ASAIO Journal 2014
Case Series
Elevation of Procalcitonin After Implantation of an Interventional Lung Assist Device in Critically Ill Patients Matthias Kott,* Burkhard Bewig,† Günther Zick,* Dirk Schaedler,* Tobias Becher,* Inéz Frerichs,* and Norbert Weiler*
A pumpless interventional arteriovenous lung assist device (iLA) facilitates the removal of carbon dioxide from the blood and is used as part of the lung-protective ventilation strategy in patients with acute respiratory distress syndrome (ARDS). In case of bacterial infection, delayed antimicrobial therapy increases the mortality in this group of high-risk critically ill patients, whereas overtreatment promotes bacterial resistance and leads to increased drug toxicity and costs. Besides clinical signs and symptoms, antimicrobial treatment is based on the kinetics of biomarkers such as procalcitonin (PCT). We hereby report an up to 10-fold increase in PCT serum concentrations in four mechanically ventilated patients with ARDS detected within 12–20 hours after iLA implantation in the absence of any infection. Procalcitonin concentrations returned to nearly baseline values in all patients on the fourth day after iLA implantation. We discuss the possible mechanisms of PCT induction in this specific patient population and recommend the onset of antibiotics administration after iLA implantation to be carefully considered in the context of other clinical findings and not solely based on the PCT kinetics. Repeated PCT measurements in short time intervals should be performed in these patients. ASAIO Journal 2014; 60:249–253.
oxygenation enables the reduction of inspiratory driving pressures and therefore the establishment of a lung-protective ventilation strategy. Mechanically ventilated patients are at high risk for the development of mostly ventilator- or catheter-associated infections. Prompt initiation of appropriate antibiotics to treat these infections reduces mortality, while overtreatment promotes bacterial resistance and leads to increased drug toxicity and costs.2 Besides physical examination, the decision to treat is often based on the kinetics of infectiological biomarkers such as C-reactive protein (CRP), leukocyte count, or procalcitonin (PCT). Procalcitonin has become a widely used marker for the diagnosis of bacterial infection in critically ill patients.3 A more than 1,000-fold increase in PCT serum concentrations compared to normal baseline concentrations has been described during severe bacterial infection, first by Assicot et al.4 in 1993. A sudden increase in PCT serum concentrations should lead to a reevaluation of the antimicrobial treatment. Certain clinical circumstances have been described in which PCT elevation cannot be attributed to bacterial infection and therefore can lead to unnecessary administration of antibiotics.5–8 We report a case of transient PCT elevation in a mechanically ventilated critically ill patient directly after the implantation of an iLA device in the absence of infection and present retrospective data on PCT kinetics in a case series of patients during iLA implantation.
Key Words: respiratory distress syndrome, adult/therapy, respiration, artificial/methods, procalcitonin, antibiotics, drug resistance, bacteria
C
Materials and Methods
ritically ill patients with need for mechanical ventilation due to acute respiratory distress syndrome (ARDS) suffer from life-threatening impairment of ventilation and oxygenation. In case of ongoing and severe hypercapnia, the implantation of a pumpless interventional arteriovenous lung assist device (iLA) can be useful to eliminate carbon dioxide from the blood.1 The partial uncoupling of carbon dioxide removal and
This retrospective study was conducted in a tertiary medical center (University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany) in 2012 and was approved by the institutional review board in compliance with the Helsinki Declaration. All patients gave informed written consent. All data were obtained from the institutional patient data management system (Critical Care Manager; Picis Inc., Wakefield, MA). Collected variables are presented as median values with interquartile ranges (IQRs).
