Protected: Polytrauma and Acute Kidney Injury: A Multidisciplinary Approach

Abstract

The development of acute kidney injury (AKI) in polytrauma patients is a common and serious complication, with an incidence ranging from 6% to 50%.
Polytrauma is a complex pathological condition that involves the collaboration of various specialists. On one hand, hemodynamic stabilization through fluid therapy and aminic support, with specific attack protocols, managed by anesthetists.
On the other hand, if necessary, the initiation of renal replacement therapy such as Continuous Renal Replacement Therapy (CRRT), managed by nephrologists.
CRRT is chosen both for managing fluid balance and ensuring the removal of toxic substances, as well as for proper control of electrolytes and acid-base balance.

Keywords: Acute Kidney Injury, Polytrauma, Continuous Renal Replacement Therapy

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Therapeutic Plasma Exchange in a Patient with Chronic Hemodialysis and a New Diagnosis of Myasthenia Gravis

Abstract

Case Report. C.S.T. (♂, 71 years old) is a patient with multiple and severe comorbidities, undergoing thrice-weekly chronic hemodialysis since 2008 due to the progression of post-lithiasic uropathy. Over the past 2 months, the patient had been experiencing progressive ptosis of the eyelids, muscle weakness, and ultimately dysphagia and dysarthria that emerged in the last few days. Urgently admitted to the Neurology department, electromyography (EMG) was performed, leading to a diagnosis of predominant cranial myasthenia gravis (with borderline anti-acetylcholine receptor antibody serology). Prompt treatment with pyridostigmine and steroids was initiated.
Considering the high risk of acute myasthenic decompensation, therapeutic plasma exchange (TPE) with centrifugation technique was promptly undertaken after femoral CVC placement. TPE sessions were alternated with hemodialysis. The patient’s condition complicated after the third TPE session, with septic shock caused by Methicillin-Sensitive Staphylococcus Aureus (MSSA). The patient was transferred to the Intensive Care Unit (ICU). Due to hemodynamic instability, continuous veno-venous hemodiafiltration (CVVHDF) with citrate anticoagulation was administered for 72 hours.
After resolving the septic condition, intermittent treatment with Acetate-Free Biofiltration (AFB) technique was resumed. The patient completed the remaining three TPE sessions and, once the acute condition was resolved, was transferred back to Neurology. Here, the patient continued the treatment and underwent a rehabilitation program, showing significant motor and functional recovery until discharge.
Conclusions. The multidisciplinary interaction among Nephrologists, Neurologists, Anesthesiologists, and experts from the Immunohematology and Transfusion Medicine Service enabled the management and treatment of a rare condition (MG) in a high-risk chronic hemodialysis patient.

Keywords: Myasthenia Gravis, Plasmapheresis, Therapeutic Plasma Exchange, Hemodialysis, Continuous Renal Replacement Therapy

Sorry, this entry is only available in Italian.

Introduzione

La Miastenia Gravis (MG) è una patologia della giunzione neuromuscolare a genesi autoimmune, causata da anticorpi contro i diversi componenti della placca neuromuscolare [1]. Gli anticorpi contro la giunzione neuromuscolare inducono debolezza dei muscoli volontari, la quale rappresenta la fondamentale manifestazione della malattia [2, 4]. La caratteristica distintiva è inoltre l’affaticabilità, per cui l’attività muscolare incrementa la debolezza muscolare [5, 6], determinando una fluttuazione della sintomatologia nell’arco di una giornata, con carattere ingravescente dalla mattina alla sera.

Spesso l’esordio può essere focale, nella maggior parte dei casi a carico della muscolatura oculare estrinseca, determinando conseguente diplopia e ptosi. Se le manifestazioni rimangono limitate ai muscoli oculari, il quadro viene definito “miastenia oculare”; tale condizione ricorre in circa il 20% dei casi. Circa il 75 % dei pazienti può sviluppare un interessamento generalizzato, solitamente entro 2-3 anni dall’esordio di malattia [5, 7, 8]. Nella forma generalizzata, vi è principalmente un coinvolgimento dei muscoli del distretto bulbare, di quelli del collo e della muscolatura prossimale degli arti. I pazienti possono presentare difficoltà nella masticazione e nella deglutizione, con conseguente disfagia prevalentemente per i liquidi, disartria, testa cadente; può inoltre comparire dispnea per affaticabilità dei muscoli respiratori [8, 9]. Nel 15-20% dei casi il paziente può presentare un quadro definito di “crisi miastenica”, con insufficienza respiratoria e conseguente necessità di supporto ventilatorio non invasivo o di ventilazione meccanica; tale quadro si associa a deficit dei muscoli del distretto bulbare e del collo.

La MG è una malattia rara. L’incidenza è stimata tra i 5 e i 30 casi per milione di abitanti/anno [10, 11]. La prevalenza è stimata tra 10 e 20 casi per 100.000 abitanti, con una tendenza all’incremento di tale dato, per il miglioramento dei trattamenti nelle decadi più recenti e conseguente maggior sopravvivenza [12, 13]. La MG può insorgenze in ogni fascia di età, ma presenta tipicamente due picchi di incidenza, rispettivamente nella terza decade e dalla sesta all’ottava decade [14].

Presentiamo un caso clinico di un paziente complesso, con plurime e severe comorbidità, in trattamento emodialitico cronico e con nuova diagnosi di MG.

