2210 PART 7 Disorders of the Respiratory System

Generally, the trajectory of decline and evolution of disease are key

indicators of the appropriate timing for referral and listing for lung

transplantation, rather than absolute thresholds of disease severity.

However, suggested guidelines for referral have been elucidated for

specific disease states. For example, in chronic obstructive pulmonary

disease, the most common obstructive lung disease for which transplantation is considered, the Body-Mass Index, Airflow Obstruction,

Dyspnea, and Exercise Capacity (BODE) Index is often used as a

marker of disease severity, with an index of 5 an appropriate indication

for referral for evaluation, and 7 for listing for transplantation. Other

suggested markers for transplant consideration in obstructive lung

disease include pulmonary function test (PFT) data, such as a forced

expiratory volume in 1 s of <25% predicted. The frequency and severity

of exacerbations of disease should also be considered in determining

the appropriate timing of referral.

With the marked advances in medical therapy for pulmonary

vascular disease over the past decade, transplantation for pulmonary

vascular disease has become less frequent but is still an important

consideration for patients who progress despite, or are refractory to,

treatment. Functional assessments such as New York Heart Association

class III or IV limitations and hemodynamic measurements such as

cardiac index <2 L/min per m2

 would suggest consideration for evaluation and listing. Patients with diagnoses generally poorly responsive to

therapy such as pulmonary veno-occlusive disease should be referred

early for evaluation.

Patients with cystic fibrosis (CF) have historically been considered

for evaluation when the FEV1 reaches approximately 30% predicted.

However, with the exciting development of therapies targeting the CF

transmembrane receptor, providers should keep in mind the potential

for improvement in pulmonary function after treatment initiation.

Despite this potential for pharmacotherapeutic response, referral

and completion of testing should be considered so that patients are

prepared for listing should they fail to see improvement or experience

worsening of disease on therapy. Moreover, patients who experience

acceleration of acute exacerbation rate, recurrent hemoptysis, worsening functional and/or nutritional status, or colonization with resistant

bacteria should also be assessed for transplantation irrespective of

pulmonary function results.

Despite treatment progress with the development of antifibrotic

therapy for IPF and other progressive fibrosing interstitial lung diseases, these therapies do not reverse the disease but only slow the rate

of lung function decline. Therefore, transplant referral for patients with

IPF and other fibrosing lung diseases should still be considered at the

time of diagnosis. Forced vital capacity <80% predicted or diffusing

capacity for carbon monoxide <40% predicted, failure to respond to

medical therapy, decline in pulmonary function tests on therapy, and

functional decline are additional indications for transplant consideration in patients with other restrictive lung diseases.

■ CONTRAINDICATIONS TO LUNG

TRANSPLANTATION

Absolute Contraindications As experience with lung transplantation increases, and as lung allocation policy prioritizes patients with

higher acuity of disease and with diseases affecting older age groups,

recipient selection criteria have become more liberal compared to prior

eras. While published guidelines suggest absolute and relative contraindications to transplantation, these criteria are in constant evolution,

and each program ultimately establishes its own selection algorithms

based upon clinical expertise, experience, program size and resources,

and referral patterns.

Examples of absolute contraindications to lung transplantation

(Table 298-1) include anatomic and technical considerations that

would affect the ability to complete the transplant procedure, such as

chest wall or spinal deformities or malacia of the large airways. Surgical

input is critical in making such determinations. In addition, untreatable and/or irreversible organ dysfunction may preclude isolated lung

transplantation. Cirrhosis of the liver, uncorrectable disease of the

coronary arteries not amenable to combined surgical intervention

TABLE 298-1 Contraindications to Lung Transplantation

ABSOLUTE

CONTRAINDICATIONS

RELATIVE

CONTRAINDICATIONS

Surgical

considerations

Anatomic abnormalities

not amenable to transplant

procedure

Age >65 years

Functional

status

Immobility, inability to

participate in physical therapy/

rehabilitation

Limited functional status as

defined by 6-minute walk

distance

Medical

comorbidities

Untreatable, irreversible organ

dysfunction

Chronic kidney disease

Active malignancy or

malignancy with insufficient

remission period

Active bacterial bloodstream

infection

Infection resistant to

treatment or of high

risk for posttransplant

morbidity/mortality

(Burkholderia cenocepacia,

Mycobacterium abscessus)

Uncontrolled viral infection

(HIV, hepatitis)

Nutritional BMI <18 or >30–35

Psychosocial Untreatable, irreversible

psychiatric disorder with

potential to impact transplant

outcome

Active substance abuse Limited social supports

Other circumstances that

would impede ability to

participate in and comply with

posttransplant care

History of noncompliance

with medical treatment

Abbreviations: BMI, body mass index; HIV, human immunodeficiency virus.

during the transplant procedure, or other forms of uncorrectable atherosclerotic or vascular disease may make transplantation too high risk

for consideration. Renal dysfunction is of particular concern given the

known nephrotoxicity of calcineurin inhibitors, which are the mainstay

of posttransplant immune suppression.

Relative Contraindications Age in and of itself is typically not

a contraindication to transplantation at most centers. However, older

patients with significant medical comorbidities may be at prohibitive

risk for transplantation, and functional status and frailty may worsen in

this setting. Published analyses of the Scientific Registry of Transplant

Recipients, a comprehensive database of transplant outcomes, have

consistently shown that functional capacity, as assessed by 6-minute

walk distance, is inversely correlated with both wait list and posttransplant mortality. As a result, most programs utilize some assessment of

functional status as a criterion for transplant candidacy.

Frailty, independent of walk distance, has also been recognized

increasingly as a marker of poor outcome after lung transplantation,

and can be assessed using a number of instruments, including the Short

Physical Performance Battery (SPPB), Fried Frailty Phenotype (FFP),

and others. Most studies utilizing these instruments have been conducted at single centers. While both SPPB and FFP have been shown

to correlate with the LAS, FFP has a stronger correlation, and SPPB

and FFP may not correlate with each other. Further study is needed

to determine prospectively the relationship between these measures

assessed in the pretransplant setting and posttransplant outcomes.

Patients with a history of malignancy are generally required to have

experienced a period of remission prior to consideration for transplantation. The necessary length of disease-free survival should be determined in the context of the type of malignancy, stage at diagnosis, and

likelihood of recurrence, and often varies by program.

A history of respiratory infection and colonization with resistant

organisms is of particular concern in the CF and bronchiectasis populations, although it could affect patients with any advanced lung

2211 Lung Transplantation CHAPTER 298

disease and a history of respiratory infection. Data on outcomes in the

presence of resistant Pseudomonas aeruginosa infection are conflicting,

but in general, patients who have demonstrated a response to an antimicrobial regimen, even if colonized with resistant organisms, can be

considered for transplantation. Burkholderia cepacia complex, another

group of gram-negative organisms that can infect patients with CF,

also presents a unique concern for transplantation. Data show that B.

cenocepacia (formerly known as Genomovar III) portends the highest

risk posttransplant, often leading to bacteremia, abscess formation, and

early mortality. B. dolosa and gladioli may cause similar posttransplant

complications. Patients colonized with other Burkholderia species

appear to have posttransplant outcomes comparable with the noncolonized population, and, therefore, can be considered for transplantation.

Published guidelines suggest that those programs offering transplantation to patients colonized with B. cenocepacia do so under a research

structure and after a specific discussion of the risks of transplantation

in this setting with the patients. Other infectious considerations in

lung transplant candidates include mycobacterial infections, particularly with rapidly growing organisms such as M. abscessus, which

can lead to chronic, refractory infections and infections of the chest

wall. In the case of fungal infection, assessment of the pathogenicity of

the organism, resistance patterns, and, in some cases, responsiveness

to pretransplant treatment, is beneficial in determining the safety of

transplantation.

A history of viral infections such as hepatitis and human immunodeficiency virus (HIV) is generally not considered a contraindication

to transplantation. Demonstration of adequate control of infection and

responsiveness to therapy are important in preparation for transplantation, and development of a treatment plan that minimizes toxicity and

drug interactions, in consultation with transplant pharmacy, should be

completed prior to placement on the wait list. Collaborative assessment

with transplant infectious disease experts is beneficial whenever the

infectious history is a concern for transplant safety.

Nutritional status is another important element to assess in determining candidacy for lung transplantation. Nutritional status has been

shown to have a U-shaped relationship with transplant outcomes,

with increased mortality risk associated with both underweight (BMI

<18) and obesity (specifically BMI >35). Consultation with nutritional

experts may allow for modification of this risk prior to transplant. In

some underweight patients, placement of an enteral feeding tube and

initiation of enteral feedings may be considered.

Psychosocial assessment is also a key component of the evaluation of

patients under consideration for lung transplantation, and a multidisciplinary approach with transplant social work, psychiatry, and financial

care coordination is often helpful. Assessment for and optimization

of psychiatric disorders such as anxiety and depression, which can be

exacerbated in the setting of transplantation, substance abuse disorders, and compliance with medical therapy recommendations are all

important parts of the pretransplant evaluation. Perioperative pain

management planning in the setting of medical therapy for opioid use

disorder may require additional multidisciplinary input, but the need

for this management plan alone should not preclude transplantation.

Transplant candidates require a strong support system given their

potential posttransplant care needs. Additionally, confirmation of

insurance coverage for all phases of transplant care, expected medication copayments, and financial resources to support other expenses in

the setting of transplantation should be completed during the transplant evaluation. Fundraising opportunities and subsidies for medications may need to be pursued in order to proceed safely with listing.

■ LUNG TRANSPLANT CANDIDATE MANAGEMENT

Lung transplant candidates need meticulous and exquisite medical care

to ensure that they are in excellent condition at the time of transplant.

Oxygen is prescribed to maintain adequate systemic oxygenation to

allow for moderate physical activity and exertion. Patients should be

enrolled in pulmonary rehabilitation programs, if available, and should

continue to participate in daily physical exercises. Fluid management

is important to consider and restriction of free water and salt intake is

recommended.