From the *Department of Anesthesiology and Intensive Care Medicine, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany; and †Department of General Internal Medicine, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany. Submitted for consideration September 2013; accepted for publication in revised form October 2013. Disclosure: The authors have no conflicts of interest to report. Reprint Requests: Matthias Kott, Department of Anesthesiology and Intensive Care Medicine, University Medical Centre Schleswig-Holstein, Campus Kiel, Schwanenweg 21, 24105 Kiel, Germany. Email: [email protected]. Copyright © 2014 by the American Society for Artificial Internal Organs
Case Report A 39-year-old male patient was admitted to hospital for elective surgery. He had a history of hemophilia type A, chronic hepatitis type B and C, and chronic iron deficiency anemia. He suffered from severe chronic abdominal pain after ileocolic resection due to Crohn’s disease in 2007 and was then operated to resolve a stricture. Postoperatively, he developed septic shock due to anastomotic leakage with ensuing ARDS and need for invasive mechanical ventilation. Surgical treatment
DOI: 10.1097/MAT.0000000000000041
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with repeated abdominal lavage was initiated and adequate antimicrobial therapy administered. He was transferred to a normal ward within 2 weeks. Later on, he developed pneumonia and a second episode of severe ARDS, which was treated successfully with high-frequency oscillatory ventilation after readmission to the intensive care unit (ICU). After return to conventional ventilation in biphasic positive airway pressure mode, the patient suffered from sustained and ongoing hypercapnia and respiratory distress. In a computed tomography scan of the thorax, signs of fibrotic alterations of the lung tissue were found, consistent with a late stage of ARDS. In the latter course of the disease, the patient developed progressive respiratory acidosis (arterial pH, 7.17; arterial oxygen pressure, 10.7 kPa; arterial carbon dioxide pressure, 14.4 kPa; standard bicarbonate, 34.3 mmol/L; base excess, +9 mmol/L) with need for high inspiratory driving pressures to maintain adequate alveolar minute ventilation (fraction of inspired oxygen, 0.35; peak inspiratory pressure, 34 cm H2O; positive endexpiratory pressure, 10 cm H2O; respiratory rate, 29 breaths/ min; ventilation, 12.0 L/min; respiratory system compliance, 11.2 ml/cm H2O; resistance, 7 cm H2O/s; see also Figure 1, A and B for radiographs). To allow for reduction in inspiratory driving pressures and to facilitate weaning, we decided to use an iLA device (Novalung, Hechingen, Germany). Successful
ltrasound-guided implantation of two cannulae in the left iliac u artery and right iliac vein was performed via modified Seldinger’s technique and the iLA device connected to these two cannulae, with an initially delivered flow of oxygen of 10 L/min and a subsequent decrease in arterial carbon dioxide (7.6 kPa) and inspiratory peak pressures (24 cm H2O). At this time point, no antimicrobial drugs were administered; the patient had no fever, no clinical signs of infection were evident, and all collected specimens (e.g., tracheal secretion, urine, drainage swaps, and blood cultures) were free of pathogens. Laboratory monitoring was carried out via serial PCT, CRP, temperature, and leukocyte count measurements. After iLA implantation, a PCT concentration peak could be observed, from 0.12 ng/ml on the day before implantation up to 0.73 ng/ml on the day after implantation. C-reactive protein showed a decline from 111.3 to 77.3 mg/L, the leukocyte count stayed in the normal range. Delayed antimicrobial therapy would have had fatal impact on the patient’s outcome in the case of a bacterial infection, and so the therapeutic team considered the start of administration of empiric broad-range antibiotics. In absence of acute worsening of the patient’s condition, another PCT measurement was performed 12 hours after the observed high PCT value which revealed a trend toward declining values. Thus, the decision was made not to administer antibiotic drugs
Figure 1. Chest X-ray photograph and computed tomography scans (from representational cross-sections) of the lung and the chest of the patient from the delineated case. A and B were taken 1 day before implantation, and C and D directly after explantation of the interventional lung assist device.
251
PROCALCITONIN AND iLA Table 1. Characteristics of Patients
Case I Case II Case III Case IV
Age
Height (m)
Weight (kg)
39 70 37 61
1.79 1.68 1.73 1.81
64 72 50 134
Sex
Indication for iLA
Catheter Size (Fr)
Pre-iLA PaCO2 (kPa)
Duration of iLA (d)
Outcome
M F M M
ARDS COPD GOLD IV α1-AT deficiency COPD GOLD IV
19 19 17 21
14.4 11.2 16 13
18 12 19 14
Discharged Dead Discharged Dead
α1-AT, α1-antitrypsin; ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; F, female; GOLD, global strategy for chronic obstructive disease classification; M, male.
at all. The patient’s PCT serum concentrations were monitored on a daily basis and they returned to baseline values on the fourth day after iLA implantation. The leukocyte count stayed in the normal range over the whole reported period, and CRP showed a delayed increase 3 days after the iLA implantation. After 18 days and marked improvement in ventilation (Figure 1, C and D), the iLA device was successfully explanted; one minor bleeding complication occurred and was resolved at the bedside. Twenty-six days after discontinuation of the iLA, the patient was successfully extubated and transferred to a normal ward after three more weeks. He was discharged from hospital 6 weeks later. Results After we observed the above described PCT kinetics in our patient, we performed a retrospective search for patients treated in our ICU in 2012 who underwent iLA implantation and serial PCT monitoring. Three more patients with a history of severe acute respiratory failure, need for mechanical ventilation, and treatment with an iLA device were found. As in the first case, no documented infections were evident. The underlying disease responsible for respiratory failure in the three additional patients was exacerbated chronic obstructive
Figure 2. Procalcitonin concentrations before and after interventional lung assist (iLA) system implantation in four mechanically ventilated patients. The box plots show the minima/maxima (whiskers), 25%/75% percentile (box), median (——), and mean (+) values.
