Venovenous extracorporeal membrane oxygenation for COVID-19 associated severe respiratory failure: Case series from a Hungarian tertiary centre.

INTRODUCTION: Venovenous extracorporeal membrane oxygenation (V-V ECMO) is recommended for the support of patients with severe COVID-19 associated severe respiratory failure (SRF). We report the characteristics and outcome of COVID-19 patients supported with V-V ECMO in a Hungarian centre. METHODS: We retrospectively collected data on all patients admitted with proven SARS CoV-2 infection who received V-V ECMO support between March 2021 and May 2022. RESULTS: Eighteen patients were placed on ECMO during this period, (5 women, age (mean ± SD) 44 ± 10 years, APACHE II score (median (interquartile range)) 12 (10-14.5)). Before ECMO support, they had been hospitalised for 6 (4-11) days. Fifteen patients received noninvasive ventilation for 4 (2-8) days, two patients had high flow nasal oxygen therapy, for one day each. They had already been intubated for 2.5 (1-6) days. Prone position was applied in 15 cases. On the day before ECMO initiation the Lung Injury Score was 3.25 (3-3.26), the PaO2/FiO2 ratio was 71 ± 19 mmHg. The duration of V-V ECMO support was 26 ± 20 days, and the longest run lasted 70 days. Patients were mechanically ventilated for 34 ± 23 days. The intensive care unit (ICU) and the hospital length of stay were 40 ± 28 days and 45 ± 31 days, respectively. Eleven patients were successfully weaned from ECMO. The ICU survival rate was 56%, the in-hospital survival was 50%. All patients who were discharged from hospital reported a good health-related quality of life Rankin score (0-2) at the 5-16 months follow-up. CONCLUSIONS: During the last three waves of the COVID-19 pandemic, we achieved a 56% ICU and a 50% hospital survival rate at our low volume centre.

Post-COVID changes in lung function 6 months after veno-venous extracorporeal membrane oxygenation: a prospective observational clinical trial.

Background: Severe coronavirus disease 2019 (COVID-19) may require veno-venous extracorporeal membrane oxygenation (V-V ECMO). While V-V ECMO is offered in severe lung injury to COVID-19, long-term respiratory follow-up in these patients is missing. Therefore, we aimed at providing comprehensive data on the long-term respiratory effects of COVID-19 requiring V-V ECMO support during the acute phase of infection. Methods: In prospective observational cohort study design, patients with severe COVID-19 receiving invasive mechanical ventilation and V-V ECMO (COVID group, n = 9) and healthy matched controls (n = 9) were evaluated 6 months after hospital discharge. Respiratory system resistance at 5 and 19 Hz (R5, R19), and the area under the reactance curve (AX5) was evaluated using oscillometry characterizing total and central airway resistances, and tissue elasticity, respectively. R5 and R19 difference (R5-R19) reflecting small airway function was also calculated. Forced expired volume in seconds (FEV1), forced expiratory vital capacity (FVC), functional residual capacity (FRC), carbon monoxide diffusion capacity (DLCO) and transfer coefficient (KCO) were measured. Results: The COVID group had a higher AX5 and R5-R19 than the healthy matched control group. However, there was no significant difference in terms of R5 or R19. The COVID group had a lower FEV1 and FVC on spirometry than the healthy matched control group. Further, the COVID group had a lower FRC on plethysmography than the healthy matched control group. Meanwhile, the COVID group had a lower DLCO than healthy matched control group. Nevertheless, its KCO was within the normal range. Conclusion: Severe acute COVID-19 requiring V-V ECMO persistently impairs small airway function and reduces respiratory tissue elasticity, primarily attributed to lung restriction. These findings also suggest that even severe pulmonary pathologies of acute COVID-19 can manifest in a moderate but still persistent lung function impairment 6 months after hospital discharge. Trial registration: NCT05812196.

Extracorporeal membrane oxygenation in intensive care unit / Extracorporalis membránoxigenizáció intenzív osztályon.