Patients with pulmonary vascular disease and severe pulmonary

hypertension awaiting lung transplantation need special attention to

maintain adequate right ventricular function. The use of pulmonary

vasodilator therapy is recommended and should not be stopped prior

to transplant. Patients who develop secondary pulmonary hypertension should also be assessed for the utility of direct pulmonary

vasodilator therapy. Periodic assessment of right ventricular function

with echocardiography is recommended, and in patients with clearly

worsening ventricular function, right heart catheterization and assessment for responsiveness to short-acting vasodilator therapy should be

considered.

In restrictive lung disease patients awaiting transplant, consideration should be given to continuation of immune modulators and/

or antifibrotic therapy. Studies are ongoing to determine the impact

of antifibrotic therapy on posttransplant wound healing. Additionally,

increased pulmonary vascular resistance can occur in these patients

as the disease progresses, and acute exacerbations have been shown to

be associated with severe acute decrease in right ventricular function.

Steroids have been utilized in the management of acute exacerbations;

however, the negative sequelae of chronic steroid use on wound healing

is well established. Therefore, steroid use should be limited as much as

possible, and if unavoidable, should be tapered rapidly.

Patients with CF can have pancreatic dysfunction leading to difficulty in maintaining normal blood glucose levels; uncontrolled diabetes mellitus can make the management of posttransplant blood glucose

very challenging. Therefore, optimization of diabetes management

should be pursued prior to transplantation.

Despite optimal medical therapy, the underlying disease in waitlisted patients will almost always continue to worsen. Prioritization of

patients awaiting lung transplant is determined by the LAS. The score

is generated by giving weight to risk factors associated with predicted

mortality while on the wait list while also accounting for the expected

posttransplant survival of the patient. This composite score is then normalized to generate a score between 0 and 100. The higher the score,

the more prioritized the patient, and the higher the probability of a

suitable donor match for the recipient. The main factors that influence

the LAS are the underlying diagnosis of the patient (such as restrictive

lung disease, as mentioned above), the demographics of the patient

(gender and age), and the patient’s current clinical status. The more

acutely ill the patient (the patient’s oxygen requirements, pulmonary

hypertension, use of invasive support systems such as mechanical

circulatory support or ventilatory support, limited mobility, lack of

independence with activities of daily living), the higher the score. This

results in a system of organ allocation that is most efficient at ensuring

that the sickest patients receive the organs available. However, despite

this prioritization strategy, patients continue to expire at a rate of 10–12

patient deaths per 100 patient-years on the wait list. It is critical for the

best outcomes in these patients that ongoing clinical assessment and

frequent updates of the LAS are routine aspects of their management.

A major consequence of improved efficiency in matching the sickest

patients to the available pool of donors has been an increased use of

extracorporeal membrane oxygenation (ECMO) devices to bridge the

most critically ill patients to transplant. Mechanical circulatory support with ECMO allows for patients to be potentially weaned from the

ventilator, to maintain physical activity and ambulation, and to be in a

state of greater robustness as they await transplant. The posttransplant

survival rate of patients bridged to transplant with ECMO is lower

than patients transplanted without the need for ECMO but better

than patients who had previously been transplanted directly from

mechanical ventilatory support. Furthermore, with improvements

in membrane oxygenator technology, platform miniaturization, and

improvements in cannula design, outcomes continue to improve.

■ DONOR CONSIDERATIONS

The ideal lung donor has remained constant since the inception of

lung transplantation in the 1980s (Table 298-2). A donor between

25–40 years of age, with a PaO2

/FiO2

 ratio >350, no smoking history,

a clear chest x-ray, clean bronchoscopy, and minimal ischemic time

is considered the ideal donor; however, it is quite rare that a donor

2212 PART 7 Disorders of the Respiratory System

meets all of these criteria for transplantation. In fact, the vast majority

of donor lungs used for transplant fall outside these ideal lung donor

criteria as established more than three decades ago. Donors must have

irreversible brain injury, and the majority of donors are brain dead.

Only 20% of all donors with brain death are suitable lung donors due to

the development of severe neurogenic pulmonary edema and increased

susceptibility of potential lung allografts to infection and injury.

Absolute contraindications to lung donation include radiographic

evidence of chronic lung disease such as emphysema and pulmonary

fibrosis. Other absolute contraindications include active malignancy, a

donor history of severe asthma requiring multiple hospitalizations, and

positive HIV status. Relative contraindications include older donor age,

severe thoracic trauma with extensive pulmonary contusions, the presence of pulmonary hypertension, and prolonged donor hypotension or

acute hypoxemia.

The standard lung donor evaluation includes a donor medical and

social history, physical examination, and laboratory examination.

Chest imaging is mandatory, as are arterial blood gases, bronchoscopy,

and serological tests for cytomegalovirus (CMV), Epstein-Barr virus

(EBV), hepatitis B and C, HIV, toxoplasma, rapid plasma reagin, and

herpes simplex virus. The presence of consolidation and atelectasis,

while not absolute contraindications to transplant, are often difficult

to assess with noncontrast radiographic imaging alone. Ventilation

parameters must be evaluated to ensure adequate compliance of the

donor lungs, with peak airway pressures <30 cmH2

O being ideal.

Direct on-site inspection of the lungs and assessment for nodules,

compliance, and full expansion are the final necessary steps before

acceptance of donor lungs for transplant.

More recently, there has been an expanded use of allografts from

donors after cardiac death (DCD) due to the ability to rehabilitate

donor lungs using ex vivo lung perfusion (EVLP). DCD donors are

patients who present with irreversible brain injury but without overt

brain death. The potential donor allografts are often exposed to a

period of prolonged warm ischemia during the donation process; there

has been a concern about early graft dysfunction after DCD donation.

Steen and colleagues in Lund demonstrated that EVLP could be used

to assess these marginal donors prior to transplant. The landmark

publication of the Normothermic Ex Vivo Lung Perfusion in Clinical

Lung Transplantation trial in 2011 generated renewed interest in DCD

lung donors. The group from the University of Toronto was also able

to demonstrate that brain-dead donors with unacceptable donor lung

parameters could be rehabilitated with the use of EVLP. They were

able to salvage up to 50% of selected unsuitable donor lung allografts

with the use of acellular normothermic hyperosmotic perfusion with

excellent short-term outcomes.

Donor Management Brain death causes severe perturbations in

the potential donor lung allograft function. The development of severe

pulmonary edema often accompanies brain death. The hemodynamic

instability and neurogenic shock that can accompany brain death are

also major stressors on the preservation of donor allograft function.

The primary goal of donor management is, therefore, the maintenance

of hemodynamic stability and preservation of donor lung function.

Judicious fluid resuscitation and avoidance of excessive resuscitation

should be employed. Volume replenishment should be limited to

maintain the central venous pressure between 5 and 8 mmHg. In

general, crystalloid fluid boluses are to be avoided. Diabetes insipidus

is common in donors and requires the use of intravenous vasopressin

to prevent excessive urine loss. In general, blood transfusions should

be avoided; however, if necessary, CMV-negative and leukocytefiltered blood should be used whenever possible. Hypothermia should

be avoided as it predisposes to ventricular arrhythmias and metabolic

acidosis.

Excessive oxygen delivery should be minimized to prevent freeradical injury to the potential lung allograft. Positive end-expiratory

pressures on the ventilator should be maintained to avoid the development of atelectasis. More recently, airway pressure release ventilation

modes of ventilation have been utilized to preserve lung function and

minimize barotrauma from prolonged ventilation.

■ PROCUREMENT OPERATION

Prior to incision, a thorough bronchoscopic evaluation is completed.

The anatomy of the donor airways is defined. Any secretions that may

be present are evacuated and the airways are examined to rule out the

presence of any lesions or masses. The epithelial lining is inspected for

evidence of excessive friability and hemorrhage, which may indicate

significant infection. A median sternotomy incision is employed to

access the chest for lung procurement. The pleural spaces are opened

and both lungs are inspected, palpated, and gently recruited to evaluate

for suspicious nodules, consolidation, and/or pulmonary infarction.

The donor is systemically heparinized, and the main pulmonary

artery is cannulated. Fifteen minutes prior to initiation of the explant,

prostacyclin is introduced into the main pulmonary artery and allowed

to circulate through the lungs. This vasoreactive prostanoid helps to

ensure adequate pulmonary flush by dilating the pulmonary vasculature. The heart is arrested first, then the pulmonoplegia solution is

instilled into the lungs at a low controlled pressure. Topical iced-saline

solution is instilled into both pleural spaces. After the heart has been

explanted, the individual pulmonic veins are flushed retrogradely. The

lungs are then re-expanded, the trachea is clamped, and the explanted

allograft is stored in ice-cold saline solution for transport. If the right

and left lungs are being procured for different recipients, the posterior

left atrium, the main pulmonary artery, and the left main-stem bronchus are divided to separate the right and left lungs, and the organs are

stored and shipped separately.

■ RECIPIENT OPERATION AND EARLY

POSTTRANSPLANT CONSIDERATIONS

Recipient Operation The recipient operation can be divided into

two parts. The first part involves the explant of the native lung and the

second part involves the implant of the new lung. There are generally

three main surgical approaches to the completion of the operation: a

right or left thoracotomy, a transverse thoracosternotomy (clamshell),

or median sternotomy. These approaches are all favored by various

centers for different benefits. The thoracotomy approach allows for

explant and implant of donor lungs without the use of cardiopulmonary bypass (CPB) and is often the preferred approach for single-lung

transplant. The clamshell incision offers the advantages of increased

exposure compared to either thoracotomy or median sternotomy

but comes at the cost of greater morbidity and postoperative wound

complications. This incision can be used to perform bilateral lung

transplants and allows for the possibility of avoiding CPB. A median

sternotomy approach can be used to perform bilateral lung transplant.