pulmonary disease in two cases and α1-antitrypsin deficiency in the other, respectively. The detailed patients’ characteristics are summarized in Table 1. All four patients taken together presented with very low (median, 0.16 ng/ml; IQR, 0.13–0.34 ng/ml) PCT concentrations before iLA implantation. On the day after iLA implantation, up to 10-fold increase in PCT concentrations was observed (median, 0.62 ng/ml; IQR, 0.65–1.61 ng/ml). Procalcitonin concentrations declined continuously in the further course of the disease, with a return to nearly baseline concentrations (median, 0.32 ng/ml; IQR, 0.21–0.97 ng/ml) on the fourth day after implantation (Figure 2). Neither CRP (Figure 3) nor the leukocyte count values (Figure 4) exhibited this time course in the studied period. Discussion PCT is produced in a variety of tissues. Müller et al.9 found a massive increase in CALC-1 gene expression in tissues such as brain, lung, liver, kidney, testes, and muscle in a septic hamster model. Russwurm et al.10 showed that CGRP-1 mRNA expression following ex vivo stimulation with tumor necrosis factor-α (TNF-α) can be observed in multiple human tissues.
Figure 3. C-reactive protein concentrations before and after interventional lung assist (iLA) system implantation in four mechanically ventilated patients. The box plots show the minima/maxima (whiskers), 25%/75% percentile (box), median (——), and mean (+) values.
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Figure 4. Leukocyte counts before and after interventional lung assist (iLA) system implantation in four mechanically ventilated patients. The box plots show the minima/maxima (whiskers), 25%/75% percentile (box), median (——), and mean (+) values.
Linscheid et al.11 found increased calcitonin mRNA expression in cultured adipocytes and monocytes after stimulation with several proinflammatory cytokines as well as in extrathyroidal adipose tissues of patients with infection and elevated serum PCT concentrations. PCT elevations in the absence of bacterial infection have already been described in literature. Certain diseases such as small cell lung cancer or C cell carcinoma and medications such as antithymocyte globulin or monoclonal OKT3 antibodies lead to pronounced hyperprocalcitoninemia.5–8,12 Increased PCT serum concentrations can be observed in noninfectious, traumatic systemic inflammatory response syndrome (SIRS) as well as in the presence of shock with severe hypotension of different etiology, where the disruption of the intestinal vascular endothelial barrier may lead to bacterial translocation and consecutive PCT induction.13 PCT elevations not related to bacterial infections have been observed directly after surgery; depending on the extent of the surgical trauma, even primary aseptic procedures may result in transient PCT elevation.6 During septic surgery, bacterial translocation from the gut following intestinal resection is thought to be one of the underlying pathomechanisms responsible for changes in PCT concentrations.14 The use of on-pump cardiopulmonary bypass (CPB) during cardiac surgery may lead to SIRS, with subsequent PCT elevation.15 Besides ischemia-reperfusion injury of the lungs and the surgical trauma itself, the contact of the blood with artificial surfaces of the CPB, including the oxygenation membrane, leads to cytokine liberation and SIRS.15 The iLA device membrane contains a heparin-coated artificial surface of about 1,300 cm2, consisting of a polymethylpentene membrane organized as hollow-fiber network.16 It is recommended to maintain a minimum blood flow of ≥1,000 ml/ min through the device to prevent clotting and to ensure an adequate carbon dioxide clearance from the blood. As this is approximately 25% of the cardiac output in most critically ill
patients, an interleukin (IL) and mediator release similar to that observed during CPB could be the underlying cause of the PCT concentration elevation observed directly after implantation of the iLA device in our patients. Introduction of the arteriovenous shunt results in an increase in left ventricular work load. The higher oxygen content of the venous blood may lead to a reduction in hypoxic pulmonary vasoconstriction and, consecutively, to a reduction in pulmonary artery pressures.17 If cardiac function is normal, pulmonary circulation could be augmented by the shunted arterial blood volume. PCT induction is linked to the release of proinflammatory mediators, such as IL-1β, IL-6, IL-8, or TNF-α, as a midstream event in the cascade of inflammation.18 Studies examining the hemocompatibility of an iLA device in pigs after lavage-induced lung injury found no changes in PCT, IL-8, or TNF-α, but data in humans are lacking.19,20 In other clinical settings where extracorporeal circulation is used, for example, during continuous renal replacement therapy, a blood flow through the membrane of only approximately 200 ml/min is used. This could explain the absence of PCT induction in this case.21 It seems implausible that the minimal tissue trauma associated with the iLA implantation could be held responsible for the observed PCT induction. Another possible mechanism for PCT elevation could have been the ongoing ischemia of the cannulated leg with subsequent cytokine liberation. However, this effect was ruled out in all four of our cases by monitoring of peripheral blood flow via continuous peripheral pulse plethysmography. In conclusion, PCT elevations can be observed in critically ill patients after iLA implantation. In the absence of clinical signs of bacterial infection, this phenomenon is most likely related to the release of proinflammatory cytokines following contact of the blood with the artificial surfaces of the iLA membrane, but the exact mechanism remains unknown. Hence, we recommend that the start of antibiotics administration should be carefully considered in the context of other clinical findings, and repeated PCT measurements should be performed in short time intervals. Author Contributions MK, GZ, and NW conceived the study, participated in its design and coordination, and drafted the manuscript. DS, BB, and IF drafted and critically revised the manuscript. TB carried out data acquisition. All authors read and approved the final manuscript.
