Non-invasive Ventilation in Immunocompromised Patients

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in Immunocompromised Patients

M. Antonelli, M. A. Pennisi, and G. Conti

Introduction

During the last two decades, the dramatic evolution of surgical techniques and the use of innovative immunosuppressive strategies has extended the applicability of solid organ transplantation to an increased number of patients suffering from end-stage failure of various organs. As a direct consequence, the survival rates after solid organ transplantation have dramatically improved. Despite this increase in the post-transplantation survival rate, respiratory complications are the principal cause of morbidity, together with acute organ rejection, and one of the main causes of mortality [1]. Approximately 5% of patients undergoing renal, hepatic, cardiac or pulmonary transplantation develop pneumonia after transplantation, with an attributable mortality of 37% [1].

Immunosuppressive treatments have produced an increase in the survival rates, but at the price of an increased susceptibility to severe infection, often caused by opportunistic agents (Table 1). The lung is the most commonly involved organ in the infectious processes.

During the immediate postoperative period, pneumonia is generally caused by Gram negative germs, that often colonize patients in the intensive care unit (ICU).

In the late postoperative phase, Cytomegalovirus (CMV) is one of the most common causes of pneumonia [2, 4]. CMV infection can be primary or can be caused by the reactivation of a previous infection. Pneumocystis carinii is also a relatively common ethiologic agent for pneumonia occurring at least three months following transplantation.

Many immunosuppressed patients with hypoxemic acute respiratory failure develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). In this situation, early application of optimal values of positive pressure ventilation is aimed for, to restore the decreased lung volume and increase oxygenation, reducing both the work of breathing and respiratory drive. Mechanical ventilation re-estab- lishes patient equilibrium and buys time to allow the etiological treatment to be effective.

Endotracheal intubation is the conventional and accepted route to administer positive pressure ventilation. However the presence of an endotracheal tube represents the main risk factor for the development of nosocomial pneumonia and associated infectious complications [5]. In immunocompetent patients, endotracheal intubation induces a 1% increased risk for pneumonia per day of mechanical

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ventilation [6]. This risk is likely to be largely increased in immunocompromised critically ill patients, but specific data are lacking.

These aspects have augmented the interest in non-invasive ventilation (NIV) techniques, which improve gas exchange with good patient tolerance and can decrease the rate of nosocomial infections.

Non-invasive Ventilation in Solid Organ Transplanted Patients and Acute Lung Injury

Over the last ten years several prospective non-randomized and randomized studies [7-15] have demonstrated the successful application of NIV in immunocompetent patients with hypoxemic acute respiratory failure of varied etiologies.

In one observational trial [9] in patients with cystic fibrosis, NIV was used as a bridge to lung transplant.

Wysocki et al [14] randomized 41 patients with acute respiratory failure to receive NIV via face mask plus conventional medical treatment versus conventional medical therapy and oxygen supplementation via a Venturi mask. NIV reduced the need for endotracheal intubation (36 vs 100%, p = 0.02), the duration of ICU stay (13 ± 15 vs 32 ± 30 days, p = 0.04) and mortality rate (9 vs 66 %, p = 0.06) in the subgroup of patients with hypercapnia (PaCO2> 45 mmHg), but had no clear advantage in the hypoxemic patients with normocapnia.

Antonelli and colleagues [15] recently conducted a prospective, randomized study comparing NIV via a face mask to endotracheal intubation with conventional mechanical ventilation, in patients with hypoxemic acute respiratory failure who met predefined criteria for mechanical ventilation, after failure to improve with aggressive medical therapy. Sixty-four consecutive patients (32 in each arm) were enrolled. After 1 h of mechanical ventilation, both groups had a significant (p < 0.05) improvement in PaO2/FiO2. Ten (31%) patients randomized to NIV required endotracheal intubation. Patients randomized to conventional ventilation developed more frequent and serious complications (38 vs 66%, p = 0.02), and infectious complications (pneumonia or sinusitis) related to the endotracheal tube Table 1. Common causes for respiratory infectious complications, in relation to the specific pattern of immunity alteration.