This approach offers the advantage of fewer wound complication

disease and a history of respiratory infection. Data on outcomes in the

presence of resistant Pseudomonas aeruginosa infection are conflicting,

but in general, patients who have demonstrated a response to an antimicrobial regimen, even if colonized with resistant organisms, can be

considered for transplantation. Burkholderia cepacia complex, another

group of gram-negative organisms that can infect patients with CF,

also presents a unique concern for transplantation. Data show that B.

cenocepacia (formerly known as Genomovar III) portends the highest

risk posttransplant, often leading to bacteremia, abscess formation, and

early mortality. B. dolosa and gladioli may cause similar posttransplant

complications. Patients colonized with other Burkholderia species

appear to have posttransplant outcomes comparable with the noncolonized population, and, therefore, can be considered for transplantation.

Published guidelines suggest that those programs offering transplantation to patients colonized with B. cenocepacia do so under a research

structure and after a specific discussion of the risks of transplantation

in this setting with the patients. Other infectious considerations in

lung transplant candidates include mycobacterial infections, particularly with rapidly growing organisms such as M. abscessus, which

can lead to chronic, refractory infections and infections of the chest

wall. In the case of fungal infection, assessment of the pathogenicity of

the organism, resistance patterns, and, in some cases, responsiveness

to pretransplant treatment, is beneficial in determining the safety of

transplantation.

A history of viral infections such as hepatitis and human immunodeficiency virus (HIV) is generally not considered a contraindication

to transplantation. Demonstration of adequate control of infection and

responsiveness to therapy are important in preparation for transplantation, and development of a treatment plan that minimizes toxicity and

drug interactions, in consultation with transplant pharmacy, should be

completed prior to placement on the wait list. Collaborative assessment

with transplant infectious disease experts is beneficial whenever the

infectious history is a concern for transplant safety.

Nutritional status is another important element to assess in determining candidacy for lung transplantation. Nutritional status has been

shown to have a U-shaped relationship with transplant outcomes,

with increased mortality risk associated with both underweight (BMI

<18) and obesity (specifically BMI >35). Consultation with nutritional

experts may allow for modification of this risk prior to transplant. In

some underweight patients, placement of an enteral feeding tube and

initiation of enteral feedings may be considered.

Psychosocial assessment is also a key component of the evaluation of

patients under consideration for lung transplantation, and a multidisciplinary approach with transplant social work, psychiatry, and financial

care coordination is often helpful. Assessment for and optimization

of psychiatric disorders such as anxiety and depression, which can be

exacerbated in the setting of transplantation, substance abuse disorders, and compliance with medical therapy recommendations are all

important parts of the pretransplant evaluation. Perioperative pain

management planning in the setting of medical therapy for opioid use

disorder may require additional multidisciplinary input, but the need

for this management plan alone should not preclude transplantation.

Transplant candidates require a strong support system given their

potential posttransplant care needs. Additionally, confirmation of

insurance coverage for all phases of transplant care, expected medication copayments, and financial resources to support other expenses in

the setting of transplantation should be completed during the transplant evaluation. Fundraising opportunities and subsidies for medications may need to be pursued in order to proceed safely with listing.

■ LUNG TRANSPLANT CANDIDATE MANAGEMENT

Lung transplant candidates need meticulous and exquisite medical care

to ensure that they are in excellent condition at the time of transplant.

Oxygen is prescribed to maintain adequate systemic oxygenation to

allow for moderate physical activity and exertion. Patients should be

enrolled in pulmonary rehabilitation programs, if available, and should

continue to participate in daily physical exercises. Fluid management

is important to consider and restriction of free water and salt intake is

recommended.

Patients with pulmonary vascular disease and severe pulmonary

hypertension awaiting lung transplantation need special attention to

maintain adequate right ventricular function. The use of pulmonary

vasodilator therapy is recommended and should not be stopped prior

to transplant. Patients who develop secondary pulmonary hypertension should also be assessed for the utility of direct pulmonary

vasodilator therapy. Periodic assessment of right ventricular function

with echocardiography is recommended, and in patients with clearly

worsening ventricular function, right heart catheterization and assessment for responsiveness to short-acting vasodilator therapy should be

considered.

In restrictive lung disease patients awaiting transplant, consideration should be given to continuation of immune modulators and/

or antifibrotic therapy. Studies are ongoing to determine the impact

of antifibrotic therapy on posttransplant wound healing. Additionally,

increased pulmonary vascular resistance can occur in these patients

as the disease progresses, and acute exacerbations have been shown to

be associated with severe acute decrease in right ventricular function.

Steroids have been utilized in the management of acute exacerbations;

however, the negative sequelae of chronic steroid use on wound healing

is well established. Therefore, steroid use should be limited as much as

possible, and if unavoidable, should be tapered rapidly.

Patients with CF can have pancreatic dysfunction leading to difficulty in maintaining normal blood glucose levels; uncontrolled diabetes mellitus can make the management of posttransplant blood glucose

very challenging. Therefore, optimization of diabetes management

should be pursued prior to transplantation.

Despite optimal medical therapy, the underlying disease in waitlisted patients will almost always continue to worsen. Prioritization of

patients awaiting lung transplant is determined by the LAS. The score

is generated by giving weight to risk factors associated with predicted

mortality while on the wait list while also accounting for the expected

posttransplant survival of the patient. This composite score is then normalized to generate a score between 0 and 100. The higher the score,

the more prioritized the patient, and the higher the probability of a

suitable donor match for the recipient. The main factors that influence

the LAS are the underlying diagnosis of the patient (such as restrictive

lung disease, as mentioned above), the demographics of the patient

(gender and age), and the patient’s current clinical status. The more

acutely ill the patient (the patient’s oxygen requirements, pulmonary

hypertension, use of invasive support systems such as mechanical

circulatory support or ventilatory support, limited mobility, lack of

independence with activities of daily living), the higher the score. This

results in a system of organ allocation that is most efficient at ensuring

that the sickest patients receive the organs available. However, despite

this prioritization strategy, patients continue to expire at a rate of 10–12

patient deaths per 100 patient-years on the wait list. It is critical for the

best outcomes in these patients that ongoing clinical assessment and

frequent updates of the LAS are routine aspects of their management.

A major consequence of improved efficiency in matching the sickest

patients to the available pool of donors has been an increased use of

extracorporeal membrane oxygenation (ECMO) devices to bridge the

most critically ill patients to transplant. Mechanical circulatory support with ECMO allows for patients to be potentially weaned from the

ventilator, to maintain physical activity and ambulation, and to be in a

state of greater robustness as they await transplant. The posttransplant

survival rate of patients bridged to transplant with ECMO is lower

than patients transplanted without the need for ECMO but better

than patients who had previously been transplanted directly from

mechanical ventilatory support. Furthermore, with improvements

in membrane oxygenator technology, platform miniaturization, and

improvements in cannula design, outcomes continue to improve.

■ DONOR CONSIDERATIONS

The ideal lung donor has remained constant since the inception of

lung transplantation in the 1980s (Table 298-2). A donor between

25–40 years of age, with a PaO2

/FiO2

 ratio >350, no smoking history,

a clear chest x-ray, clean bronchoscopy, and minimal ischemic time

is considered the ideal donor; however, it is quite rare that a donor

2212 PART 7 Disorders of the Respiratory System

meets all of these criteria for transplantation. In fact, the vast majority

of donor lungs used for transplant fall outside these ideal lung donor

criteria as established more than three decades ago. Donors must have

irreversible brain injury, and the majority of donors are brain dead.

Only 20% of all donors with brain death are suitable lung donors due to

the development of severe neurogenic pulmonary edema and increased

susceptibility of potential lung allografts to infection and injury.

Absolute contraindications to lung donation include radiographic

evidence of chronic lung disease such as emphysema and pulmonary

fibrosis. Other absolute contraindications include active malignancy, a

donor history of severe asthma requiring multiple hospitalizations, and

positive HIV status. Relative contraindications include older donor age,

severe thoracic trauma with extensive pulmonary contusions, the presence of pulmonary hypertension, and prolonged donor hypotension or

acute hypoxemia.

The standard lung donor evaluation includes a donor medical and

social history, physical examination, and laboratory examination.

Chest imaging is mandatory, as are arterial blood gases, bronchoscopy,

and serological tests for cytomegalovirus (CMV), Epstein-Barr virus

(EBV), hepatitis B and C, HIV, toxoplasma, rapid plasma reagin, and

herpes simplex virus. The presence of consolidation and atelectasis,

while not absolute contraindications to transplant, are often difficult

to assess with noncontrast radiographic imaging alone. Ventilation

parameters must be evaluated to ensure adequate compliance of the

donor lungs, with peak airway pressures <30 cmH2

O being ideal.

Direct on-site inspection of the lungs and assessment for nodules,

compliance, and full expansion are the final necessary steps before

acceptance of donor lungs for transplant.

More recently, there has been an expanded use of allografts from

donors after cardiac death (DCD) due to the ability to rehabilitate

donor lungs using ex vivo lung perfusion (EVLP). DCD donors are

patients who present with irreversible brain injury but without overt

brain death. The potential donor allografts are often exposed to a

period of prolonged warm ischemia during the donation process; there

has been a concern about early graft dysfunction after DCD donation.

Steen and colleagues in Lund demonstrated that EVLP could be used

to assess these marginal donors prior to transplant. The landmark

publication of the Normothermic Ex Vivo Lung Perfusion in Clinical

Lung Transplantation trial in 2011 generated renewed interest in DCD

lung donors. The group from the University of Toronto was also able

to demonstrate that brain-dead donors with unacceptable donor lung

parameters could be rehabilitated with the use of EVLP. They were

able to salvage up to 50% of selected unsuitable donor lung allografts

with the use of acellular normothermic hyperosmotic perfusion with

excellent short-term outcomes.

Donor Management Brain death causes severe perturbations in

the potential donor lung allograft function. The development of severe

pulmonary edema often accompanies brain death. The hemodynamic

instability and neurogenic shock that can accompany brain death are

also major stressors on the preservation of donor allograft function.

The primary goal of donor management is, therefore, the maintenance

of hemodynamic stability and preservation of donor lung function.