References 1. Liebold A, Reng CM, Philipp A, Pfeifer M, Birnbaum DE: Pumpless extracorporeal lung assist—Experience with the first 20 cases. Eur J Cardiothorac Surg 17: 608–613, 2000. 2. Kumar A, Roberts D, Wood KE, et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34: 1589–1596, 2006. 3. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY: Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: A systematic review and meta-analysis. Crit Care Med 34: 1996–2003, 2006. 4. Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C: High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 341: 515–518, 1993. 5. Kuse ER, Jaeger K: Procalcitonin increase after anti-CD3 monoclonal antibody therapy does not indicate infectious disease. Transpl Int 14: 55, 2001.
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6. Meisner M, Tschaikowsky K, Hutzler A, Schick C, Schüttler J: Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med 24: 680–684, 1998. 7. Brodska H, Drabek T, Malickova K, et al: Marked increase of procalcitonin after the administration of anti-thymocyte globulin in patients before hematopoietic stem cell transplantation does not indicate sepsis: A prospective study. Crit Care 13: R37, 2009. 8. Walter MA, Meier C, Radimerski T, et al: Procalcitonin levels predict clinical course and progression-free survival in patients with medullary thyroid cancer. Cancer 116: 31–40, 2010. 9. Müller B, White JC, Nylén ES, Snider RH, Becker KL, Habener JF: Ubiquitous expression of the calcitonin-i gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab 86: 396–404, 2001. 10. Russwurm S, Stonans I, Stonane E, et al: Procalcitonin and CGRP-1 mrna expression in various human tissues. Shock 16: 109–112, 2001. 11. Linscheid P, Seboek D, Nylen ES, et al: In vitro and in vivo calcitonin I gene expression in parenchymal cells: A novel product of human adipose tissue. Endocrinology 144: 5578–5584, 2003. 12. Cate CC, Pettengill OS, Sorenson GD: Biosynthesis of procalcitonin in small cell carcinoma of the lung. Cancer Res 46: 812– 818, 1986. 13. Brunkhorst FM, Wegscheider K, Forycki ZF, Brunkhorst R: Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med 26 (Suppl 2): S148–S152, 2000.
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14. Sarbinowski R, Arvidsson S, Tylman M, Oresland T, Bengtsson A: Plasma concentration of procalcitonin and systemic inflammatory response syndrome after colorectal surgery. Acta Anaesthesiol Scand 49: 191–196, 2005. 15. Maruna P, Klein AA, Kunstýř J, Plocová KM, Mlejnský F, Lindner J: Aprotinin reduces the procalcitonin rise associated with complex cardiac surgery and cardiopulmonary bypass. Physiol Res 62: 27–33, 2013. 16. Kopp R, Bensberg R, Henzler D, et al: Hemocompatibility of a miniaturized extracorporeal membrane oxygenation and a pumpless interventional lung assist in experimental lung injury. Artif Organs 34: 13–21, 2010. 17. Zick G, Frerichs I, Schädler D, et al: Oxygenation effect of interventional lung assist in a lavage model of acute lung injury: A prospective experimental study. Crit Care 10: R56, 2006. 18. Matwiyoff GN, Prahl JD, Miller RJ, et al: Immune regulation of procalcitonin: A biomarker and mediator of infection. Inflamm Res 61: 401–409, 2012. 19. Walles T: Clinical experience with the iLA Membrane Ventilator pumpless extracorporeal lung-assist device. Expert Rev Med Devices 4: 297–305, 2007. 20. Dembinski R, Hochhausen N, Terbeck S, et al: Pumpless extracorporeal lung assist for protective mechanical ventilation in experimental lung injury. Crit Care Med 35: 2359–2366, 2007. 21. Steinbach G, Bölke E, Grünert A, Störck M, Orth K: Procalcitonin in patients with acute and chronic renal insufficiency. Wien Klin Wochenschr 116: 849–853, 2004.