Cellular immunity alterations: – intracellular bacteria (mycobacteria, atypic mycobacteria) – fungal infections (Pneumocystis carinii)

– viral infections (CMV; Herpes virus)

Humoral immunity alterations: – bacterial infections (mainly capsulated germs)

– viral infections (syncitial respiratory virus, influenza virus, and parainfluenza virus)

Neutropenia: – bacteria (Gram + and Gram -) – fungal infections (Candida, Aspergillus)

– viral infections (herpes, syncitial respiratory virus)

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(3 vs 31%; p = 0.004). Among survivors, patients randomized to NIV had a lower duration of mechanical ventilation (p = 0.006) and a shorter ICU stay (p = 0.002).

In conclusion, NIV was found to be as effective as conventional ventilation with endotracheal intubation in improving gas exchange. In the subgroup of patients successfully treated with NIV and who avoided endotracheal intubation the development of ventilator-associated pneumonia (VAP) was unlikely [15]

A recent prospective epidemiological survey of 320 consecutive immunocompetent patients with acute respiratory failure reported a lower rate of VAP in patients supported with NIV in comparison with those on conventional ventilation (0.16 per 100 days of NIV vs 0.85 per 100 days of tracheal intubation, p=0.004) [16].

For its positive effects on gas exchange, good tolerability and reduction in the incidence of nosocomial infections, NIV should be considered with interest also in the treatment of immunosuppressed patients. Small non-controlled studies in patients receiving lung transplantation have reported the efficacy of NIV in pre- venting endotracheal intubation, and treating acute respiratory failure [17-19]. In 1995, Kilger and colleagues described the successful application of NIV in a group of 6 patients who developed hypoxemic acute respiratory failure after bilateral lung transplantation. The authors administered pressure support ventilation-continuous positive airway pressure (PSV-CPAP) through a facial mask without side effects [17]. Two case reports described similar results in patients with single lung transplantation [18, 19].

We recently conducted a prospective randomized study to compare NIV delivered through a face mask to standard treatment with supplemental oxygen administration as a modality to avoid endotracheal intubation in 40 solid organ transplant recipients with acute hypoxemic respiratory failure [20]. Twenty patients were randomized to receive NIV and 20 to receive standard treatment with supplemental oxygen administration. Within the first hour of treatment, 14 (70%) patients in the NIV group, and 5 (25%) in the standard treatment group improved their PaO2/FiO2. Over time, a sustained improvement in PaO2/FiO2was noted in 12 (60%) patients in the NIV group, but only in 5 patients (25%) randomized to standard treatment (p=0.03). The use of NIV was associated with a significant reduction in the rate of endotracheal intubation (20 vs 70%; p = 0.002), rate of fatal complications (20 vs 50%; p = 0.05), length of ICU stay (5.5 ± 3 vs 9 ± 4 days; p = 0.03) and ICU mortality (20 vs 50%; p = 0.05).

Rocco et al. [21], in a prospective non-randomized study, evaluated the application of NIV in a group of 21 patients developing postoperative acute respiratory failure after bilateral lung transplantation: the technique was well tolerated, improved gas exchange, and avoided endotracheal intubation in 86% of cases.

These data suggest that transplantation programs should consider the inclusion of NIV among the clinical tools for the treatment of transplant recipients with acute respiratory failure, especially if this approach can be used in an early phase of the respiratory failure, to prevent endotracheal intubation and its associated complications.

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Practical Aspects of NIV Administration

As in immunocompetent patients with hypoxemic acute respiratory failure, in immunocompromised patients NIV should be administered preferably through a facial mask, which is generally well tolerated. A nasal mask can be used in a later phase, in selected and stabilized patients, for continuing the treatment. Mechanical ventilation is usually delivered in PSV mode, with variable levels of positive end-expiratory pressure (PEEP, usually within a range between 5 and 10 cmH2O), according to the level of hypoxemia and clinical tolerance.