Judicious fluid resuscitation and avoidance of excessive resuscitation

should be employed. Volume replenishment should be limited to

maintain the central venous pressure between 5 and 8 mmHg. In

general, crystalloid fluid boluses are to be avoided. Diabetes insipidus

is common in donors and requires the use of intravenous vasopressin

to prevent excessive urine loss. In general, blood transfusions should

be avoided; however, if necessary, CMV-negative and leukocytefiltered blood should be used whenever possible. Hypothermia should

be avoided as it predisposes to ventricular arrhythmias and metabolic

acidosis.

Excessive oxygen delivery should be minimized to prevent freeradical injury to the potential lung allograft. Positive end-expiratory

pressures on the ventilator should be maintained to avoid the development of atelectasis. More recently, airway pressure release ventilation

modes of ventilation have been utilized to preserve lung function and

minimize barotrauma from prolonged ventilation.

■ PROCUREMENT OPERATION

Prior to incision, a thorough bronchoscopic evaluation is completed.

The anatomy of the donor airways is defined. Any secretions that may

be present are evacuated and the airways are examined to rule out the

presence of any lesions or masses. The epithelial lining is inspected for

evidence of excessive friability and hemorrhage, which may indicate

significant infection. A median sternotomy incision is employed to

access the chest for lung procurement. The pleural spaces are opened

and both lungs are inspected, palpated, and gently recruited to evaluate

for suspicious nodules, consolidation, and/or pulmonary infarction.

The donor is systemically heparinized, and the main pulmonary

artery is cannulated. Fifteen minutes prior to initiation of the explant,

prostacyclin is introduced into the main pulmonary artery and allowed

to circulate through the lungs. This vasoreactive prostanoid helps to

ensure adequate pulmonary flush by dilating the pulmonary vasculature. The heart is arrested first, then the pulmonoplegia solution is

instilled into the lungs at a low controlled pressure. Topical iced-saline

solution is instilled into both pleural spaces. After the heart has been

explanted, the individual pulmonic veins are flushed retrogradely. The

lungs are then re-expanded, the trachea is clamped, and the explanted

allograft is stored in ice-cold saline solution for transport. If the right

and left lungs are being procured for different recipients, the posterior

left atrium, the main pulmonary artery, and the left main-stem bronchus are divided to separate the right and left lungs, and the organs are

stored and shipped separately.

■ RECIPIENT OPERATION AND EARLY

POSTTRANSPLANT CONSIDERATIONS

Recipient Operation The recipient operation can be divided into

two parts. The first part involves the explant of the native lung and the

second part involves the implant of the new lung. There are generally

three main surgical approaches to the completion of the operation: a

right or left thoracotomy, a transverse thoracosternotomy (clamshell),

or median sternotomy. These approaches are all favored by various

centers for different benefits. The thoracotomy approach allows for

explant and implant of donor lungs without the use of cardiopulmonary bypass (CPB) and is often the preferred approach for single-lung

transplant. The clamshell incision offers the advantages of increased

exposure compared to either thoracotomy or median sternotomy

but comes at the cost of greater morbidity and postoperative wound

complications. This incision can be used to perform bilateral lung

transplants and allows for the possibility of avoiding CPB. A median

sternotomy approach can be used to perform bilateral lung transplant.

This approach offers the advantage of fewer wound complications,

less postoperative pain, and flexibility with more complex or concomitant cardiac procedures at the time of lung transplant. This approach

mandates the use of CPB. The routine use of CPB allows for early

pneumonectomies without hemodynamic compromise and can significantly reduce the ischemic time to the second allograft. Additionally,

overcirculation to the first allograft can be minimized with the routine

use of CPB. Others prefer to avoid CPB as avoidance may be associated

TABLE 298-2 Characteristics of the Ideal Lung Donor

Donor age <55 years

ABO compatibility Identical

Chest radiograph Clear

PaO2

:FiO2 >300 on PEEP 5-cm H2

O

Tobacco history <20 pack-years

Chest trauma Absent

Evidence of aspiration Absent

Prior thoracic surgery None

Sputum gram stain Negative

Bronchoscopy findings No purulent secretions

2213 Lung Transplantation CHAPTER 298

with decreased need for blood product administration and lower incidence of primary graft dysfunction.

Anesthetic monitoring for lung transplant should include arterial

pressure monitoring, pulse oximetry, continuous electrocardiographic

monitoring, temperature monitoring, and urine output monitoring.

Large-bore IV access and central venous access are vital to manage

the patient safely. On a selective basis, pulmonary artery pressure

monitoring and transesophageal echocardiographic monitoring may

be useful. For patients without the planned use of CPB, double-lumen

endotracheal tubes are mandatory, whereas they can be avoided for

patients transplanted on CPB.

Once access to the thorax has been completed, the hilar structures

are isolated and divided. The bronchial anastomosis is completed first,

and the anastomosis is checked to ensure that it is secure by insufflating the lung gently while keeping the anastomosis under saline

solution to observe for bubbles. The donor left atrial cuff incorporating the pulmonary vein is connected to the native left atrium and

the donor right or left pulmonary artery is connected to the native

pulmonary artery. After completion of the vascular anastomoses, the

lungs are gently reperfused. During this early reperfusion period, lungprotective ventilation strategies are employed and oxygen tension is

reduced. The patient is transitioned to normal ventilation, drains are

placed in the thoracic cavity, and the wounds are closed.

Induction of Immunosuppression Initiation of immunosuppression starts with induction of the patient under general anesthesia.

Many programs utilize an induction agent (most commonly an IL-2

receptor/CD25 antagonist, but antithymocyte globulin, anti-CD52

monoclonal antibodies, or other induction agents may also be used),

and systemic corticosteroids and purine modulators are administered

after induction is complete. If an IL2 receptor antagonist is utilized

for induction, a second dose is administered 4 days after the original

dose. An additional dose of methylprednisolone is administered after

allograft reperfusion in the operating room. Three-drug immune suppression is initiated with a calcineurin inhibitor, purine modulator, and

continued systemic corticosteroids. In patients with severe acute renal

dysfunction, calcineurin inhibitor initiation may be delayed.

Perioperative Considerations and Complications Early morbidity and mortality after lung transplant most commonly are sequelae

of primary graft dysfunction or infection. Very rarely, hyperacute

rejection has been observed; however, with the implementation of

robust systems to ensure ABO and HLA compatibility at the time of

transplant, the occurrence of hyperacute rejection is extremely uncommon. Primary graft dysfunction (PGD) encompasses a constellation of

findings that result in poor early graft function after transplant. This

phenomenon is often the consequence of ischemia-reperfusion injury

in the allograft and is not related to infection or rejection. It is characterized by a diffuse pattern of infiltrates on the chest x-ray and poor

pulmonary gas exchange with PaO2

:FiO2

 ratios <300, with severe PGD

characterized by diffuse severe infiltrates and a P:F ratio of <100 at 72 h

posttransplant. Most cases of PGD are mild and self-limiting, resolving

with supportive care. However, if the PGD is severe and worsening

despite maximal medical therapy, diuresis, inotropic therapy, maximal

ventilation support, and paralysis of the patient, mechanical circulatory

support with ECMO can become necessary. The incidence of severe

PGD has been steady over the past two decades at approximately

10–15% in most programs.

Bacterial, viral, and fungal infections are leading causes of morbidity and mortality in lung transplantation. The lung is one of the few

solid organs that is in continuous contact with the environment. Each

breath has the potential to introduce new organisms, and the reduced

lymphatic function and mucociliary clearance in the transplanted

lung increase the risk of serious infection. The highest incidence of

infection is early after lung transplant and coincides with the intensity of immune suppression. Early infections, occurring within the

first month after transplantation, are commonly bacterial (especially

gram-negative bacilli) and manifest as pneumonia, mediastinitis,

urinary tract infections, catheter sepsis, and skin infections. Patients

can develop pathogenic infections with organisms associated with

pretransplant colonization, and perioperative antibiotic regimens are

often deployed to address this. Viral infections, and CMV infections,

in particular, can lead to severe recipient disease and early loss of

graft and life. The majority of transplant programs employ antiviral

prophylaxis in the early transplant period to avoid such complications.

Invasive fungal infections peak in frequency between 10 days and

2 months after transplantation. Fungal prophylaxis regimens in the

early posttransplant period vary widely. Treatment consists of inhaled

amphotericin B in the setting of airway infection and/or azole therapy

with more advanced or invasive disease. The institution of prophylaxis

with oral trimethoprim-sulfamethoxazole (or inhalational pentamidine for sulfa-allergic patients) has effectively prevented Pneumocystis

pneumonia. The risk of Pneumocystis infection is highest during the

first year after transplant. However, as infections can also occur late

after transplant, most centers recommend prophylactic therapy be

continued for life.

■ LONG-TERM MANAGEMENT OF LUNG

TRANSPLANT RECIPIENTS

While survival after lung transplantation continues to improve by era,

the survival rates in this group are lower than in other solid-organ

cohorts. Approximately 50% of lung transplant recipients will experience at least one episode of acute rejection in the first posttransplant

year, and by 5 years posttransplant, approximately half will have

developed chronic rejection. As a result, posttransplant immune suppression regimens may be more aggressive than in other solid-organ

recipients, as described above. The immunosuppressive regimen must

be balanced against the potential toxicities that accrue with these medications over time.

Acute cellular rejection in lung transplant recipients is most common in the first posttransplant year, with a decreased but not absent

frequency thereafter. Infections can stimulate cellular rejection, most

clearly demonstrated in the setting of CMV infection, but also noted

after other infections. Most programs incorporate a schedule of routine

surveillance bronchoscopy to assess for acute cellular rejection posttransplant. Acute cellular rejection manifests as a lymphocytic infiltrate

involving the distal small vessels and capillaries and/or a lymphocytic

bronchiolitis involving the distal airways of the lung. Acute cellular

rejection, a risk factor for the development of chronic lung allograft

dysfunction (CLAD), is treated with augmented immune suppression. Antibody-mediated rejection in its classic form is a neutrophilic

vasculitis associated with the small vessels and capillaries of the lung,

with associated deposition of by-products of the complement cascade,

in the setting of allograft dysfunction and circulating donor-specific

HLA antibodies in the blood. The manifestations of antibody-mediated

rejection in the lung allograft are less specific than in other organs.