Összefoglaló. Az extracorporalis membránoxigenizációt egyre gyakrabban alkalmazzák világszerte refrakter légzési és/vagy keringési elégtelenség kezelésében. Intézetünkben 2015-ben kezdtük meg a program elokészítését és felépítését. Célunk az extracorporalis membránoxigenizációs kezelés élettani alapjainak rövid ismertetése, különös tekintettel a venovenosus konfigurációra, és az eddig kezelt eseteink eredményeinek összefoglalása. Az irodalom szisztematikus áttekintése és a kezelt esetek adatainak retrospektív értékelése voltak a módszereink. 2016 óta összesen 14 beteg esetében használtunk extracorporalis membránoxigenizációt (8 férfi, 6 no, életkor 51 ± 15 év, APACHE II. score 24 ± 7). Az indikáció 9 esetben súlyos refrakter hypoxaemiás légzési elégtelenség, 1 esetben tracheooesophagealis fistula és légzési elégtelenség, 1 esetben mutét alatti támogatás tervezett trachearekonstrukció során és 3 beteg esetében refrakter cardiogen shock volt. Az extracorporalis membránoxigenizáció 11 betegben a légzés, 3 betegben a keringés támogatását szolgálta, 13 venovenosus, 1 venoarteriosus konfigurációban. Az extracorporalis támogatás ideje légzéstámogatás esetében 14 ± 6 nap, a cardialis támogatások esetében 5 ± 4 nap volt. Az intenzív osztályos ápolási ido 27 ± 13, illetve 21 ± 17 nap volt a két betegcsoportban. 9 beteget jó funkcionális állapotban bocsátottunk el, 5 beteg halt meg osztályunkon, további 3 késobb a kórházi bennfekvés során. Az extracorporalis membránoxigenizációs program regionális centrumokban Magyarországon is megvalósítható. A nemzetközi ajánlások, oktatási módszerek alkalmazásával a nemzetközi irodalomban közölt túlélési eredményekhez hasonló eredmények érhetok el hazánkban is. Orv Hetil. 2021; 162(11): 425-431. Summary. Extracorporeal membrane oxygenisation is commonly used worldwide for refractory respiratory and circulatory failure. We started to organise the introduction of this therapeutic modality in 2015. Our aim is to give a short review about extracorporeal life support, especially veno-venous extracorporeal membrane oxygenation, and to present our first results. We provide a systematic review of the currently available literature and a summary of our first treatments. As of 2016, we supported 14 patients with extracorporeal membrane oxygenisation (8 men, age 51 ± 15 years, APACHE II score 24 ± 7). The indications were refractory hypoxaemic respiratory failure in 9, tracheo-oesophageal fistula and respiratory failure in 1, support during surgery for planned tracheal reconstruction in 1, and refractory cardiogenic shock in 3 patients. We provided respiratory support in 11, circulatory support in 3 cases, with 13 veno-venous and 1 veno-arterial configuration. The support lasted for 14 ± 6 days in respiratory, and for 5 ± 4 days in cardiac cases. Intensive care length of stay was 27 ± 13 and 21 ± 17 days in the two patient groups. We discharged 9 patients in good functional state, 5 patients died during intensive care and further 3 later, during the hospital stay. Our results show that the implementation of an extracoporeal membrane oxygenation program is feasible in Hungarian tertiary centers. In line with international recommendations and adapting international training courses, the survival is very similar to that reported in the literature. Orv Hetil. 2021; 162(11): 425-431.

Paradoxical pulse / Paradox pulzus

For thousands of years, palpation of the peripheral pulse was the most important source of information for the physicians about their patients' circulation. The rate, amplitude, and pattern of the pulse served as a basis of amazing observations, although several of them have been also confirmed and substantiated by modern medicine. One of the classical signs is "paradoxical pulse" (PP), which signals potentially life-threatening conditions with various mechanisms in certain diseases. In our review, we demonstrate the pathophysiological bases of PP, and show the equivalents of this sign provided by modern medical equipments. Orv Hetil. 2020; 161(38): 1629-1635.

Cyclic Nonrespiratory Pulse Pressure Oscillations Caused by Atrioventricular Dissociation.

Dynamic preload assessment tests, especially pulse pressure variation (PPV) and stroke volume variation (SVV), are increasingly acknowledged in mechanically ventilated patients as being predictors of fluid responsiveness. However, the limitations of this method are often neglected or overlooked. One of the prerequisites for PPV and SVV evaluation, in addition to intermittent positive pressure ventilation, is a "regular heart rhythm," which may be an ambiguous term. We present a case where, despite a regular (paced) rhythm, atrioventricular dissociation was present and resulted in marked PPV elevation, which subsequently disappeared once sinus rhythm returned. Our case indicates that PPV and SVV should be interpreted with caution when atrioventricular dissociation is present.

Non-invasive detection of hypovolemia or fluid responsiveness in spontaneously breathing subjects.