 

Caso clinico

C.S.T. (♂, 71 anni) è un paziente in trattamento emodialitico cronico presso l’Emodialisi della UO di Nefrologia dell’Ospedale ‘Maurizio Bufalini’ di Cesena. In anamnesi, il paziente presenta molteplici comorbidità:

1) cardiovascolari: una insufficienza cardiaca cronica a frazione d’eiezione conservata secondaria a una cardiopatia ischemica post-infartuale (angioplastica con posizionamento di stent medicati nel 2014 e 2019 sui rami interventricolare anteriore e circonflessa) e ad una stenosi aortica severa (trattata nel 2021 con valvuloplastica aortica percutanea). Il paziente è inoltre portatore di pacemaker per blocco atrio-ventricolare di I grado;

2) oncologiche: adenocarcinoma prostatico diagnosticato nel 2020 e trattato con radioterapia stereotassica e ormonoterapia (Leuprolide);

3) metaboliche: Diabete Mellito di tipo 2, obesità di grado I e dislipidemia;

4) polmonari: broncopneumopatia a fenotipo restrittivo;

5) altre: una gastrite cronica Helicobacter Pylori relata (patogeno trattato con terapia eradicante), una diverticolosi del sigma.

Dal punto di vista nefrologico, il paziente presenta una malattia renale cronica in stadio G5 secondo la classificazione della ‘Kidney Disease: Improving Global Outcomes’ (KDIGO) [15] secondaria a uropatia ostruttiva su base litiasica bilateralmente. Inizia il trattamento emodialitico nel giugno 2008 previo confezionamento di fistola artero-venosa (FAV) distale destra.

Tre anni fa, il paziente aveva lamentato la comparsa di diplopia transitoria, insorta secondariamente a una condizione riferita di forte stress personale e risoltasi spontaneamente nel giro di 3 giorni. In tale occasione veniva eseguita valutazione neurologica che non riscontrava all’esame obiettivo neurologico (EON) deficit stenici focali o bilaterali e le prove di affaticabilità risultavano negative. Veniva inoltre richiesto dosaggio sierico del TSH, fT3, fT4 e degli anticorpi anti-recettore dell’acetilcolina che risultavano nella norma. Una valutazione oculistica e ortottica inoltre faceva porre diagnosi di diplopia verticale ai vetri striati ben compensata ad angolo corretto per cui non veniva iniziata alcuna terapia specifica.

Da circa due mesi il paziente accusa una sintomatologia di nuova insorgenza, caratterizzata dapprima da ptosi all’occhio sinistro e dopo alcune settimane interessante anche il controlaterale. Tale disturbo tende a peggiorare nel corso della giornata. Con il passare delle settimane compare astenia con progressivo calo della forza prevalentemente agli arti inferiori, tanto che il paziente non è più in grado di deambulare ed è costretto a usare la carrozzina. Infine, è insorta una difficoltà nella deglutizione con episodi di disfagia e nell’articolazione della parola (disartria) per cui viene richiesta ed eseguita valutazione neurologica urgente al termine di una regolare seduta emodialitica.

All’EON si riscontra ptosi palpebrale bilaterale più evidente all’occhio di destra, peggiorata dopo prove di affaticabilità, non diplopia, lieve disartria, spianamento del solco naso-genieno dell’emivolto destro e una ipostenia prossimale dei quattro arti (4/5 agli arti inferiori e 2-3/5 agli arti inferiori scala Medical Research Council) con impossibilità a mantenere il Mingazzini II. Viene eseguita una emogasanalisi arteriosa che non rileva alterazioni elettrolitiche e dell’equilibrio acido-base (pH 7,37, pO2 78,4 mmHg, pCO2 41,2 mmHg, Na+ 140 mmol/L, K+ 4,2 mmol/L, HCO3- 24 mmol/L). Viene inoltre eseguita TC encefalo urgente che mostra “presenza di un esito malacico cortico-sottocorticale in regione parietale paramediana sinistra cui si associano alcune lacune suggestive di spazi perivascolari ampliati in regione capsulo insulare bilaterale e talamica destra. Sistema ventricolare e spazi liquorali di normale morfologia e contenuto. Strutture della linea mediana in asse’’. Tali reperti vengono valutati suggestivi di encefalopatia vascolare cronica compatibile con la storia clinico-anamnestica del paziente, ma non tali da giustificare la sintomatologia acuta insorta negli ultimi due mesi. Nel forte sospetto di una patologia della giunzione neuromuscolare, il paziente si ricovera nel reparto di Neurologia dell’Ospedale “M. Bufalini” di Cesena.

Nel corso del ricovero si eseguono numerosi accertamenti, in particolare in relazione all’ipotesi eziologica:

  • dosaggio degli anticorpi anti-recettore dell’acetilcolina (0,48, valori normali [[vn]] <0,45, borderline da 0,45 a 1,50, positivo >1,50 nmol/L), anti-chinasi muscolo specifica (MusK) (0,06, vn <0,4 U/mL), anti LRP4, anti-rianodina, anti-titina e anti-canali del calcio inviati all’ Istituto “Carlo Besta” di Milano (risultati negativi);
  • TC torace-addome negativa per masse mediastiniche e addominali;
  • EMG: quadro compatibile con sindrome miasteniforme prevalente nel distretto cranico (esame non completo in quanto il paziente è portatore di PM).