Further research is ongoing into the diagnostic and treatment considerations of this entity in lung transplantation.

CLAD is an overarching description of the syndrome of long-term

allograft rejection. The classic manifestation of CLAD is obliterative

bronchiolitis, the development of fibrinous material within the distal

airways that leads to small-airways obstruction. As transbronchial

biopsies are insensitive for diagnosing obliterative bronchiolitis, a clinical diagnostic designation of bronchiolitis obliterans syndrome can

be made when specific PFT criteria are met and other causes of PFT

decline are excluded. CLAD can also present as a restrictive phenotype,

with imaging demonstrating upper lobe–predominant pleural thickening, small lung volumes, and interstitial changes on high-resolution

CT. Numerous therapies for CLAD have been utilized, including azithromycin, montelukast, extracorporeal photopheresis, alemtuzumab,

and others, with varying degrees of success.

Infection is a significant complication of lung transplantation, with

persistent risk over the lifetime of the transplant recipient. As time

progresses, the chance of opportunistic infection increases. The risk of

bacterial infection and fungal infection remains, and can affect the lung

parenchyma, airways and anastomotic sites, and other organs. Viral

infections such as CMV reactivation and infection, EBV-associated

2214 PART 7 Disorders of the Respiratory System

TABLE 298-3 Predictors of Survival After Lung Transplantation

1 YEAR SURVIVAL ≥10 YEAR SURVIVAL

Donor Factors HCV donor

Recipient Factors Age <70 years Age 18–35 years

Diagnosis other than

pulmonary fibrosis,

pulmonary hypertension,

sarcoidosis, A1AT

O2

 requirement <5 L

CI >2

Outpatient at time of

transplant

Preserved recipient eGFR

Total bilirubin <2

Donor/Recipient Factors Non female to male

transplant

Higher levels of HLA

matching

Donor/recipient weight

ratio >0.7

Operative Factors Avoidance of unplanned

conversion to

cardiopulmonary bypass

Bilateral lung transplant

Decreased ischemic time

Posttransplant Factors PaO2

/FIO2

 >260 at 72 h Fewer hospitalizations

for rejection

Absent need for

postoperative ECMO

support

Other Factors Higher center volume Higher center volume

Abbreviations: A1AT, alpha-1 antitrypsin deficiency; ECMO, extracorporeal

membrane oxygenation; eGFR, estimated glomerular filtration rate; FIO2

, fraction of

inspired oxygen; HCV, hepatitis C virus; PaO2

, partial pressure of oxygen.

Interventional pulmonary medicine is a subspecialty of pulmonary and

critical care medicine focusing on the evaluation and management of

patients with thoracic malignancy, central airway obstruction, pleural

disease, and advanced obstructive lung disease such as chronic obstructive pulmonary disease (COPD)/emphysema and asthma. Novel minimally invasive interventions have drastically changed the way we care

for patients. In this chapter, we will summarize recent developments

and evolving technologies in interventional pulmonology (IP).

DIAGNOSTIC BRONCHOSCOPY

With the introduction of the rigid bronchoscope by Gustav Killian in

1897, the mortality associated with foreign-body aspiration dropped

from over 90% to less than 5%, as patients no longer had to suffer from

airway obstruction and postobstructive pneumonia. Shigeto Ikeda

developed the flexible bronchoscope in 1967, allowing access to the

peripheral airways and lung parenchyma. Bronchoscopy has remained

an important diagnostic and therapeutic procedure, and recent technology has significantly increased its utility.

■ ENDOBRONCHIAL ULTRASOUND

The diagnosis and staging of lung cancer remains one of the most

important roles of advanced diagnostic bronchoscopy and IP. Convex endobronchial ultrasound (cEBUS) is a flexible bronchoscope

combined with ultrasound technology that allows for real-time

visualization during transbronchial needle aspiration (TBNA) of

mediastinal and hilar lymph nodes and masses adjacent to the airways (Fig. 299-1).

With a sensitivity of 90% and a specificity of 100%, cEBUS has

become the gold standard for lung cancer staging and can provide sufficient tissue to perform molecular profiling to guide targeted therapies

in lung cancer with adequacy rates for testing that exceed 95%. cEBUS

is also extremely helpful in diagnosing mediastinal and hilar adenopathy due to sarcoidosis and lymphoma.

299 Interventional Pulmonary

Medicine

Lonny Yarmus, David Feller-Kopman

FIGURE 299-1 Endobronchial ultrasound transbronchial needle aspiration image

of needle under ultrasound guidance sampling station 4L lymph node. AO, aorta;

PA, pulmonary artery.

posttransplant lymphoproliferative disease, and other rarer infections

can also develop in the later posttransplant setting as well.

Numerous longer-term medical complications can be seen in lung

transplant recipients. Essential hypertension, diabetes mellitus, chronic

renal insufficiency, and bone loss are some examples of chronic medical conditions observed following transplantation. A multidisciplinary

approach to care that involves the patient’s primary care physician,

local pulmonologist, and appropriate subspecialists, along with transplant pharmacy, as well as social work and care coordination, is beneficial in addressing the complex needs of lung transplant recipients

over time. Predictors of short- and long-term outcomes after lung

transplantation are outlined in Table 298-3.

■ FURTHER READING

Cypel M et al: Normothermic ex vivo lung perfusion in clinical lung

transplantation. N Engl J Med 364:1431, 2011.

Orens JB et al: A review of lung transplant donor acceptability criteria.

J Heart Lung Transplant 22:1183, 2003.

Russo MJ et al: Who is the high-risk recipient? Predicting mortality

after lung transplantation using pretransplant risk factors. J Thorac

Cardiovasc Surg 138:1234, 2009.

Tejwani V et al: Complications of lung transplantation: A roentgenographic perspective. Chest 149:1535, 2016.

Weill D et al: A consensus document for the selection of lung transplant candidates: 2014—An update from the Pulmonary Transplantation Council of the International Society for Heart and Lung

Transplantation. J Heart Lung Transplant 34:1, 2015.

Weiss ES et al: Factors indicative of long-term survival after lung

transplantation: A review of 836 10-year survivors. J Heart Lung

Transplant 29:240, 2010.

Yusen RD et al: The Registry of the International Society for Heart

and Lung Transplantation: Thirty-third Adult Lung and Heart–Lung

Transplant Report—2016; Focus Theme: Primary Diagnostic Indications for Transplant. J Heart Lung Transplant 35:1170, 2016.

2215 Interventional Pulmonary Medicine CHAPTER 299

■ ABLATIVE THERAPIES FOR CAO

Ablative therapy in the airway consists of both heat (laser, electrocautery, and argon plasma coagulation) and cold (cryotherapy) modalities.

These techniques are most commonly used to destroy tumor and

provide hemostasis. The cryoprobe can also be used for foreign-body

removal. Other modalities, such as brachytherapy (BRT) and photodynamic therapy (PDT), have a delayed therapeutic effect and are often

not suitable for situations where immediate relief of airway obstruction

is desired.

■ PERIPHERAL BRONCHOSCOPY

Evaluations of pulmonary nodules and lung masses are frequent indications for bronchoscopy as a way to achieve a minimally invasive

diagnosis. Historically, the diagnostic yield of bronchoscopy to target

peripheral pulmonary lesions was approximately <60%. To improve on

targeting success, multiple guidance platforms allow for more distal

improved access in the periphery of the lung.

Smaller bronchoscopes that are <4 mm in diameter can be combined with available imaging tools to improve target localization.

Radial-probe endobronchial ultrasound utilizes a radial scanning

ultrasound probe that is inserted through the bronchoscope and into

the lung, producing a real-time image of the target lesion. Electromagnetic navigation bronchoscopy (ENB) involves image-guidance systems

that manipulate thin-slice CT images to create virtual airway reconstructions used as guided maps during bronchoscopy. Robotic-assisted

bronchoscopic platforms offer the enhanced articulation and stability

of a robotic arm replacing the traditional flexible bronchoscope. Additional studies are currently underway to explore further the utility of

these systems for peripheral lesion biopsy.

THERAPEUTIC BRONCHOSCOPY

Therapeutic bronchoscopy is indicated for the relief of malignant and

nonmalignant central airway obstruction, asthma, and emphysema.

Active research is also focusing on the utility of bronchoscopy for the

ablation of early-stage lung cancer, as well as the treatment of chronic

bronchitis.

■ CENTRAL AIRWAY OBSTRUCTION

Central airway obstruction (CAO) describes obstruction of the trachea, main stem bronchi, bronchus intermedius, and/or lobar bronchi,

and can present as intrinsic (endoluminal), extrinsic (extraluminal), or

mixed (extraluminal tumor resulting in mass effect and endoluminal

involvement) (Fig. 299-2). The differential diagnosis of CAO is shown

in Table 299-1.

Patients often initially present with cough and exertional dyspnea,

but then progress with increasing severity of obstruction to dyspnea at

rest, stridor, and respiratory failure. Patients may also have wheezing,

hemoptysis, or symptoms of postobstructive infection. Rigid bronchoscopy is the preferred tool to manage CAO in conjunction with ablative

therapies, balloon bronchoplasty, and airway stenting to offer rapid

symptomatic relief with immediate reductions in the level of required

care. Therapeutic bronchoscopy for CAO has been shown to improve

significantly both quality of life and survival.

A B C

Intrinsic Extrinsic Mixed

FIGURE 299-2 Types of central airway obstruction.