BACKGROUND: In the assessment of hypovolemia the value of functional hemodynamic monitoring during spontaneous breathing is debated. The aim of our study was to investigate in spontaneously breathing subjects the changes in hemodynamic parameters during graded central hypovolemia and to test whether slow patterned breathing improved the discriminative value of stroke volume (SV), pulse pressure (PP), and their variations (SVV, PPV). In addition, we tested the alterations in labial microcirculation. METHODS: 20 healthy volunteers participated in our study. Central hypovolemia was induced by lower body negative pressure (LBNP). Continuous signals of ECG, non-invasive blood pressure and central venous pressure were recorded. During baseline and each stage of LBNP the labial microcirculation was investigated by orthogonal polarization spectral imaging, 3 minute periods of patterned breathing at 6 and 15/min respiratory rate were performed, and central venous blood gas analysis was done. Data from baseline and those of different LBNP levels were compared by analysis of variance and those of different breathing rates by t-test. Finally, we performed ROC analysis to assess the discriminative values of SV, PP, SVV and PPV. RESULTS: Moderate central hypovolemia induced by LBNP caused significant, clinically relevant falls in PP (p < 0.05) and SV and central venous oxygen saturation (ScvO2) (p < 0.001). The proportion of perfused vessels (p < 0.001) and microvascular flow index decreased (p < 0.05). PPV increased (p < 0.001), however the magnitude of fluctuations was greater during slow patterned breathing (p < 0.001). SVV increased only during slow patterned breathing (p < 0.001). ROC analysis confirmed the best predictive value for SV (at 56 ml cut-off AUC 0.97, sensitivity 94%, specificity 95%). Slow patterned breathing improved the discriminative value of SVV (p = 0.0023). CONCLUSIONS: Functional hemodynamic monitoring with slow patterned breathing to control spontaneous respiration may be worthy for further study in different populations for the assessment of hypovolemia and the prediction of volume responsiveness.

The effects of acute blood loss on blood pressure recovery from the Valsalva maneuver.

Human baroreflex regulation plays an important role in stabilising blood pressure. Though we have several indices to quantify cardiovagal responses, sympathetic baroreflex gain remains difficult to assess. We investigated how the recently validated pressure recovery time (PRT) and sympathetic baroreflex gain (SBRS) derived from the Valsalva maneuver was influenced by acute blood loss. 26 healthy blood donors were included in the study (age 35 ± 15 years; 20 men). SBRS was derived from the blood pressure drop (SAP delta) and pressure recovery time during the Valsalva maneuver. Besides we calculated cardiovagal baroreflex parameters, the Valsalva ratio (VR) and a simplified baroreflex gain (VBRS). We compared these parameters before and after the withdrawal of 350-400 ml blood. The baseline systolic blood pressure was the same before and after blood donation (123 ± 17 vs 126 ± 23 mm Hg, NS). The minimum systolic pressure (SAP min) during phase III was significantly lower, and the SAP delta significantly greater after blood withdrawal (SAP min 83 ± 24 mm Hg vs 69 ± 27 mm Hg, p<0.001; SAP delta 41 ± 15 mm Hg vs 57 ± 16 mm Hg, p<0.001). PRT increased significantly (from 2.0 to 3.6s, p<0.006). SBRS did not change between the study conditions (24 ± 12 mm Hg/s vs 22 ± 10 mm Hg/s, NS), nor did the VR and the VBRS: In conclusion, after the acute loss of approximately 350-400 ml blood there was a greater blood pressure drop in phase II and III and a slower blood pressure recovery in phase IV of the Valsalva maneuver that resulted in an unchanged SBRS.

[A simple miracle of water]. / Egyszeru vízi csoda.

Chronic orthostasis intolerance or postural tachycardia syndrome (POTS) is a common problem, which is related to the more severe forms of autonomic neuropathy. Upright posture regularly elicits uncomfortable symptoms in these patients, which impairs their quality of life. We present a typical case, where orthostatic hemodynamic response was significantly improved by ingestion of 500 ml tap water. This simple measure could be a potent, long-term therapeutic tool.

Respiratory effects on the reproducibility of cardiovascular autonomic parameters.