Viene dunque iniziata terapia con piridostigmina (dose ridotta del 25% in relazione all’insufficienza renale) e steroide alla dose iniziale di 1 mg/kg/die, con parziale beneficio. Dato che la sintomatologia neurologica appare ancora significativa con interessamento del settore cranico e ritenendo elevato il rischio di scompenso miastenico acuto, si considera per implementazione terapeutica con ciclo di immunoglobuline per via endovenosa (IgV) o di TPE. Dopo valutazione collegiale tra Neurologi, Nefrologi e Medici del Servizio di Immunoematologia e Medicina Trasfusionale si opta per ciclo di 6 sedute di TPE.

La tecnica aferetica scelta è la plasma-centrifugazione. Pertanto, viene reperito un nuovo accesso vascolare con posizionamento in ecoguida di catetere venoso centrale (CVC) di calibro 12 French e 24 centimetri di lunghezza in vena femorale destra e inizia il ciclo di TPE presso il Servizio di Immunoematologia e Medicina Trasfusionale. Si decide di eseguire le sedute di TPE a giorni alternati a quelli delle regolari sedute di HD.

Eseguite le prime 3 sedute, si assiste a un netto miglioramento del quadro neurologico; tuttavia, il paziente va incontro a episodio di ipossiemia acuta necessitante prima ossigenoterapia ad alti flussi e successivamente intubazione orotracheale. Il quadro si complica con l’insorgenza di shock emodinamico per il quale il paziente viene trasferito in Terapia Intensiva per il monitoraggio e il supporto vitale avanzato. Nel forte sospetto di uno shock settico secondario a batteriemia CVC relata, il device viene prontamente rimosso previa esecuzione di emocolture e si inizia terapia antibiotica empirica con Linezolid e Piperacillina/Tazobactam a dosaggio adeguato al filtrato glomerulare. Dato il successivo isolamento agli esami colturali di Staphylococcus Aureus Meticillino-Sensibile (MSSA), veniva sostituita la terapia antibiotica empirica con una terapia mirata con Oxacillina su indicazione infettivologica.

Nel corso della degenza in TI, a causa dell’instabilità emodinamica secondaria allo shock settico con necessità di supporto con amine, si sospende temporaneamente il trattamento con plasmaferesi e si inizia un trattamento con Continuous Renal Replacement Therapy (CRRT) in sostituzione delle sedute di emodialisi intermittente. Viene posizionato un CVC da HD di calibro 12 French e della lunghezza di 15 centimetri in giugulare destra e si inizia il trattamento di CVVHDF. Dopo un ciclo di 72 ore di CRRT, il paziente registrava un significativo miglioramento del quadro emodinamico con progressivo svezzamento dal supporto aminico. Inoltre, conseguentemente al miglioramento degli scambi respiratori, si procede a estubazione del paziente e si riprende il trattamento emodialitico intermittente con AFB. Nei giorni successivi vengono riprese le sedute di TPE, sempre alternate a quelle di HD, fino alla conclusione del ciclo plasmferetico previsto.

Dimesso dalla Terapia Intensiva, il paziente torna nel reparto Neurologia dove prosegue la terapia antibiotica, il monitoraggio clinico e inizia il trattamento riabilitativo con discreto recupero motorio e funzionale. Nello specifico, all’EON, il paziente tiene il Mingazzini I senza difficoltà, tiene il Mingazzini II per 25 secondi, prove in espirium fino a 40 secondi senza disartria o affaticamento, ROT presenti e simmetrici. Si è assistito a un recupero della capacità di deambulazione con marcia cauta, con necessità talvolta di ausilio con deambulatore a causa di residuo ipostenico del muscolo ileo-psoas. Si è inoltre assistito a una completa risoluzione della disfagia.

Il programma alla dimissione dalla Neurologia prevede terapia specifica con prednisone 75 mg/die a dosaggio a scalare e piridostigmina 30 mg 4 volte/die e plasmaferesi di mantenimento ogni 3 settimane.

Il paziente prosegue le regolari sedute di HD cronica come di consueto.

 

Materiali e Metodi

Le sedute di plasmaferesi sono state eseguite con tecnica di plasmacentrifugazione tramite macchina Spectra Optia (SPO, Terumo BCT, Lakewood, CO, USA). L’accesso vascolare è stato prima un CVC femorale destro e poi un CVC giugulare destro. La sostanza di scambio soluzione fisiologica albuminata al 4% per volume. L’anticoagulazione del circuito è stata locoregionale con citrato.

Le sedute dialitiche croniche sono state eseguite con tecnica di emodiafiltrazione online tramite macchina Dialog iQ con dializzatore Xevonta Hi 23 (B. Braun Melsungen AG, Melsungen, Germany). L’accesso vascolare è stata la FAV distale destra. L’anticoagulazione del circuito è stata eseguita con eparina a basso peso molecolare (EBPM).

La seduta di CVVHDF è stata eseguita tramite macchina Multifiltrate con dializzatore AV 1000 (Fresenius Medical Care AG, Bad Homburg vor der Höhe, Germany). L’accesso vascolare è stato un CVC giugulare destro. L’anticoagulazione del circuito è stata regionale con citrato.

La seduta di dialisi intermittente in TI è stata eseguita con tecnica di Acetate Free Biofiltration tramite macchina Gambro Artis con dializzatore Gambro Evodial 1.6 (Gambro, Deerfield, Illinois, USA). L’accesso vascolare è stato la FAV distale destra. L’anticoagulazione del circuito è stata con EBPM.