Case Series
Elevation of Procalcitonin After Implantation of an Interventional Lung Assist Device in Critically Ill Patients Matthias Kott,* Burkhard Bewig,† Günther Zick,* Dirk Schaedler,* Tobias Becher,* Inéz Frerichs,* and Norbert Weiler*
A pumpless interventional arteriovenous lung assist device (iLA) facilitates the removal of carbon dioxide from the blood and is used as part of the lung-protective ventilation strategy in patients with acute respiratory distress syndrome (ARDS). In case of bacterial infection, delayed antimicrobial therapy increases the mortality in this group of high-risk critically ill patients, whereas overtreatment promotes bacterial resistance and leads to increased drug toxicity and costs. Besides clinical signs and symptoms, antimicrobial treatment is based on the kinetics of biomarkers such as procalcitonin (PCT). We hereby report an up to 10-fold increase in PCT serum concentrations in four mechanically ventilated patients with ARDS detected within 12–20 hours after iLA implantation in the absence of any infection. Procalcitonin concentrations returned to nearly baseline values in all patients on the fourth day after iLA implantation. We discuss the possible mechanisms of PCT induction in this specific patient population and recommend the onset of antibiotics administration after iLA implantation to be carefully considered in the context of other clinical findings and not solely based on the PCT kinetics. Repeated PCT measurements in short time intervals should be performed in these patients. ASAIO Journal 2014; 60:249–253.
oxygenation enables the reduction of inspiratory driving pressures and therefore the establishment of a lung-protective ventilation strategy. Mechanically ventilated patients are at high risk for the development of mostly ventilator- or catheter-associated infections. Prompt initiation of appropriate antibiotics to treat these infections reduces mortality, while overtreatment promotes bacterial resistance and leads to increased drug toxicity and costs.2 Besides physical examination, the decision to treat is often based on the kinetics of infectiological biomarkers such as C-reactive protein (CRP), leukocyte count, or procalcitonin (PCT). Procalcitonin has become a widely used marker for the diagnosis of bacterial infection in critically ill patients.3 A more than 1,000-fold increase in PCT serum concentrations compared to normal baseline concentrations has been described during severe bacterial infection, first by Assicot et al.4 in 1993. A sudden increase in PCT serum concentrations should lead to a reevaluation of the antimicrobial treatment. Certain clinical circumstances have been described in which PCT elevation cannot be attributed to bacterial infection and therefore can lead to unnecessary administration of antibiotics.5–8 We report a case of transient PCT elevation in a mechanically ventilated critically ill patient directly after the implantation of an iLA device in the absence of infection and present retrospective data on PCT kinetics in a case series of patients during iLA implantation.
Key Words: respiratory distress syndrome, adult/therapy, respiration, artificial/methods, procalcitonin, antibiotics, drug resistance, bacteria
C
Materials and Methods
ritically ill patients with need for mechanical ventilation due to acute respiratory distress syndrome (ARDS) suffer from life-threatening impairment of ventilation and oxygenation. In case of ongoing and severe hypercapnia, the implantation of a pumpless interventional arteriovenous lung assist device (iLA) can be useful to eliminate carbon dioxide from the blood.1 The partial uncoupling of carbon dioxide removal and
This retrospective study was conducted in a tertiary medical center (University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany) in 2012 and was approved by the institutional review board in compliance with the Helsinki Declaration. All patients gave informed written consent. All data were obtained from the institutional patient data management system (Critical Care Manager; Picis Inc., Wakefield, MA). Collected variables are presented as median values with interquartile ranges (IQRs).
From the *Department of Anesthesiology and Intensive Care Medicine, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany; and †Department of General Internal Medicine, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany. Submitted for consideration September 2013; accepted for publication in revised form October 2013. Disclosure: The authors have no conflicts of interest to report. Reprint Requests: Matthias Kott, Department of Anesthesiology and Intensive Care Medicine, University Medical Centre Schleswig-Holstein, Campus Kiel, Schwanenweg 21, 24105 Kiel, Germany. Email: [email protected]. Copyright © 2014 by the American Society for Artificial Internal Organs
Case Report A 39-year-old male patient was admitted to hospital for elective surgery. He had a history of hemophilia type A, chronic hepatitis type B and C, and chronic iron deficiency anemia. He suffered from severe chronic abdominal pain after ileocolic resection due to Crohn’s disease in 2007 and was then operated to resolve a stricture. Postoperatively, he developed septic shock due to anastomotic leakage with ensuing ARDS and need for invasive mechanical ventilation. Surgical treatment
DOI: 10.1097/MAT.0000000000000041
249
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KOTT et al.