The aim of this study was to assess the influence of breathing pattern on the reproducibility of the most commonly used heart rate and blood pressure variability parameters and baroreflex indices. 5-5 min ECG and blood pressure recordings were made and repeated for 10 healthy volunteers in supine rest on 10 consecutive days during spontaneous and 6 min(-1) patterned breathing. We investigated the following parameters: mean RR interval (RRI); the standard deviation of RR intervals (SDRR); the root mean square of successive differences in RRI (RMSSD); the percentage of RRIs which differed by 50% from the proceeding RRI (PNN50); mean systolic arterial pressure (SAP); the standard deviation of SAP (SAP SD); mean mean arterial pressure (MAP); mean diastolic blood pressure (DAP) and baroreflex indices from spontaneous sequence method (upBRS and downBRS) and from cross spectral analysis (LF alpha, HF alpha). To assess reproducibility for each parameter within- and between-subject variability values were calculated and the ratio of within- and between-subject variability was assessed. In addition, we calculated intraclass correlation coefficient (ICC). Compared to spontaneous respiration during 6 min(-1) patterned breathing the heart rate and blood pressure variability increased; upBRS, LF alpha and HF alpha increased, downBRS did not change. However, ICC showed good reproducibility for most parameters, which did not improve further with controlled breathing. In conclusion, respiration had a strong influence on the most widely used cardiovascular autonomic parameters. The controlling of breathing did not result in consistent improvement in their reproducibility.

[Valsalva maneuver, Müller maneuver: hemodynamic and reflex mechanisms, relevance]. / Valsalva-manover, Müller-manover: Keringési és reflexmechanizmusok, relevanciák.

The time honored ancient reflex tests, the Valsalva and Müller maneuvers are still popular in the everyday clinical practice. These maneuvers are capable of imitating both trivial situations and significant pathological conditions. The Valsalva maneuver is still frequently used for the assessment of autonomic neuropathy. Addition of continuous noninvasive blood pressure monitoring allows assessment of both cardiac vagal and sympathetic driven peripheral vasomotor responses. The Müller maneuver has recently gained renewed popularity in simulating episodes of obstructive sleep apnea (OSA). Continuous monitoring of arterial pressure and muscle sympathetic nerve activity (MSNA) casts light on the close relationship between OSA and circulatory abnormalities.

A case of interstitial pneumonitis in a patient with ulcerative colitis treated with azathioprine.

The early hypersensitivity reaction and late bone marrow depression are well-known side-effects of azathioprine, whereas interstitial pneumonia is a rare complication. A 40-year old male patient had been treated with azathioprine in consequence of extensive ulcerative colitis for 10 years. He then complained of 7 d of fever, cough and catarrhal signs, without symptoms of active colitis. Opportunistic infections were ruled out. The chest X-ray, CT and lung biopsy demonstrated the presence of interstitial inflammation. Azathioprine therapy was discontinued as a potential source of the pulmonary infiltrate. In response to steroid therapy, and intensive care, the pulmonary infiltrate gradually decreased within 4 wk. Three months later, his ulcerative colitis relapsed, and ileo-anal pouch surgery was performed. In cases of atypical pneumonia, without a proven infection, azathioprine-associated interstitial pneumonitis may be present, which heals after withdrawal of the drug.

[Azathioprine-associated interstitial pneumonitis]. / Azathioprin okozta interstitialis pneumonitis.

Azathioprine-associated interstitial pneumonitis. The early hypersensitivity reaction and the late bone marrow depression are well known side effects of the azathioprine; the interstitial pneumonia is a rare complication. A 40-year old male patient was treated with azathioprine due to extensive ulcerative colitis for ten years. He complained seven days of fever, cough and catarrhal signs, without the symptoms of active colitis. The opportunistic infections were ruled out. Chest X-ray, CT and lung biopsy proved the presence of interstitial inflammation. The azathioprine therapy was discontinued as the potential source of the pulmonary infiltrate. As a result of steroid therapy, as well as emergency unit care, the pulmonary infiltrates decreased gradually. Three months later his ulcerative colitis relapsed, for this an ileo-anal pouch surgery was done. In case of atypical pneumonia, without proven opportunistic infection, azathioprine-associated interstitial pneumonitis may be present, which heal after cessation of the drug.

Human autonomic responses to blood donation.