 

Discussione

La MG è una malattia cronica della giunzione neuromuscolare, a volte molto invalidante ma che può essere trattata efficacemente una volta diagnosticata. Infatti, molti pazienti possono raggiungere una remissione sostenuta dei sintomi e un pieno recupero delle loro capacità funzionali. Per i pazienti con forme lievi-moderate, gli inibitori delle acetilcolinesterasi e la terapia immunosoppressiva cronica con corticosteroidi rappresentano la terapia di scelta. Tuttavia, nei pazienti con crisi miastenica e nei quadri più gravi con segni di pericolo di vita come l’insufficienza respiratoria o la disfagia, il TPE e le IgV sono indicati come trattamenti a breve termine in associazione alla terapia immunomodulante e immunosoppressiva [16].

L’uso di IgV presenta ampia applicazione nel trattamento delle forme più gravi di miastenia e nella crisi miastenica; presentano un rapido effetto terapeutico entro pochi giorni, risposta massima entro 7-10 giorni e il loro effetto dura 28-60 giorni. Possibili complicanze più gravi, seppur non frequenti, sono la meningite asettica, il danno renale acuto (AKI) ed eventi tromboembolici [17, 18]. La plasmaferesi è stata introdotta nel trattamento della MG nel 1976 e la sua efficacia è correlata principalmente alla rimozione diretta degli anticorpi [19, 20]. Viene spesso preferita alle IgV nei pazienti altamente critici per la rapidità di efficacia già dopo pochissimi giorni dall’inizio del trattamento. Le complicanze che possono insorgere sono correlate alla procedura o dovute al posizionamento di un accesso venoso centrale [21]. Molti studi hanno dimostrato un’efficacia sovrapponibile tra i due trattamenti [22, 23]. La scelta dipende in primis dalle caratteristiche del paziente e dal suo quadro clinico, ma anche dall’esperienza clinica del Neurologo, dalla disponibilità di esecuzione di plasmaferesi e anche da aspetti economici. Nel 2016 il gruppo di esperti internazionali che hanno redatto la guida per il trattamento della MG suggeriscono che nella crisi miastenica la plasmaferesi si presenta più efficace e più rapida [24].

Il TPE è una terapia extracorporea che prevede la rimozione del plasma e dei suoi componenti solubili dal sangue del paziente (plasmaferesi) in cambio di un fluido di sostituzione, che di solito è costituito dal plasma o dalle soluzioni albuminate. Questa terapia mira a rimuovere immunocomplessi, allo- ed auto-anticorpi o immunoglobuline che contribuiscono alla patogenesi di alcune patologie. Inoltre, sembra avere un effetto stimolante su vari sistemi come quello immunitario. Esistono due principali metodiche per eseguire il TPE: la plasmafiltrazione e la centrifugazione [25, 26].

La plasmafiltrazione prevede la rimozione non selettiva del plasma e dei suoi costituenti dal sangue attraverso una membrana semipermeabile. È una tecnica simile all’ultrafiltrazione isolata in HD. Infatti, può essere eseguita con le macchine da HD standard utilizzando la loro modalità di ultrafiltrazione isolata senza bagno dialisi e montando membrane ad elevata permeabilità. Inoltre, la plasmafiltrazione può essere eseguita utilizzando le macchine per la CRRT. A differenza dell’HD e dell’emofiltrazione, che rimuovono sostanze con peso molecolare medio e basso, la plasmafiltrazione rimuove le molecole ad alto peso molecolare, tra cui gli anticorpi implicati nella MG. La centrifugazione, invece, è in grado non solo di separare il plasma dal siero, ma può separare anche ciascuna delle altre componenti del sangue, come gli eritrociti o le piastrine, ed è quindi la tecnica di elezione quando sono richieste specifiche frazioni del sangue. Inoltre, quest’ultima sembra essere più efficace nella rimozione di molecole a peso molecolare molto alto come le IgM, il fibrinogeno e gli immunocomplessi. La plasmafiltrazione sfrutta un flusso sangue elevato, da 150 a 200 ml/min, e necessita pertanto di un accesso vascolare a portata più elevata come un CVC o una FAV. Nella centrifugazione, invece, il flusso sangue varia da 50 a 120 mL/min e può essere eseguita sia tramite CVC che catetere venoso periferico (CVP). Sebbene un CVP possa essere più tollerato dai pazienti e consente di evitare complicanze CVC relate, è associato a sedute più lunge e può portare a lungo termine a un depauperamento del patrimonio venoso [25 – 27]. Entrambe le tecniche sono in grado di garantire sedute efficaci e sicure di TPE; generalmente, la centrifugazione è la tecnica di preferenza dei Medici del Servizio Trasfusionale mentre la plasmafiltrazione risulta più affine ai Nefrologi. Nel caso in questione, infatti, dato che le sedute di TPE sono state gestite dal Servizio di Immunoematologia e Medicina Trasfusionale, che, nel nostro Centro, ha più esperienza clinica con la tecnica di plasmacentrifugazione, questa è stata la tecnica aferetica di scelta. In letteratura sono presenti studi di comparazione tra le due tecniche di plasmaferesi, che non hanno mostrato differenze significative di efficacia nella rimozione delle molecole a medio ed elevato peso molecolare tra di esse, mentre la plasmacentrifugazione solitamente risulta in sedute più brevi a fronte di una più elevata Plasma Removal Efficacy [27, 28].