with repeated abdominal lavage was initiated and adequate antimicrobial therapy administered. He was transferred to a normal ward within 2 weeks. Later on, he developed pneumonia and a second episode of severe ARDS, which was treated successfully with high-frequency oscillatory ventilation after readmission to the intensive care unit (ICU). After return to conventional ventilation in biphasic positive airway pressure mode, the patient suffered from sustained and ongoing hypercapnia and respiratory distress. In a computed tomography scan of the thorax, signs of fibrotic alterations of the lung tissue were found, consistent with a late stage of ARDS. In the latter course of the disease, the patient developed progressive respiratory acidosis (arterial pH, 7.17; arterial oxygen pressure, 10.7 kPa; arterial carbon dioxide pressure, 14.4 kPa; standard bicarbonate, 34.3 mmol/L; base excess, +9 mmol/L) with need for high inspiratory driving pressures to maintain adequate alveolar minute ventilation (fraction of inspired oxygen, 0.35; peak inspiratory pressure, 34 cm H2O; positive endexpiratory pressure, 10 cm H2O; respiratory rate, 29 breaths/ min; ventilation, 12.0 L/min; respiratory system compliance, 11.2 ml/cm H2O; resistance, 7 cm H2O/s; see also Figure 1, A and B for radiographs). To allow for reduction in inspiratory driving pressures and to facilitate weaning, we decided to use an iLA device (Novalung, Hechingen, Germany). Successful
ltrasound-guided implantation of two cannulae in the left iliac u artery and right iliac vein was performed via modified Seldinger’s technique and the iLA device connected to these two cannulae, with an initially delivered flow of oxygen of 10 L/min and a subsequent decrease in arterial carbon dioxide (7.6 kPa) and inspiratory peak pressures (24 cm H2O). At this time point, no antimicrobial drugs were administered; the patient had no fever, no clinical signs of infection were evident, and all collected specimens (e.g., tracheal secretion, urine, drainage swaps, and blood cultures) were free of pathogens. Laboratory monitoring was carried out via serial PCT, CRP, temperature, and leukocyte count measurements. After iLA implantation, a PCT concentration peak could be observed, from 0.12 ng/ml on the day before implantation up to 0.73 ng/ml on the day after implantation. C-reactive protein showed a decline from 111.3 to 77.3 mg/L, the leukocyte count stayed in the normal range. Delayed antimicrobial therapy would have had fatal impact on the patient’s outcome in the case of a bacterial infection, and so the therapeutic team considered the start of administration of empiric broad-range antibiotics. In absence of acute worsening of the patient’s condition, another PCT measurement was performed 12 hours after the observed high PCT value which revealed a trend toward declining values. Thus, the decision was made not to administer antibiotic drugs
Figure 1. Chest X-ray photograph and computed tomography scans (from representational cross-sections) of the lung and the chest of the patient from the delineated case. A and B were taken 1 day before implantation, and C and D directly after explantation of the interventional lung assist device.
251
PROCALCITONIN AND iLA Table 1. Characteristics of Patients
Case I Case II Case III Case IV
Age
Height (m)
Weight (kg)
39 70 37 61
1.79 1.68 1.73 1.81
64 72 50 134
Sex
Indication for iLA
Catheter Size (Fr)
Pre-iLA PaCO2 (kPa)
Duration of iLA (d)
Outcome
M F M M
ARDS COPD GOLD IV α1-AT deficiency COPD GOLD IV
19 19 17 21
14.4 11.2 16 13
18 12 19 14
Discharged Dead Discharged Dead
α1-AT, α1-antitrypsin; ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; F, female; GOLD, global strategy for chronic obstructive disease classification; M, male.
at all. The patient’s PCT serum concentrations were monitored on a daily basis and they returned to baseline values on the fourth day after iLA implantation. The leukocyte count stayed in the normal range over the whole reported period, and CRP showed a delayed increase 3 days after the iLA implantation. After 18 days and marked improvement in ventilation (Figure 1, C and D), the iLA device was successfully explanted; one minor bleeding complication occurred and was resolved at the bedside. Twenty-six days after discontinuation of the iLA, the patient was successfully extubated and transferred to a normal ward after three more weeks. He was discharged from hospital 6 weeks later. Results After we observed the above described PCT kinetics in our patient, we performed a retrospective search for patients treated in our ICU in 2012 who underwent iLA implantation and serial PCT monitoring. Three more patients with a history of severe acute respiratory failure, need for mechanical ventilation, and treatment with an iLA device were found. As in the first case, no documented infections were evident. The underlying disease responsible for respiratory failure in the three additional patients was exacerbated chronic obstructive
Figure 2. Procalcitonin concentrations before and after interventional lung assist (iLA) system implantation in four mechanically ventilated patients. The box plots show the minima/maxima (whiskers), 25%/75% percentile (box), median (——), and mean (+) values.