TABLE 299-1 Differential Diagnosis of Central Airway Obstruction

MALIGNANT NONMALIGNANT

Primary airway carcinoma Lymphadenopathy

Bronchogenic Sarcoidosis

Carcinoid adenoid cystic Infectious (i.e., tuberculosis, histoplasmosis)

Mucoepidermoid Cartilage

Metastatic carcinoma to the

airway

Relapsing polychondritis

Bronchogenic Granulation tissue from endotracheal tubes

Renal cell Tracheostomy tubes

Breast Airway stents

Thyroid Foreign bodies

Colon Surgical anastomosis

Sarcoma Wegener’s granulomatosis

Melanoma Pseudotumor

Laryngeal carcinoma Hamartomas

Esophageal carcinoma Amyloid

Mediastinal tumors Papillomatosis

Thymus Hyperdynamic

Thyroid Tracheomalacia

Germ cell Bronchomalacia

Lymphadenopathy Idiopathic

Lymphoma Tuberculosis

Sarcoidosis

Other

Foreign-body goiter

Mucus plug

Blood clot

2216 PART 7 Disorders of the Respiratory System

■ BRONCHOPLASTY

Bronchoplasty (or bronchial dilation) can be achieved with the barrel

of the rigid bronchoscope or with balloons that can be passed via

the rigid or flexible bronchoscope. Bronchoplasty is most commonly

used for dilation of stenotic airways or disruption of webs related to

nonmalignant causes of airway diseases. Although dilation generally

leads to immediate relief of the stenosis, results can be short-lived and,

hence, this technique is often combined with airway stenting. Complications are rare but can include airway tears if proper techniques are

not followed.

■ AIRWAY STENTING

After airway patency is achieved, airway stents can be utilized to prevent recurrence of CAO. Reports of endoscopically implantable stents

for the airways date back to 1914. Airway stents are commonly used to

treat patients with CAO due to extrinsic compression from a variety of

malignant and nonmalignant disorders. Stents are effective and lead to

symptomatic relief in >90% of patients. A variety of airway stents are

available, each with its own benefits and detriments; it is important to

choose the right stent for the specific indication. Stent complications

are not uncommon and include mucostasis, infection, and the development of granulation tissue. First-generation biodegradable stents,

custom 3-dimensional-printed stents, and drug-coated stents are

currently being evaluated, working toward a personalized medicine

approach wherein stents are tailored to an individual’s airway anatomy

and underlying disease.

■ ENDOBRONCHIAL INTRATUMORAL

CHEMOTHERAPY

Endobronchial intratumoral chemotherapy (EITC) is an intervention

aimed at improving and/or maintaining airway patency in patients

with malignant CAO, with the potential to eliminate the need for airway stenting and its associated complications. Under bronchoscopic

guidance, high-dose therapeutics can be injected directly into tumor

to enhance response and limit systemic side effects. Most recently, a

novel microneedle injection catheter has been used to optimize drug

delivery of paclitaxel, and was shown to be both feasible and safe with

no restenosis. Additional studies are needed to assess the long-term

effects of EITC.

■ ABLATIVE THERAPIES FOR EARLY-STAGE

LUNG CANCER

Bronchoscopic ablation of early-stage lung cancer has long been

described as the “holy grail” of bronchoscopy due to the appeal of staging, diagnosing, and treating biopsy-proven early-stage lung cancer in

one procedural setting. There is limited experience with bronchoscopic

radiofrequency ablation (B-RFA) and microwave ablation (MWA) as a

potential means to treat early-stage lung cancer. Ultimately, the efficacy

of bronchoscopic ablation of early-stage nonoperable lung cancer must

be proven in longitudinal studies demonstrating noninferiority in

survival as compared to the current gold standard of stereotactic body

radiation (SBRT).

■ BRONCHOSCOPIC THERAPIES FOR ASTHMA

Bronchial thermoplasty (BT) is a treatment for patients with severe

persistent asthma who remain symptomatic despite maximal medical

treatment that delivers radiofrequency energy to the airways to reduce

their smooth muscle mass. A pivotal randomized clinical trial did not

show a change in FEV1

 or airway hyperresponsiveness, but was able

to demonstrate an improvement in quality of life and reduction in

exacerbation rates, visits to the emergency department, and days lost

from school or work. At this time, the ideal asthma phenotypes and

ideal candidates for this treatment modality remain to be determined.

■ BRONCHOSCOPIC THERAPIES FOR CHRONIC

OBSTRUCTIVE PULMONARY DISEASE

The National Emphysema Treatment Trial (NETT), published in 2003,

demonstrated that lung volume reduction (LVR) surgery for severe

emphysema confers improved survival and exercise capacity in patients

with upper lobe–predominant disease and poor exercise capacity. At

the same time, it showed high perioperative morbidity and mortality.

During the last decade, several bronchoscopic therapeutic modalities

have been tested, including valves, coils, steam, stents, and foam, in

patients with severe emphysema to mimic the physiologic effects of

surgical lung volume reduction (SLVR) in a less invasive fashion.

■ BRONCHOSCOPIC LUNG VOLUME REDUCTION

Bronchoscopic lung volume reduction (BLVR) via valve placement

involves placement of one-way valves in airways leading to areas of the

lung with significant emphysema, allowing air and mucus to exit but

blocking air entry to achieve lobar collapse. Several clinical trials on

BLVR with valves have demonstrated improvements in lung function

and overall improvement in quality of life and exercise tolerance. The

overall safety profile of these valve systems compares favorably with

surgical LVR with a much lower rate of perioperative morbidity and

mortality.

■ TARGETED LUNG DENERVATION

Targeted lung denervation is a novel therapy that involves bronchoscopic ablation of peribronchial parasympathetic nerves in order

to achieve permanent bronchodilation. Unlike bronchoscopic LVR,

which focuses exclusively on patients with emphysema, targeted

lung denervation is potentially applicable more broadly to all COPD

patients, with studies showing a reduction in pulmonary exacerbations

when compared with a sham denervated group.

■ PLEURAL INTERVENTIONS

Thoracic ultrasound has become invaluable in the evaluation of

patients with pleural effusion and pneumothorax. Medical thoracoscopy (also called pleuroscopy) is a minimally invasive technique most

commonly used to evaluate recurrent exudative pleural effusions, and

is associated with a diagnostic yield of >95%.

Indwelling pleural catheters (IPCs) have gained tremendous popularity and have been declared by evidence-based guidelines to be as

acceptable as chemical pleurodesis for the management of symptomatic malignant pleural effusions. When comparing IPC and pleurodesis

via talc slurry, two multicentered, open-label, randomized controlled

trials demonstrated IPC effectively relieved dyspnea, decreased the

duration of hospital stay, and lessened the need for future procedures.

Pleural infection (empyema or complex parapneumonic effusion)

is commonly encountered in clinical practice. The mainstay of therapy

typically consisted of antibiotics, drainage of the infected pleural space

with tube thoracostomy, and possible need for surgical decortication.

The landmark Multicenter Intrapleural Sepsis Trial (MIST2) demonstrated that intrapleural sequential administration of rTPA and DNase

resulted in significant radiographic and clinical improvements and

allowed >90% of patients to avoid surgery.

■ PNEUMOTHORAX AND PERSISTENT AIR LEAK

Persistent air leak is defined as a nonresolving pneumothorax with

an air leak lasting more than 5–7 days. For over a decade, the U.S.

Food and Drug Administration has maintained a humanitarian device

exemption for compassionate use of the Spiration Valve System for

management of persistent air leak following lobectomy, segmentectomy, or LVR surgery, although the device has also been used “off label”

for the treatment of persistent air leak due to primary and secondary

spontaneous pneumothoraces.

SUMMARY

IP provides diagnostic and therapeutic options that span the spectrum

of benign and malignant airway and pleural disorders. The constant

innovations in diagnostic and treatment modalities have continued to

help push the boundaries of pulmonary medicine.

■ FURTHER READING

Shafiq M et al: Recent Advances in Interventional Pulmonology. Ann

Am Thorac Soc 16:786, 2019.

Wahidi MM et al: State of the Art: Interventional Pulmonology. Chest

157:734, 2020.

Section 1 Respiratory Critical Care

Critical Care Medicine PART 8

300 Approach to the Patient

with Critical Illness

Rebecca M. Baron, Anthony F. Massaro

The care of critically ill patients requires a thorough understanding of

pathophysiology and centers initially on the resuscitation of patients

at the extremes of physiologic deterioration. This resuscitation is

often fast-paced and occurs early, when a detailed awareness of the

patient’s chronic medical problems may not yet be possible. While

physiologic stabilization is taking place, intensivists attempt to gather

important background medical information to supplement the realtime assessment of the patient’s current physiologic conditions.

Numerous tools are available to assist intensivists in the assessment of

pathophysiology and management of incipient organ failure, offering

a window of opportunity for diagnosing and treating underlying disease(s) in a stabilized patient. However, despite these tools, ongoing

clinical bedside assessment is imperative for care of the critically ill

patient. Indeed, the use of interventions to support the patient such

as mechanical ventilation and renal replacement therapy is commonplace in the intensive care unit (ICU). An appreciation of the risks and

benefits of such aggressive and often invasive interventions is vital to

ensure an optimal outcome. Nonetheless, intensivists must recognize

when a patient’s chances for recovery are remote or nonexistent and

must counsel and comfort dying patients and their significant others

if an initial trial of invasive supportive care is either not effective or

is not appropriate for the patient’s current condition. Critical care

physicians often must redirect the goals of care from resuscitation

and cure to comfort when the resolution of an underlying illness is

not possible. The COVID-19 pandemic has heightened the need and

priority for effective critical care practices (Chap. 199).

ASSESSMENT OF ILLNESS SEVERITY

In the ICU, illnesses are frequently categorized by degree of severity.

Numerous severity-of-illness (SOI) scoring systems have been developed and validated over the past three decades. Although these scoring

systems have been validated as tools to assess populations of critically

ill patients, their utility in predicting individual patient outcomes at

the bedside is not clear. Their utility may be more applicable toward

defining patient populations for clinical trial outcomes and broader

epidemiologic studies. SOI scores are also useful in guiding hospital

administrative policies, directing the allocation of resources such as

nursing and ancillary care, and assisting in assessments of quality of

ICU care over time. Scoring system validations are based on the premise that age, chronic medical illnesses, and derangements from normal

physiology are associated with increased mortality rates. All existing

SOI scoring systems are derived from patients who have already been

admitted to the ICU. Nevertheless, there has been increased recent

clinical use of scoring systems due to revised consensus guidelines for

definitions of sepsis, as will be detailed below.