Per quanto non frequente, non è del tutto inusuale per i Nefrologi la contingenza di dover gestire pazienti in cui il trattamento emodialitico e quello plasmaferetico procedano di pari passo. Infatti, sebbene le attuali linee guida della KDIGO raccomandino l’utilizzo della TPE solo per la malattia causata dagli anticorpi anti-membrana basale glomerulare (anti-GBM) (grading 1C) e le linee guida dell’American Society of Apherisis per le vasculiti ANCA (grading 1B) e per la malattia da anticorpi anti-GBM (grading 1 C),  nella pratica clinica, trova impiego in una più ampia gamma di patologie nefrologiche come la microangiopatia trombotica, le stesse vasculiti ANCA associate, il mieloma multiplo e le crioglobulinemie [29, 31]. Queste patologie sono spesso associate ad AKI o a danno d’organo terminale che richiedono la terapia renale sostitutiva. Per far fronte a questa condizione, alcuni centri si sono addirittura specializzati nell’utilizzo in combinazione di queste tecniche in una singola seduta [32, 35]. Povera invece è la letteratura scientifica per quanto riguarda casi di pazienti emodializzati cronici che hanno avuto la necessità di sottoporsi a trattamento aferetico per patologie di nuova insorgenza non di pertinenza nefrologica (come, ad esempio nel nostro caso, la Miastenia Gravis).

 

Conclusioni

Il presente caso insegna che, nonostante le complicanze insorte nel percorso clinico di un paziente complesso, con plurime comorbidità, in HD cronica e con nuova diagnosi di MG con gravi sintomi neurologici, la gestione multidisciplinare e la collaborazione tra vari servizi specialistici permette di gestire con successo l’iter diagnostico-terapeutico di una patologia rara ma che può mettere a rischio la sopravvivenza del paziente a breve termine.

 

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Combined extracorporeal CO2 removal and renal replacement therapy in a pregnant patient with COVID-19: a case report

Abstract

Background. Pregnant women are at high risk of Coronavirus disease 2019 (COVID-19) complications, including acute respiratory distress syndrome. Currently, one of the cornerstones in the treatment of this condition is lung-protective ventilation (LPV) with low tidal volumes. However, the occurrence of hypercapnia may limit this ventilatory strategy. So, different extracorporeal CO2 removal (ECCO2R) procedures have been developed. ECCO2R comprises a variety of techniques, including low-flow and high-flow systems, that may be performed with dedicated devices or combined with continuous renal replacement therapy (CRRT).
Case description. Here, we report a unique case of a pregnant patient affected by COVID-19 who required extracorporeal support for multiorgan failure. While on LPV, because of the concomitant hypercapnia and acute kidney injury, the patient was treated with an ECCO2R membrane inserted in series after a hemofilter in a CRRT platform. This combined treatment reducing hypercapnia allowed LPV maintenance at the same time while providing kidney replacement and ensuring maternal and fetal hemodynamic stability. Adverse effects consisted of minor bleeding episodes due to the anticoagulation required to maintain the extracorporeal circuit patency. The patient’s pulmonary and kidney function progressively recovered, permitting the withdrawal of any extracorporeal treatment. At the 25th gestational week, the patient underwent spontaneous premature vaginal delivery because of placental abruption. She gave birth to an 800-gram female baby, who three days later died because of multiorgan failure related to extreme prematurity.
Conclusions. This case supports using ECCO2R-CRRT combined treatment as a suitable approach in the management of complex conditions, such as pregnancy, even in the case of severe COVID-19.

Keywords: pregnancy, COVID-19, lung-protective ventilation, hypercapnia, CO2 removal, acute kidney injury, continuous renal replacement therapy

Introduction

Pulmonary involvement in Coronavirus disease 2019 (COVID-19) is highly heterogeneous, with clinical presentation ranging from asymptomatic forms to acute respiratory distress syndrome (ARDS) [1]. This heterogenicity may be explained by demographic factors, history of comorbidities, distinctive genetic background, and pharmacological treatments [2].

Among the different populations of COVID-19 patients, pregnant women deserve specific attention. Indeed, these patients, due to immunological and cardiorespiratory changes occurring in pregnancy, are at risk of the more severe complications of the disease, including ARDS [3, 4].

Most patients with ARDS require mechanical ventilation (MV), and in some cases also extracorporeal respiratory support (ECLS) [5].

These therapies encompass extracorporeal membrane oxygenation (ECMO) and the extracorporeal carbon dioxide removal system (ECCO2R). Briefly, ECMO takes over the gas exchange function of the lungs ensuring full oxygenation and CO2 removal, while ECCO2R is a CO2 removal system that does not affect oxygenation, and whose principal aim is consenting to lung protection (Table 1).

Extracorporeal life support (ECLS)

    Indications

Main Effects

Extracorporeal Membrane Oxigenation (ECMO)

VA-ECMO

 

VV-ECMO

 

VVA-ECMO*

Cardiac failure

 

Respiratory failure

with severe hypoxemia

 

Cardio-respiratory failure

Hemodynamic support

 

Oxygenation and decarboxylation

 

Hemodynamic and respiratory support

Extracorporeal Carbon dioxide Removal (ECCO2R)

VV-ECCO2R

(low-flow)

 

AV-ECCO2R

(high-flow)

Respiratory failure with severe hypercapnia

Decarboxylation (lung protection)

Table 1: Nomenclature and clinical indications of the extracorporeal life support systems.
Abbreviations: A, arterial; V, venous. *Other techniques of triple cannulation ECMO have also been described (for a full description, see Ref [32]).