pulmonary disease in two cases and α1-antitrypsin deficiency in the other, respectively. The detailed patients’ characteristics are summarized in Table 1. All four patients taken together presented with very low (median, 0.16 ng/ml; IQR, 0.13–0.34 ng/ml) PCT concentrations before iLA implantation. On the day after iLA implantation, up to 10-fold increase in PCT concentrations was observed (median, 0.62 ng/ml; IQR, 0.65–1.61 ng/ml). Procalcitonin concentrations declined continuously in the further course of the disease, with a return to nearly baseline concentrations (median, 0.32 ng/ml; IQR, 0.21–0.97 ng/ml) on the fourth day after implantation (Figure 2). Neither CRP (Figure 3) nor the leukocyte count values (Figure 4) exhibited this time course in the studied period. Discussion PCT is produced in a variety of tissues. Müller et al.9 found a massive increase in CALC-1 gene expression in tissues such as brain, lung, liver, kidney, testes, and muscle in a septic hamster model. Russwurm et al.10 showed that CGRP-1 mRNA expression following ex vivo stimulation with tumor necrosis factor-α (TNF-α) can be observed in multiple human tissues.
Figure 3. C-reactive protein concentrations before and after interventional lung assist (iLA) system implantation in four mechanically ventilated patients. The box plots show the minima/maxima (whiskers), 25%/75% percentile (box), median (——), and mean (+) values.
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Figure 4. Leukocyte counts before and after interventional lung assist (iLA) system implantation in four mechanically ventilated patients. The box plots show the minima/maxima (whiskers), 25%/75% percentile (box), median (——), and mean (+) values.
Linscheid et al.11 found increased calcitonin mRNA expression in cultured adipocytes and monocytes after stimulation with several proinflammatory cytokines as well as in extrathyroidal adipose tissues of patients with infection and elevated serum PCT concentrations. PCT elevations in the absence of bacterial infection have already been described in literature. Certain diseases such as small cell lung cancer or C cell carcinoma and medications such as antithymocyte globulin or monoclonal OKT3 antibodies lead to pronounced hyperprocalcitoninemia.5–8,12 Increased PCT serum concentrations can be observed in noninfectious, traumatic systemic inflammatory response syndrome (SIRS) as well as in the presence of shock with severe hypotension of different etiology, where the disruption of the intestinal vascular endothelial barrier may lead to bacterial translocation and consecutive PCT induction.13 PCT elevations not related to bacterial infections have been observed directly after surgery; depending on the extent of the surgical trauma, even primary aseptic procedures may result in transient PCT elevation.6 During septic surgery, bacterial translocation from the gut following intestinal resection is thought to be one of the underlying pathomechanisms responsible for changes in PCT concentrations.14 The use of on-pump cardiopulmonary bypass (CPB) during cardiac surgery may lead to SIRS, with subsequent PCT elevation.15 Besides ischemia-reperfusion injury of the lungs and the surgical trauma itself, the contact of the blood with artificial surfaces of the CPB, including the oxygenation membrane, leads to cytokine liberation and SIRS.15 The iLA device membrane contains a heparin-coated artificial surface of about 1,300 cm2, consisting of a polymethylpentene membrane organized as hollow-fiber network.16 It is recommended to maintain a minimum blood flow of ≥1,000 ml/ min through the device to prevent clotting and to ensure an adequate carbon dioxide clearance from the blood. As this is approximately 25% of the cardiac output in most critically ill
patients, an interleukin (IL) and mediator release similar to that observed during CPB could be the underlying cause of the PCT concentration elevation observed directly after implantation of the iLA device in our patients. Introduction of the arteriovenous shunt results in an increase in left ventricular work load. The higher oxygen content of the venous blood may lead to a reduction in hypoxic pulmonary vasoconstriction and, consecutively, to a reduction in pulmonary artery pressures.17 If cardiac function is normal, pulmonary circulation could be augmented by the shunted arterial blood volume. PCT induction is linked to the release of proinflammatory mediators, such as IL-1β, IL-6, IL-8, or TNF-α, as a midstream event in the cascade of inflammation.18 Studies examining the hemocompatibility of an iLA device in pigs after lavage-induced lung injury found no changes in PCT, IL-8, or TNF-α, but data in humans are lacking.19,20 In other clinical settings where extracorporeal circulation is used, for example, during continuous renal replacement therapy, a blood flow through the membrane of only approximately 200 ml/min is used. This could explain the absence of PCT induction in this case.21 It seems implausible that the minimal tissue trauma associated with the iLA implantation could be held responsible for the observed PCT induction. Another possible mechanism for PCT elevation could have been the ongoing ischemia of the cannulated leg with subsequent cytokine liberation. However, this effect was ruled out in all four of our cases by monitoring of peripheral blood flow via continuous peripheral pulse plethysmography. In conclusion, PCT elevations can be observed in critically ill patients after iLA implantation. In the absence of clinical signs of bacterial infection, this phenomenon is most likely related to the release of proinflammatory cytokines following contact of the blood with the artificial surfaces of the iLA membrane, but the exact mechanism remains unknown. Hence, we recommend that the start of antibiotics administration should be carefully considered in the context of other clinical findings, and repeated PCT measurements should be performed in short time intervals. Author Contributions MK, GZ, and NW conceived the study, participated in its design and coordination, and drafted the manuscript. DS, BB, and IF drafted and critically revised the manuscript. TB carried out data acquisition. All authors read and approved the final manuscript.
