on the studies available to date including ivermectin and tocilizumab [36] . However, the medications used for COVID 19 patients were modified as new scientific evidence appeared, discarding those that the scientific evidence did not support. Thus, the clinical management based on drugs evolved together with the pandemic.

The most frequent causes of death in the ICU of the patients in our study were: Multiorgan dysfunction syndrome, followed by acute respiratory distress syndrome secondary to COVID 19 pneumonia, shock of different etiologies (septic, obstructive, cardiogenic, and mixed), acute renal failure, refractory pneumothorax complicated by bronchopleural fistula.

Blood biomarkers remained key for appropriate management of seriously ill patients with COVID-19. Overall, we observed that those patients with biomarker levels above the cutoff point (including the CRP, procalcitonin, D-dimer, creatinine, BUN, ferritin, hypertriglyceridemia, IL-6, leukocytes, lower PaO2/FiO2 ratio) had higher mortality rate.

For example, emerging evidence support the notion that dyslipidemia promotes endothelial dysfunction and activation, which leads to an increase in pro-inflammatory cytokines such as interleukin 1 among others and the formation of reactive oxygen species [11, 14] . This situation could exacerbate a systemic inflammatory response in those with chronic diseases or even those who do not present them during COVID-19. In addition, we noted a higher mortality in those who presented hypertriglyceridemia as mentioned before, however, we cannot establish a direct correlation with the level of severity COVID-19 and causality. Altogether, the blood biomarkers remain as main clues to predict mortality outcome among ICU admitted patients.

Another cause of early death among COVID-19 patient admitted to ICU includes infectious complications. As their stay is prolonged, nosocomial infections complication arise, complicating the condition and inducing mortality. In our study, nearly three quarters of the patients had an infection associated with clinical management at hospital. Similarly, all other changes during pandemic peak increases like in different countries in this first sixth months including: 1) ICU room remodeling; 2) rushed training for non-ICU personnel; 3) lack of personal protection implements; and 4) fear of personnel to handle COVID-19 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 10, 2022. ; https://doi.org/10.1101/2022.05.08.22274803 doi: medRxiv preprint 1 4 patients. This situation become complicated with nosocomial infection with multidrug resistant strains [37] . All together, these factors contributed to the mortality rate observed in our study. Further efforts are warranted to assure clinical management of critical patient, especially during crisis conditions such as the current pandemic.

Multidrug resistant bacteria complicate the management of critically ill COVID-19 patients [37] . In our study, we observed Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinetobacter baumannii predominated in cultures of endotracheal secretions.

Regarding blood cultures, Staphylococcus species predominated, interpreted mostly as contaminants, indicating the difficulty in obtaining good blood samples in these patients due in part to the personal protective equipment that health personnel must wear. The same bacteria found in endotracheal secretions predominated as blood pathogens. This study has several limitations. First, among the limitations we highlight those inherent to the type of study carried out (cross section descriptive observational study). We did not study causality, we only limited ourselves to describing our population.

Second, the nature of the database did not allow more detailed information to be obtained, such as ventilatory monitoring of days after baseline or more specific laboratory data taken on days other than those officially designated for the study (for example, on weekends, no data was recorded in this regard). The number of cases is small, so there may be independent determinants of mortality that could not be identified. The sustained work burden on health personnel by COVID-19 could also have contributed to lack of some important information on medical records on the specific days designated for obtain it.

Thus, further studies should allocate dedicated resource to tackle these limitations and assure a complete data set.

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The copyright holder for this preprint this version posted May 10, 2022. ; https://doi.org/10.1101/2022.05.08.22274803 doi: medRxiv preprint COVID-19 mortality rate upon admission to ICU in the first sixth month of pandemic rely on epidemiological and clinical patient characteristics, blood biomarkers and clinical management. The survival of critically ill COVID-19 patients greatly depends on an accurate management based on the interaction with all above factors. Our study provides the most common characteristics of these patients, including most of clinical variables similar to those described to date in other international reports. Such resource will aid in being able to better understand and set up the best strategy to save lives of the critical ill COVID-19 patients. Future studies should focus efforts to understand causality effect of every risk factor on inducing death after admission to ICU. Such strategy will provide concepts of evidence-based medicine and thus be able to contribute to create more appropriate management strategies for COVID-19 patients. Until now, our study only provides the baseline characteristic of ICU admitted patient. We believe, above evidence will help on the global effort on developing promising medications to treat severe COVID-19. In the meantime, supportive care continues to be the cornerstone for its management, ventilation strategies, hemodynamic control, fluid administration and prevention of thromboembolic complications (with anticoagulants), corticosteroids, prevention, and treatment of coinfections.

Authors declare no competing interests.

We thank all the patients affected by COVID-19 for their participation in our study. We also thank the health care workers from all ICU at Complejo Hospitalario Metropolitano Dr.

Arnulfo Arias Madrid for their contributions to patient information and providing access to patient's files. Lastly, we thank Colleen Goodridge for her critical review of the manuscript and valuable suggestions.

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This research was supported by Panama's Sistema Nacional de Investigación (SNI) from Secretaría Nacional de Ciencia Tecnología e Innovación (SENACYT); as well as Caja de Seguro Social.