Growing evidence suggests that similarly to other forms of ARDS, also in COVID-19 pneumonia lung-protective ventilation (LPV) – defined by low tidal volume (TV) of 4-6 ml/kg of predicted body weight (PBW) and plateau pressure (Pplat) less than 30 cmH2O – could constitute the most appropriate approach to limit ventilator-induced lung injury (VILI) [6, 7]. However, one of the main concerns regarding the use of LPV is the risk of developing hypercapnia, which may limit the clinical application of this strategy [8]. This is why ECCO2R techniques have been developed [9]. They include low-flow or high-flow systems that may be performed with dedicated platforms or, alternatively, combined with continuous renal replacement therapy (CRRT). The suitability of ECCO2R and CRRT (ECCO2R-CRRT) combination, providing simultaneous CO2 removal and kidney support, has been reported in recent studies in patients with sepsis, chronic obstructive pulmonary disease, and ARDS, both in small retrospective and prospective studies [10]. As expected, the clinical experience of ECCO2R-CRRT in patients with COVID-19 is very limited [11], while it is completely absent in pregnant women. So, here we report our experience with a unique case of a pregnant woman with multiorgan failure (MOF), occurring as a sequela of COVID-19 and treated with a combined ECCO2R-CRRT strategy.

 

Case description

In November 2020, a 34-year-old pregnant woman in the 19th week of gestational age, without past medical history, was admitted to the Emergency Department of a peripheral hospital because of dyspnea. The molecular nasal swab resulted positive for SARS-CoV-2 infection, so a diagnosis of COVID-19 was made. At admission, the patient presented dyspnea, with a respiratory rate (RR) of 24 breaths/minute, mean arterial pressure (MAP) was 72 mmHg, heart rate (HR) of 120 beats/minute, and peripheral oxygen saturation (SpO2) 90%. Laboratory examinations showed a white blood cell count (WBC) of 16.9 x 103/μL, anemia (Hb 9.1 g/dl), elevated lactate dehydrogenase (LDH 462 U/L), C-reactive protein (CRP) 203 mg/dl, serum creatinine (sCr) of 0.8 mg/dl and normal electrolytes levels.

She was initially treated with an oxygen mask at FiO2 60%, but after the worsening of the PaO2/FiO2 ratio to 120 mmHg, respiratory support with helmet continuous positive airway pressure (CPAP) at FiO2 100% was started. Three days after, because of further deterioration of respiratory function, the patient was transferred to the ICU, where invasive mechanical pressure-controlled ventilation (PCV) was started. The patient underwent cycles of prolonged prone positioning lasting 16 hours/day. Seven days after ICU admission, a percutaneous tracheostomy was performed.

During the hospitalization, the patient presented septic shock associated with evidence of colonization of the lower respiratory tract with Burkholderia cepacia.

Therefore, after infectious disease consultation, large-spectrum antimicrobial therapy with meropenem, ceftazidime/avibactam, and amphotericin B was initiated. On day 22, due to the clinical complexity of the case, the patient was centralized to our third-level University Hospital. At that time, beyond antimicrobial treatments, the patient was on therapy with corticosteroids, low molecular weight heparin, and norepinephrine (0.25 mcg/kg/min).

The molecular nasal swab for SARS-CoV-2 was negative, while laboratory examinations showed: sCr 1.6 mg/dl, LDH 492 U/L, and CRP 131 mg/dl. MAP was 88 mmHg and PaO2/FiO2 ratio 188 mmHg, in PCV with FiO2 0.6, according to an LPV strategy (TV 4.5 ml/PBW).

A CT scan showed extensive bilateral ground glass opacities associated with thickened interlobular and intralobular septa, without signs of pulmonary embolism.

The gynecological evaluation showed regular placental circulation and a vital fetus compatible with gestational age. Two days after the admission to our ICU, the patient presented a deterioration of gas exchanges, with the progressive onset of hypercapnia (PaCO2 80) with pH 7.43, mmHg, base excess (BE) 25.7 mmol/l, HCO3 53 mmol/L, lactate 0.6 mmol/l.

The day after, due to the persistence of hypercapnia (PaCO2 75.5 mmHg) and the ongoing AKI (as evidenced by increased sCr levels to 2.5 mg/dl and reduced urinary output to 0.5 ml/kg/h), ECCO2R treatment in association with renal support was started.

ECCO2R was provided using a polymethylpentene, hollow fiber, gas-exchanger membrane (1.35 m2 multiECCO2R, Eurosets, Medolla, Italy). The ECCO2R membrane was inserted in series after a hemofilter (Ultraflux AV 1000S 1.8 m2, Fresenius Medical Care, Bad Homburg, Germany) in the Multifiltrate CRRT platform (Fresenius Medical Care, Bad Homburg, Germany) (Figure 1).

Schematic representation of the circuit used to treat the patient
Figure 1: Schematic representation of the circuit used to treat the patient reported in this case. ECCO2R membrane was set after the hemofilter to obtain combined ECCO2R and RRT. Anticoagulation was provided by systemic heparinization. ECCO2R: extracorporeal CO2 removal; RRT: renal replacement therapy.

ECCO2R-CRRT was set in continuous venovenous hemodialysis (CVVHD) mode and was commenced, through a 13.5 Fr central venous catheter, at a blood flow of 300 ml/min, with a sweep gas flow of 5 l/min. CVVHD was delivered with an effluent dose of 25 ml/kg/h and net ultrafiltration of 1 ml/kg/h. Systemic anticoagulation was obtained by continuous administration of unfractionated heparin (UFH), with a target-activated partial thromboplastin time (aPTT) of 70-80 seconds. Table 2 reassumes the ventilatory and hemodynamic parameters collected during ECCO2R-CRRT treatment.