References 1. Liebold A, Reng CM, Philipp A, Pfeifer M, Birnbaum DE: Pumpless extracorporeal lung assist—Experience with the first 20 cases. Eur J Cardiothorac Surg 17: 608–613, 2000. 2. Kumar A, Roberts D, Wood KE, et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34: 1589–1596, 2006. 3. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY: Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: A systematic review and meta-analysis. Crit Care Med 34: 1996–2003, 2006. 4. Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C: High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 341: 515–518, 1993. 5. Kuse ER, Jaeger K: Procalcitonin increase after anti-CD3 monoclonal antibody therapy does not indicate infectious disease. Transpl Int 14: 55, 2001.
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6. Meisner M, Tschaikowsky K, Hutzler A, Schick C, Schüttler J: Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med 24: 680–684, 1998. 7. Brodska H, Drabek T, Malickova K, et al: Marked increase of procalcitonin after the administration of anti-thymocyte globulin in patients before hematopoietic stem cell transplantation does not indicate sepsis: A prospective study. Crit Care 13: R37, 2009. 8. Walter MA, Meier C, Radimerski T, et al: Procalcitonin levels predict clinical course and progression-free survival in patients with medullary thyroid cancer. Cancer 116: 31–40, 2010. 9. Müller B, White JC, Nylén ES, Snider RH, Becker KL, Habener JF: Ubiquitous expression of the calcitonin-i gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab 86: 396–404, 2001. 10. Russwurm S, Stonans I, Stonane E, et al: Procalcitonin and CGRP-1 mrna expression in various human tissues. Shock 16: 109–112, 2001. 11. Linscheid P, Seboek D, Nylen ES, et al: In vitro and in vivo calcitonin I gene expression in parenchymal cells: A novel product of human adipose tissue. Endocrinology 144: 5578–5584, 2003. 12. Cate CC, Pettengill OS, Sorenson GD: Biosynthesis of procalcitonin in small cell carcinoma of the lung. Cancer Res 46: 812– 818, 1986. 13. Brunkhorst FM, Wegscheider K, Forycki ZF, Brunkhorst R: Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med 26 (Suppl 2): S148–S152, 2000.
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14. Sarbinowski R, Arvidsson S, Tylman M, Oresland T, Bengtsson A: Plasma concentration of procalcitonin and systemic inflammatory response syndrome after colorectal surgery. Acta Anaesthesiol Scand 49: 191–196, 2005. 15. Maruna P, Klein AA, Kunstýř J, Plocová KM, Mlejnský F, Lindner J: Aprotinin reduces the procalcitonin rise associated with complex cardiac surgery and cardiopulmonary bypass. Physiol Res 62: 27–33, 2013. 16. Kopp R, Bensberg R, Henzler D, et al: Hemocompatibility of a miniaturized extracorporeal membrane oxygenation and a pumpless interventional lung assist in experimental lung injury. Artif Organs 34: 13–21, 2010. 17. Zick G, Frerichs I, Schädler D, et al: Oxygenation effect of interventional lung assist in a lavage model of acute lung injury: A prospective experimental study. Crit Care 10: R56, 2006. 18. Matwiyoff GN, Prahl JD, Miller RJ, et al: Immune regulation of procalcitonin: A biomarker and mediator of infection. Inflamm Res 61: 401–409, 2012. 19. Walles T: Clinical experience with the iLA Membrane Ventilator pumpless extracorporeal lung-assist device. Expert Rev Med Devices 4: 297–305, 2007. 20. Dembinski R, Hochhausen N, Terbeck S, et al: Pumpless extracorporeal lung assist for protective mechanical ventilation in experimental lung injury. Crit Care Med 35: 2359–2366, 2007. 21. Steinbach G, Bölke E, Grünert A, Störck M, Orth K: Procalcitonin in patients with acute and chronic renal insufficiency. Wien Klin Wochenschr 116: 849–853, 2004.