The most commonly utilized scoring systems are the SOFA (Sequential Organ Failure Assessment) and the APACHE (Acute Physiology

and Chronic Health Evaluation). There has been more recent interest

in the use of a “quick” or qSOFA scoring system for prognostication of

sepsis outcomes.

■ THE SOFA SCORING SYSTEM

The SOFA scoring system is composed of scores from six organ

systems, graded from 0 to 4 according to the degree of dysfunction

(Table 300-1). The score accounts for clinical interventions; it can be

measured repeatedly (i.e., each day), and rising scores correlate well

with increasing mortality. The most recent sepsis consensus conference

guidelines incorporated an increase of at least two points in the SOFA

score from baseline as diagnostic of sepsis in the setting of suspected

or documented infection. Patients with suspected infection can be

predicted to have poor outcomes typical of sepsis if they have at least

two of the following clinical criteria: respiratory rate ≥22 breaths/min,

altered mental status, or systolic blood pressure ≤100 mmHg. Recently,

a new bedside clinical score using two or more of the above clinical

TABLE 300-1 Calculation of SOFA Scorea

SCORE

SYSTEM 0 1 2 3 4

Respiration

Pao2

/Fio2

, mmHg (kPa) ≥400 (53.3) <400 (53.3) <300 (40) <200 (26.7) with respiratory

support

<100 (13.3) with

respiratory support

Coagulation

Platelets, × 103

/μL ≥150 <150 <100 <50 <20

Liver

 Bilirubin, mg/dL (μmol/L) <1.2 (20) 1.2–1.9 (20–32) 2.0–5.9 (33–101) 6.0–11.9 (102–204) >12.0 (204)

Cardiovascular MAP ≥70 mmHg MAP <70 mmHg Dopamine <5 or

dobutamine (any dose)b

Dopamine 5.1–15 or

epinephrine ≤0.1 or

norepinephrine ≤0.1b

Dopamine >15 or

epinephrine >0.1 or

norepinephrine >0.1b

Central nervous system

Glasgow Coma Scalec 15 13–14 10–12 6–9 <6

Renal

 Creatinine, mg/dL (μmol/L)

or urine output, mL/day

<1.2 (110) 1.2–1.9 (110–170) 2.0–3.4 (171–299) 3.5–4.9 (300–440)

or

<500

>5.0 (440)

or

<200

a

Adapted from JL Vincent et al: Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. The SOFA (Sepsis-related Organ Failure

Assessment) score to describe organ dysfunction/failure. Intensive Care Med 22(7):707, 1996. b

Catecholamine doses are given as μg/kg per min for at least 1 h. c

Glasgow

Coma Scale scores range from 3 to 15; higher score indicates better neurological function.

Abbreviations: Fio2

, fraction of inspired oxygen; MAP, mean arterial pressure; Pao2

, partial pressure of oxygen.

2218 PART 8 Critical Care Medicine

criteria has emerged and is termed quick SOFA (qSOFA). qSOFA is

intended to screen patients for risk of poor outcomes from sepsis from

out-of-hospital, emergency department, and hospital ward settings.

qSOFA was not developed as a sepsis diagnostic screening tool, but

studies are investigating its utility as such, especially in resource-poor

settings that may not have the ability to measure all of the components

of the SOFA score.

■ THE APACHE II SCORING SYSTEM

The APACHE II system is the most commonly used SOI scoring

system in North America. Age, type of ICU admission (after elective

surgery vs nonsurgical or after emergency surgery), chronic health

problems, and 12 physiologic variables (the worst values for each in the

first 24 h after ICU admission) are used to derive a score. The predicted

hospital mortality rate is derived from a formula that takes into account

the APACHE II score, the need for emergency surgery, and a weighted,

disease-specific diagnostic category (Table 300-2). The relationship

between APACHE II score and mortality risk is illustrated in Fig. 300-1.

Updated versions of the APACHE scoring system (APACHE III and

APACHE IV) have been published.

■ OTHER SCORING SYSTEMS

There are numerous other scoring systems that have been developed,

and there are ongoing studies evaluating their utility. In particular,

there is increasing interest in utilizing electronic health medical record

scoring systems that might better incorporate larger and real-time data

sets from patients, and that can alert providers to patients at risk for

sepsis and/or poor outcomes from clinical illness.

SHOCK (SEE ALSO CHAP. 303)

■ INITIAL EVALUATION

Shock, a common condition necessitating ICU admission or occurring

in the course of critical care, is defined by the presence of multisystem end-organ hypoperfusion. Clinical indicators include reduced

mean arterial pressure (MAP), tachycardia, tachypnea, cool skin and

extremities, acute altered mental status, and oliguria. The end result of

multiorgan hypoperfusion is tissue hypoxia, often with accompanying

lactic acidosis. Because the MAP is the product of cardiac output and

systemic vascular resistance (SVR), reductions in blood pressure can be

caused by decreases in cardiac output and/or SVR. Accordingly, once

TABLE 300-2 Calculation of Acute Physiology and Chronic Health Evaluation II (APACHE II) Scorea

Acute Physiology Score

SCORE +4 +3 +2 +1 +0 +1 +2 +3 +4

Rectal temperature (°C) ≥41 39.0–40.9 38.5–38.9 36.0–38.4 34.0–35.9 32.0–33.9 30.0–31.9 ≤29.9

Mean blood pressure (mmHg) ≥160 130–159 110–129 70–109 50–69 ≤49

Heart rate (beats/min) ≥180 140–179 110–139 70–109 55–69 40–54 ≤39

Respiratory rate (breaths/min) ≥50 35–49 25–34 12–24 10–11 6–9 ≤5

Arterial pH ≥7.70 7.60–7.69 7.50–7.59 7.33–7.49 7.25–7.32 7.15–7.24 <7.15

Oxygenation

If FIo2

 >0.5, use (A – a) Do2 ≥500 350–499 200–349 <200

If FIo2

 ≤0.5, use Pao2 >70 61–70 55–60 <55

Serum sodium (meq/L) ≥180 160–179 155–159 150–154 130–149 120–129 111–119 ≤110

Serum potassium (meq/L) ≥7.0 6.0–6.9 5.5–5.9 3.5–5.4 3.0–3.4 2.5–2.9 <2.5

Serum creatinine (mg/dL) ≥3.5 2.0–3.4 1.5–1.9 0.6–1.4 <0.6

Hematocrit (%) ≥60 50–59.9 46–49.9 30–45.9 20–29.9 <20

WBC count (103

/mL) ≥40 20–39.9 15–19.9 3–14.9 1–2.9 <1

Glasgow Coma Scoreb,c

EYE OPENING VERBAL (NONINTUBATED) VERBAL (INTUBATED) MOTOR ACTIVITY

4—Spontaneous 5—Oriented and talks 5—Seems able to talk 6—Verbal command

3—Verbal stimuli 4—Disoriented and talks 3—Questionable ability to talk 5—Localizes to pain

2—Painful stimuli 3—Inappropriate words 1—Generally unresponsive 4—Withdraws from pain

1—No response 2—Incomprehensible sounds 3—Decorticate

1—No response 2—Decerebrate

1—No response

Points Assigned to Age and Chronic Disease

AGE, YEARS SCORE

<45 0

45–54 2

55–64 3

65–74 5

≥75 6

CHRONIC HEALTH (HISTORY OF CHRONIC CONDITIONS)d SCORE

None 0

If patient is admitted after elective surgery 2

If patient is admitted after emergency surgery or for reason other than after elective

surgery

5

a

The APACHE II score is the sum of the acute physiology score (vital signs, oxygenation, laboratory values), the Glasgow coma score, age, and chronic health points. The

worst values during the first 24 h in the ICU should be used. For serum creatinine, double the point score for acute renal failure. b

Glasgow coma score (GCS) = eye-opening

score + verbal (intubated or nonintubated) score + motor score. c

For GCS component of acute physiology score, subtract GCS from 15 to obtain points assigned. d

Hepatic:

cirrhosis with portal hypertension or encephalopathy; cardiovascular: class IV angina (at rest or with minimal self-care activities); pulmonary: chronic hypoxemia or

hypercapnia, polycythemia, ventilator dependence; renal: chronic peritoneal or hemodialysis; immune: immunocompromised host.

Abbreviations: (A – a) Do2

, alveolar-arterial oxygen difference; FIo2

, fraction of inspired oxygen; Pao2

, partial pressure of oxygen; WBC, white blood cell count.

2219Approach to the Patient with Critical Illness CHAPTER 300

shock is contemplated, the initial evaluation of a hypotensive patient

should include an early bedside assessment of the adequacy of cardiac

output (Fig. 300-2). Clinical evidence of diminished cardiac output

includes a narrow pulse pressure (systolic BP minus diastolic BP)—a

marker that correlates with stroke volume—and cool extremities with

delayed capillary refill, colloquially termed “cold shock.” It is important

to palpate proximal extremities (e.g., thigh region) rather than distal

extremities to determine relative “coolness,” because patients with

peripheral vascular disease may always have cool distal extremities.

Signs of increased cardiac output include a widened pulse pressure

(particularly with a reduced diastolic pressure), warm extremities with

bounding pulses, and rapid capillary refill, colloquially termed “warm

shock.” If a hypotensive patient has clinical signs of increased cardiac

output, it can be inferred that the reduced blood pressure is from

decreased SVR.

In hypotensive patients with signs of reduced cardiac output, an

assessment of intravascular volume status is appropriate. A hypotensive patient with decreased intravascular volume status may have a

history suggesting hemorrhage or other volume losses (e.g., vomiting,

diarrhea, polyuria). Although evidence of a reduced jugular venous

pressure (JVP) is often sought, static measures of right atrial pressure

do not predict fluid responsiveness reliably; the change in right atrial

pressure as a function of spontaneous respiration is a better predictor

of fluid responsiveness (Fig. 300-3). Patients with fluid-responsive (i.e.,

hypovolemic) shock also may manifest large changes in pulse pressure

as a function of respiration during mechanical ventilation (Fig. 300-4).