  Pre 6 h 12 h Day 1* Day 2 * Day 3 Day 4

End

Day 5

Post

Blood flow, ml/min 300 300 300 300 300 300 150
Sweep gas flow, l/min 5 5 5 5 3 4.5
aPTT, sec 39.8 84.1 79.7 77 72.4 53 56.2 46.6
Heparin dose (UI/h) 1000 1300 1250 1400 1400 1100 1200 750
Diuresis, ml/kg/h 0.5 0.5 0.5 0.3 0.2 0.3 0.3 0.3
CRRT effluent rate, ml/kg/h 25 25 25 25 30 25 25
CRRT ultrafiltration rate, ml/kg/h 1 1 2 2 3 3 2
Arterial blood gas
pH 7.39 7.4 7.32 7.29 7.32 7.33 7.38 7.41
PaCO2, mmHg 75.5 63 66 67.2 58 73 57 54
PaO2, mmHg 111 138 158 132 178 119 202 135
HCO3, mmol/l 46.6 39 34 31.5 30.3 35 33.5 27.1
BE, mmol/l 19.3 11.8 7.1 4.6 3.1 11.2 7 0.3
Ventilator parameters
TV, ml/PBW 4.3 3.6 2.5 3.5 4 3.6 4.5 4.5
RR, breaths/min 35 28 26 26 26 26 26 26
Pplat, cmH20 28 28 27 27 27 27 27 27
PEEP, cmH2O 12 12 12 14 12 12 12 12
PaO2/FiO2 ratio, mmHg 220 276 395 330 356 238 404 338
Hemodynamic parameters
Mean arterial pressure, mmHg 95 98 94 77 84 97 87 95
Heart rate, beats/min 118 100 89 100 125 120 130 128
Norepinephrine dose, mcg/kg/min 0.3 0.25 0.1 0.15 0.15 0.3 0.3 0.25
Table 2: Time course of operation characteristics, ventilatory and hemodynamic parameters during ECCO2R-CRRT treatment.
aPTT: activated partial thromboplastin time; COVID-19: coronavirus disease 2019; CRRT: continuous renal replacement therapy; ECCO2R: extracorporeal carbon dioxide removal; FiO2: fraction of inspired oxygen; HCO3: bicarbonate; BE: base excess; PaCO2: arterial partial pressure of carbon dioxide; PaO2: arterial partial pressure of oxygen; PBW: predicted body weight; PEEP: positive end-expiratory pressure; Pplat: plateau pressure; RR: respiratory rate; TV: tidal volume.
* Bleeding complications

At the end of the ECCO2R-CRRT treatment cycle, PaCO2 was 54 mmHg and pH 7.41. During the treatment, TV, PEEP, and Pplat were maintained according to LPV, while RR was reduced. The PaO2/FiO2 ratio increased from 202 to 338 mmHg and the hemodynamics remained stable.

Overall, ECCO2R-CRRT lasted four days (with the change of hemofilter on the third day) and was discontinued due to a sustained improvement in hypercapnia and concern about mild hemorrhagic complications (hematuria and bleeding from tracheostomy). After ECCO2R treatment termination, CRRT was continued because of persistent AKI and oliguria, using regional citrate as an anticoagulation strategy. Then, no further bleeding episodes occurred. During the ECCO2R-CRRT cycle, the fetal status was constantly monitored, revealing a vital fetus with normal HR (mean values of about 130 beats/minute) and movements. However, two weeks after ECCO2R discontinuation, corresponding to the 25th gestational week, the patient underwent spontaneous premature vaginal delivery because of placental abruption. She gave birth to an 800-gram female baby admitted to the Neonatal Intensive Care Unit, where she died three days later because of multiorgan failure related to extreme prematurity.

During the following days, the patient’s conditions stabilized, while kidney function and diuresis increased, with the possibility of withdrawing CRRT (for a total treatment duration of 21 days). At that time, ventilatory parameters were TV 4.6 ml/PBW, Pplat 28 cmH2O, RR 30 breaths/min, and FiO2 0.45, while ABG showed pH 7.45, PaCO2 59 mmHg and PaO2 111 mmHg.

One week later, it was possible to shift to pressure support ventilation, and then the patient was completely weaned from mechanical ventilation (Figure 2). Finally, she was transferred to the Rehabilitation Clinics, from which she was discharged one month later, with complete renal recovery.

Time course and main clinical events occurring during the hospitalization.
Figure 2: Time course and main clinical events occurring during the hospitalization. ICU: intensive care unit; MV: mechanical ventilation; ECCO2R: extracorporeal CO2 removal; CRRT: continuous renal replacement therapy.

 

Discussion

To our knowledge, here we present the first case of a pregnant woman affected by COVID-19 treated with a combined ECCO2R-CRRT approach.

The management of this patient offers the possibility to discuss some points of crucial relevance in clinical practice. First, as already reported, we found that COVID-19-related MOF may also occur in young people without significant medical history. This observation was especially valid in patients who, such as in our case, resulted affected by COVID-19 during the first pandemic waves, when vaccination and antiviral drugs were still unavailable [12]. COVID-19-related organ damage may be a direct consequence of infection or a sequela of the complications developing during the disease course. In our case, while acute lung injury was directly attributable to COVID-19, the pathogenesis of severe kidney injury was less clear and not specifically studied, being probably the consequence of multiple factors, including hemodynamic instability, nephrotoxic drugs, and ARDS-related AKI [13]. Moreover, in line with available Literature, it is possible that pregnancy constituted an additional risk factor for a severe form of COVID-19 [14].