In our experience the continuous application of NIV is crucial, at least for the first 24 hours of treatment [15, 20], as these patients show a rapid deterioration of gas exchange if NIV is discontinued during the early phases of the disease. The ventilator is generally connected with conventional tubing to a clear, full face mask provided with an inflatable soft cushion seal. The mask is gently fitted to the patient’s face, and secured with head straps. For patients with a nasogastric tube, a specific seal connector in the dome of the mask should be used to minimize air-leaks, especially if using ICU machines without leak compensation. After the mask is secured, the level of pressure support can be progressively increased to obtain an exhaled tidal volume (VT) of 8-10 ml/kg with a respiratory rate less than 25 breaths/min and no accessory muscle contraction or paradoxical abdominal movements. Ventilator settings are then adjusted according to continuous pulse- oximetry and arterial blood gas data.

Contraindications to NIV application in immunosuppressed patients are generally similar to those described in patients with acute respiratory failure and are not specific (Table 2).

Table 2. Main contraindications to NIV in immunocompromised patients with acute respiratory failure.

– Hemodynamic and/or rhythm instability – Neurologic alterations

– Uncooperative patients – Facial deformitiy

– More than two organ failures – Claustrophobia

– Recent acute myocardial infarction – Severe anxiety

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Non-invasive Ventilation in Immunocompromised Patients

Acute respiratory failure due to pulmonary infections represents a relatively common complication of hematological malignancies and their treatment. In the last twenty years, several investigators have underlined the negative prognosis for granulocytopenic patients with acute respiratory failure requiring endotracheal intubation and conventional mechanical ventilation [22-27]. This dramatically increased risk of death [25, 26] results from the combination of the damage induced by opportunistic infections, the direct toxicity of chemotherapy on pulmonary interstitial structures, and the complications directly related to endotracheal intubation.

Despite the fact that NIV could reduce the number of endotracheal intubations and the associated infection rate in these patients, the number of published studies on this topic is still very limited [27, 28]. Tognet and colleagues first reported good clinical results with the intermittent application of NIV in patients with hematological malignancies; 6 out of 11 patients with acute respiratory failure were successfully treated with NIV through a face-mask, using different levels of pressure support and PEEP [28]. Conti et al. evaluated the effects of NIV delivered via nasal mask utilizing a BiPAP®. ventilator (Respironics, USA) in 16 consecutive patients with hematological malignancies and acute respiratory failure [29]. Fifteen out of 16 individuals had an early and sustained improvement in gas exchange:

PaO2/FiO2after 1 h of treatment increased from 87 ± 22 to 175 ± 64 mmHg, and continued to improve in the following 24 h (p < 0.01). One patient failed to improve and another become intolerant to NIV, both were intubated and died from sepsis.

Three other patients died from complications unrelated to respiratory failure.

Eleven patients were successfully discharged from the ICU after 4.3 ± 2.4 days.

A recent randomized trial evaluated NIV as a means to avoid intubation and associated complications in immunocompromised patients admitted to the ICU for hypoxemic acute respiratory failure (PaO2/FiO2below 200 mmHg), fever and lung infiltrates [30]. Fifty-two patients were enrolled in this study (30 patients with hematological malignancies and neutropenia,18 who received immunosuppressive treatment to prevent rejection after solid organ transplantation, bone marrow transplantation, or for other reasons, and four with acquired immunodeficiency syndrome [AIDS]) and were randomized to receive conventional treatment (O2

plus aggressive medical therapy) or NIV plus conventional treatment [30]. NIV was intermittently administered with a face mask in PSV-CPAP. The two groups were comparable at study inclusion. NIV significantly reduced the rate of intubation (46 vs 77%, p=0.003) and serious complications (50 vs 81%, p=0.02). Both ICU (38 vs 69%, p=0.03) and hospital (50 vs 81%, p=0.02) mortality were significantly reduced.