In order to characterize autonomic responses to acute volume loss, supine ECG, blood pressure (BP) and uncalibrated breathing signal (UBS) recordings were taken before and after blood donation in 48 healthy volunteers. Time and frequency domain parameters of RR interval (RRI), BP and UBS variability were determined. Baroreflex gain was calculated by the technique of the spontaneous sequences and cross-spectral analysis. The systolic (SAP), diastolic (DAP) and mean BP (MAP) increased after the blood withdrawal. The central frequency of breathing and mean heart rate did not change. RRI variability increased in low frequency band (LF), tended to decrease in high frequency band (HF). Systolic BP variability increased in both frequency bands, but was statistically significant only in the high frequency band. Diastolic BP power increased in both frequencies. From the different baroreflex gain estimates, up sequence BRS and HF alpha index decreased significantly. The phase angle between RRI and systolic blood pressure powers in LF band did not change (-58 +/- 24 degrees and -54 +/- 26 degrees ). In the high frequency range, the phase became more negative (-1 +/- 29 degrees and -17 +/- 32 degrees, p = 0.001). The withdrawal of 350-400 ml blood in 5 min resulted in sympathetic activation, which was reflected in increased systolic, diastolic and mean BP. The increased BP oscillation was a sensitive marker of the minor volume depletion. This was coupled by increased RRI oscillation via baroreflex mechanisms in the LF band. Changes in the RRI and BP oscillations in the HF band showed no similar coupling. That points to the fact that RRI oscillations in this band should not be explained entirely by baroreflex mechanisms. Vagal withdrawal was reflected in decreased root mean square of successive differences (RMSSD), decreased HF RRI power and decreased up sequence BRS.

Oesophageal acid stimulation in humans: does it alter baroreflex function?

The aim of this study was to investigate if oesophagel acid stimulation (Bernstein test) had an influence on heart rate and blood prsure variability and baroreflex gain. We compared the cardiovascular responses in 10 patients with established gastro-esophageal reflux disease (Group 1) and 10 control subjects (Group 2) during esophageal saline and 0.1 mol/l hydrochloric acid instillation. Indices of heart rate and blood pressure variability and baroreflex gain (derived from linear spontaneous sequences and cross spectral analysis) were calculated. In Group 1 the standard deviation of RR intervals (SDRR: 46 ms vs 51 ms, p=0.030) and the root mean square of successive differences (RMSSD: 24 ms vs. 26 ms p=0.027) were significantly lower during acid infusions, than during saline. We found no significant difference in minimum, maximum and mean RR intervals and systolic blood pressures and in the percentage of RR intervals, which differed from adjacent cycles by more than 50 ms (PNN50). The power spectra of RR intervals in the high frequency band tended to be lower during acid infusion (p=0.055). There was no significant difference in blood pressure spectra, neither in low nor in high frequency band. In Group 2 there was no significant difference between any parameters measured during acid and saline. The baroreflex gain was not changed during the studied conditions in any group. Neither increased vagal tone, nor increased vagal variability occurred and the baroreflex gain was not altered during oesophageal acid simulation.

Measures of cardiovascular autonomic regulation derived from spontaneous methods and the Valsalva maneuver.

The response of heart rate to a given change of systolic blood pressure is a fundamental characteristic of the cardiovascular system. The assessment of baroreflex gain (BRS) as an index of baroreflex function is based on the quantification of RR interval changes related to blood pressure changes. The spontaneous sequence and cross spectral methods describe baroreflex gain derived from spontaneous fluctuations of these parameters, yielding the up sequence and down sequence BRS and the alfa index. Phase IV of the Valsalva maneuver is also used to calculate cardiac vagal baroreflex gain. In this study, we compared the two spontaneous methods and the Valsalva maneuver in assessing baroreflex gain in 56 healthy volunteers. The BRS values calculated from different methods were as follows: up sequence BRS 12 +/- 8.6 ms/mm Hg, down sequence BRS 10 +/- 6.1 ms/mm Hg, low frequency alfa index 12.1 +/- 8.2 ms/mm Hg, Valsalva BRS 9.7 +/- 7.2 ms/mm Hg. We found close relationship between baroreflex gain derived from up and down sequences (R = 0.91, p < 0.001), down sequence BRS and low frequency alfa index (R = 0.81, p < 0.001); significant correlation between up sequence BRS and low frequency alfa index (R = 0.65, p < 0.001), the Valsalva-derived BRS and down sequence BRS (R = 0.37, p = 0.043), but no correlation between the Valsalva BRS and up sequence BRS, the Valsalva BRS and low frequency alfa index. BRS values calculated by different methods decreased with increasing age. There was no influence of age on mean arterial blood pressure elevation in late phase II of the Valsalva maneuver, nor any indication that the Valsalva BRS was related to the MAP changes. We concluded that all of these methods are useful in calculating baroreflex gain, but owing to the differences in underlying physiological mechanisms, they are not necessarily in correlation with each other.