Then, we observed that using a low-flow ECCO2R-CRRT in a single circuit effectively controlled hypercapnia, allowing the maintenance of the LPV strategy.

Briefly, ECCO2R is a technique that, taking advantage of its high diffusivity, removes CO2 without providing significant oxygenation [15].

It consists of a circuit where blood is drained through a cannula from a central vein or artery and returned to the venous system after CO2 removal by a membrane lung (acting as an artificial gas exchanger). Inside the membrane lung, a “sweep gas” (medical air or oxygen) running along the other side of the membrane generates a diffusion gradient driving CO2 removal.

Many different devices and membrane lungs are available, but essentially ECCO2R devices can be grouped into two main categories: arteriovenous pumpless systems (AV-ECCO2R) and venovenous pump-driven devices (VV-ECCO2R) [16]. In turn, VV-ECCO2R may be performed with low-flow or high-flow systems. Low-flow ECCO2R systems operate with a low blood flow rate (between 200 and 400 ml/min) and offer the possibility of using CRRT platforms and dual-lumen dialysis catheters. Conversely, high-flow systems (i.e., blood flow rate higher than 500 ml/min) require dedicated devices and larger cannulas. Apart from technical issues, the main difference between these two strategies is the effectiveness of CO2 removal. So, while a blood flow rate of 200-300 ml/min may remove 40-60 ml CO2/min, representing 20%-25% of total CO2 production, an increase in the blood flow rate may remove until 150 ml CO2/min, representing approximately 50%-60% of total CO2 [17, 18].

However, experimental evidence suggests that, due to limitations of blood flow and membrane efficiency, the actual removal capacity is inferior and, in particular, low-flow systems may remove up to 25% of carbon dioxide production [19].

In our case, since the patient did not present respiratory acidosis and the goals of the treatment were maintaining LPV and supporting kidney function, a low-flow ECCO2R-CRRT approach was chosen. This combined treatment allowed for controlling fluid balance and kidney function replacement, leading to the stability of both ventilatory and maternal and fetal hemodynamic parameters. The effectiveness and suitability of combined ECCO2R-CRRT treatment are in line with what is described in previous case reports and clinical studies on ARDS patients in different clinical contexts [2022].

So, for example, Nentwich et al. evaluated twenty hypercapnic critically ill patients with renal failure who were treated with a combined system incorporating a membrane lung in series with a hemofilter on a conventional CRRT circuit. They found that this system was effective in decreasing PaCO2 and reducing ventilation requirements with a decrease in TV [23].

Regarding the specific setting of pregnant women, experience with ECLS is scarce.

Recently, a systematic review evaluated 358 patients undergoing ECLS in the peripartum period, including 81 pregnant women [24]. The most common indications for ECLS were ARDS and cardiac failure. Despite some episodes of major bleeding and the need for preterm delivery in about 50% of the cases, overall maternal survival at 30 days was 75% and fetal survival was 64.7%. Therefore, these data support the use of ECLS in peripartum women. However, looking at specific ECLS techniques, only a few patients underwent ECCO2R and none of them were in combination with CRRT [25, 26]. If the information on the general population is poor, data on pregnant patients with COVID-19 are completely lacking. In general, the experience of ECCO2R in COVID-19 is limited. Ding et al. reported the data of twelve COVID-19 patients with refractory hypercapnia treated with a low-flow ECCO2R system based on the CRRT platform [27]. They observed the application of the ECCO2R system enabled CO2 removal associated with a significant decrease in TV and Pplat. However, none of these patients had AKI at the initiation of ECCO2R-CRRT treatment.

Similarly, Husain-Syed F. et al. in a small prospective study that enrolled four patients, including one with AKI, reported that treatment with an ECCO2R circuit inserted in a CRRT platform was safe and feasible, both when used alone and in combination with renal support treatment [28]. However, although effective, this approach is not risk-free. The review of the pertinent Literature has shown that the ECCO2R-related adverse effects include hemorrhages, heparin-induced thrombocytopenia, circuit clot, and limb ischemia [29].

In our patient, the main adverse events consisted of bleedings related to the anticoagulation required to maintain the patency of a low-flow extracorporeal circuit. This aspect should be considered when prescribing ECCO2R-CRRT. Indeed, while in clinical trials and daily practice the most diffuse strategy is systemic anticoagulation with heparin, the possibility to use citrate-based regional anticoagulation could promote the investigation of alternative anticoagulation protocols (for example, combining low-dose systemic UFH with regional citrate anticoagulation in the CRRT circuit) [5]. Finally, it should be noticed that, despite numerous studies reporting the benefits of ECCO2R [30], the recent REST trial has questioned the usefulness of ECCO2R, showing non-additional advantages of this treatment in patients with acute hypoxemic respiratory failure treated with low tidal volume mechanical ventilation [31]. However, these results are inconclusive since this study may be underpowered to detect significant findings.

 

Conclusions

Since the limitations of available studies, mainly due to the small number of patients enrolled and short observation time, further evidence from specific-designed randomized clinical trials and high-quality prospective studies is needed to determine the actual clinical impact of ECCO2R on specific patient populations and guide decision-making.

In the meantime, we believe that the available evidence is strong enough to support the use of ECCO2R, also integrated into a CRRT circuit, in selected patients in the context of multi-organ supportive therapy. In this view, continuous active reporting of clinical experience and cohort studies remain essential to define and confirm the suitability and safety of this approach. 

 

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