The authors concluded that the early intermittent application of NIV ameliorates the prognosis of immunocompromised patients admitted to the ICU. In this randomized study on immunocompromised patients treated with NIV, the results obtained in the subgroup of patients with hematologic malignancies and neutropenia were highly significant, suggesting an extended clinical role for the application of NIV to these conditions.

Table 3 summarizes the main studies on immunocompromised pantients.

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NIV in Patients with Human Immunodeficiency Virus (HIV) Infection

Despite the dramatic improvement in the prognosis of HIV-infected patients due to the new anti-retroviral drugs, acute respiratory failure due to P. carinii and other opportunistic agents remains the main cause for ICU admission and mortality among patients with AIDS. These patients are generally treated with face-mask CPAP. Two groups have reported the use of non-invasive positive pressure ventilation (NPPV, CPAP + PSV) in patients with AIDS and hypoxemic acute respiratory failure [31-32].

In the first paper, 12 patients were treated with NPPV, 10 of them improved gas exchange and avoided intubation. PaO2/FiO2increased from a baseline of 132 ± 71 to 222 ± 116 mmHg at 1 h and 285 ± 80 mmHg at 2-6 h. One of three patients failing to improve refused intubation and died. Overall, ICU survival was 67% (8 of 12), and hospital survival was 58%. Duration of NPPV was longer (39 ± 28 h) than in other conditions causing hypoxemic acute respiratory failure, but was safe (only two cases of facial skin necrosis) and well tolerated [31].

Table 3. Main characteristics of the studies dedicated to the use of NIV in hypoxic acute respiratory failure in immunosuppressed and immunocompromised patients.

Author Study No of Disease Pts on Mask PEEP Modes of Success Mortality

[ref] patients NIV ventilation rate (%)

Kilger NR 30 Lung 6 Facial NE PSV/CPAP NE NE

[18] transplant

Varon NR 60 Solid cancer 60 Facial NE BiPAP 70 % 0%

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Tognet NR 11 Hematologic 11 Facial 5 PSV/CPAP 55% 45%

[28] malignancy

Conti NR 16 Hematologic 16 Nasal 5 BiPAP 62% 38%

[29] malignancy

Antonelli R 40 Organ 20 Facial 6 PSV/CPAP 80% 20%

[20] transplant

Hilbert R 52 Mixed 26 Facial 6 PSV-CPAP 50% 38%

[30] immuno-

compromised

Rocco [21] NR 21 Lung 21 Facial 6 PSV-CPAP 86% 9%

transplant

R = randomized; NR = non randomized; PEEP = positive end expiratory pressure; PSV = pressure support ventilation; CPAP = continous positive airways pressure ; BiPAP = bilevel positive airways pressure; NE = not evaluated

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Rabbat et al. [32] reported on 18 patients suffering from acute respiratory failure complicating AIDS, treated with face-mask PSV-CPAP; NIV was successful and avoided endotracheal intubation in 13 patients, while five individuals failed and required endotracheal intubation (four of these patients died).

A recent case-control study by Confalonieri and colleagues [33] compared the results obtained with early NIV in 24 patients with AIDS and P. carinii pneumonia with those obtained in 24 matched controls treated with conventional ventilation for the same disease. NIV was successful and avoided endotracheal intubation in 67% of cases. Patients treated with NIV had a lower mortality rate not only in the ICU and in the hospital, but also at the two month follow up after the study entry.

Despite the relatively small amount of published data, it is reasonable to consider NIV as a useful therapeutic tool to avoid endotracheal intubation and associated infectious complications also when treating AIDS patients with acute respiratory failure.

Conclusion

The application of NIV to patients with immunological deficiencies is still considered a new approach that needs further clinical validation. A restricted number of studies focusing on the clinical use of NIV in immunocompromised and immunosuppressed patients have been published so far, but some evidence support a careful consideration of this approach when facing early respiratory decompensa- tion.

NIV must be considered as a first-line treatment in patients who refuse sedation and endotracheal intubation, but agree to receive mechanical ventilatory support.

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