Other bedside metrics can help with judging whether a patient remains

fluid-responsive, including responses to volume challenge or a straight

leg raise (that increases venous return) that correlate with improved

perfusion. Such tools include judging changes in JVP or central venous

oxygen saturation, assessing changes in pulse pressure variation, determining changes in inferior vena cava collapse by ultrasound, and examining changes in left ventricular stroke volume using echocardiography.

None of these measurements has been shown to be independently correlative, but a combination of these assessments with clinical judgment

can help determine whether a patient remains volume-responsive. A

hypotensive patient with increased intravascular volume and cardiac

dysfunction may have S3

 and/or S4

 gallops on examination, increased

JVP, extremity edema, and crackles on lung auscultation. The chest

x-ray may show cardiomegaly, widening of the vascular pedicle, Kerley

B lines, and pulmonary edema. Chest pain and electrocardiographic

changes consistent with ischemia may be noted (Chap. 305).

In hypotensive patients with clinical evidence of increased cardiac output, a search for causes of decreased SVR is appropriate.

These patients usually require targeted initial volume resuscitation (as

described above) to achieve euvolemia, and often require vasopressors to

maintain vascular tone. The most common cause of high-cardiac-output

hypotension is sepsis (Chap. 304). Other causes include liver failure,

severe pancreatitis, adrenal insufficiency, burns, trauma, anaphylaxis,

thyrotoxicosis, and peripheral arteriovenous shunts.

Insertion of lines for monitoring and caring for critically ill patients

may be necessary. Over the last two decades, management of shock

has improved to the point where not all patients will require central

venous and arterial lines. However, if a patient demonstrates that shock

is not quickly resolving, as indicated by a persistent need for vasopressors and/or repeated measurement of the JVP and/or central venous

O2

 saturation, then insertion of an arterial line for monitoring blood

pressures and arterial blood gases, as well as a central venous line for

administration of vasoactive agents and monitoring of the JVP and/

or central venous O2

 saturation, may be required. Ideally, lines should

be inserted under sterile conditions using a protocolized checklist

approach, and lines should be removed as soon as they are no longer

necessary to avoid risk of line-associated infection.

In summary, the most common categories of shock are hypovolemic,

cardiogenic, and high-cardiac-output with decreased SVR (highoutput hypotension). Certainly, more than one category can occur

simultaneously (e.g., hypovolemic and septic shock). It may often be

the case that an initial presentation with septic shock can present a

cardiac strain, especially in patients with underlying heart dysfunction,

such that later cardiac insufficiency may arise.

The initial assessment of a patient in shock should take only a

few minutes. It is important that aggressive targeted resuscitation

is instituted on the basis of the initial assessment, particularly since

early resuscitation from septic and cardiogenic shock may improve

survival (see below). If the initial bedside assessment yields equivocal

or confounding data, more objective assessments such as ultrasound/

echocardiography may be useful as described above. In spontaneously

breathing patients, inferior vena cava collapse seen on ultrasound

0–4 10–14

5–9 15–19

APACHE II Score

25–29 35+

20–24 30–34

Mortality rate, %

100

90

80

70

60

50

40

30

20

10

0

FIGURE 300-1 APACHE II survival curve. Blue, nonoperative; green, postoperative.

Inotropes, afterload

reduction

Heart is “full”

(cardiogenic shock)

Evaluate for myocardial

ischemia

Cold, clammy

extremities

Warm, bounding

extremities

High cardiac output

No improvement

What does not fit?

Adrenal crisis, right heart syndrome,

pericardial disease

Consider echocardiogram,

invasive vascular monitoring

Consider echocardiogram,

invasive vascular monitoring

Septic shock,

liver failure

Low cardiac output

JVP, crackles JVP, orthostasis

Intravenous fluids

Antibiotics, aggressive

resuscitation

May

convert

to

SHOCK

Heart is “empty”

(hypovolemic shock)

FIGURE 300-2 Approach to the patient in shock. JVP, jugular venous pressure.

2220 PART 8 Critical Care Medicine

Spontaneous inspiration

Time

Pressure

FIGURE 300-3 Right atrial pressure change during spontaneous respiration in a patient with shock whose cardiac

output will increase in response to intravenous fluid administration. The right atrial pressure decreases from 7 mmHg to

4 mmHg. The horizontal bar marks the time of spontaneous inspiration.

90

60

30

0

Time

Pressure (mmHg)

FIGURE 300-4 Pulse pressure change during mechanical ventilation in a patient with shock whose cardiac output will

increase in response to intravenous fluid administration. The pulse pressure (systolic minus diastolic blood pressure)

changes during mechanical ventilation in a patient with septic shock.

predicts a fluid-responsive state. Increasingly, ultrasound of the thorax

and abdomen is used by intensivists as an extension of the physical

examination to assess rapidly imputed filling volumes, adequacy of

cardiac performance, and for indices of other specific conditions

(e.g., pericardial tamponade, pulmonary embolus, pulmonary edema,

pneumothorax). The goal of aggressive resuscitation is to reestablish

adequate tissue perfusion and thus to prevent or minimize end-organ

injury. It is equally important not to over-resuscitate patients, as it is

increasingly appreciated that excess fluid resuscitation is likely not

beneficial. Thus, targeted fluid resuscitation is the goal.

■ MECHANICAL VENTILATORY SUPPORT

(SEE ALSO CHAP. 302)

During the initial resuscitation of patients in shock, principles of

advanced cardiac life support should be followed. An early assessment

of the ability of a patient to protect his or her airway and to maintain

adequate gas exchange is mandatory. Early intubation and mechanical

ventilation often are required. Reasons for the institution of endotracheal intubation and mechanical ventilation include acute hypoxemic

respiratory failure and ventilatory failure, which frequently accompany

shock. Acute hypoxemic respiratory failure may occur in patients with

cardiogenic shock and pulmonary edema (Chap. 305) as well as in

those who are in septic shock with pneumonia or acute respiratory

distress syndrome (ARDS) (Chaps. 199, 301, and 304). Ventilatory

failure often occurs as a consequence of an increased load on the

respiratory system in the form of acute metabolic (often lactic) acidosis

or decreased lung compliance due to pulmonary edema. Inadequate

perfusion to respiratory muscles in the setting of shock may be another

reason for early intubation and mechanical ventilation. Normally, the

respiratory muscles receive a very small percentage of the cardiac output. However, in patients who are in shock with respiratory distress,

the percentage of cardiac output dedicated to respiratory muscles may

increase by ten-fold or more. Lactic acid production from inefficient

respiratory muscle activity presents an additional ventilatory load.

Mechanical ventilation may relieve the work of breathing and

allow redistribution of a limited cardiac output to other vital organs.

Patients demonstrate respiratory distress by an inability to speak full

sentences, accessory use of respiratory muscles, paradoxical abdominal

muscle activity, extreme tachypnea (>40 breaths/min), and decreasing

respiratory rate despite an increasing drive to breathe. When patients

with shock are supported with mechanical ventilation, a major goal is

for the ventilator to initially assume all or the majority of the work of

breathing, facilitating a state of minimal respiratory muscle work. With

the institution of mechanical ventilation for shock, further declines in

MAP are frequently seen. The reasons

include impeded venous return from

positive-pressure ventilation, reduced

endogenous catecholamine secretion

once the stress associated with respiratory failure abates, and the actions

of drugs used to facilitate endotracheal

intubation (e.g., propofol, opiates).

Patients with right heart dysfunction

or preexisting pulmonary hypertension may also have diminished

cardiac output related to the increases in right ventricular afterload

resulting from positive-pressure ventilation. Accordingly, hypotension

should be anticipated during and following endotracheal intubation.

Because many of these patients may be fluid-responsive, IV volume

administration should be considered and vasopressor support periintubation may also be necessary. Figure 300-2 summarizes the diagnosis and treatment of different types of shock. For further discussion

of individual forms of shock, see Chaps. 303, 304, and 305.

RESPIRATORY FAILURE

Respiratory failure is one of the most common reasons for ICU admission. In some ICUs, ≥75% of patients require mechanical ventilation

during their stay. Respiratory failure can be categorized mechanistically

on the basis of pathophysiologic derangements in respiratory function.

■ TYPE I: ACUTE HYPOXEMIC RESPIRATORY

FAILURE

This type of respiratory failure occurs with alveolar flooding and subsequent ventilation-perfusion mismatch and intrapulmonary shunt physiology. Alveolar flooding may be a consequence of pulmonary edema,

lung injury, pneumonia, or alveolar hemorrhage. Pulmonary edema

can be further categorized as occurring due to elevated pulmonary

microvascular pressures, as seen in heart failure and intravascular volume

overload or ARDS (“low-pressure pulmonary edema,” Chap. 301). This

syndrome is defined by acute onset (≤1 week) of bilateral opacities on

chest imaging that are not fully explained by cardiac failure or fluid

overload and of ventilation-perfusion mismatch, and shunt physiology

requiring positive end-expiratory pressure (PEEP). Type I respiratory

failure occurs in clinical settings such as sepsis, gastric aspiration,

pneumonia, COVID-19 (Chap. 199), near-drowning, multiple blood

transfusions, and pancreatitis. The mortality rate among patients with

ARDS was traditionally very high (50–70%), although changes in

patient care have led to mortality rates closer to 30% (see below). The

COVID-19 pandemic has resulted in a substantially increased incidence of viral-mediated ARDS, and studies are ongoing to determine

whether management of COVID-19 ARDS should fully mirror that of

non-COVID ARDS. The established mechanical ventilation practices

for non-COVID-19 ARDS have been largely applied to the support of

COVID-19 ARDS patients (Chap. 199).

It is well established that mechanical ventilation of patients with

ARDS may propagate lung injury. As seen in Fig. 300-5, the pressurevolume relationship of the lung in ARDS

is not linear. Alveoli may collapse at very

low lung volumes. Animal studies have

suggested that repeated stretching and

overdistention of injured alveoli during

mechanical ventilation can further injure

the lung. Concern over this alveolar

overdistention, termed ventilator-induced

“volutrauma,” led to a multicenter, randomized, prospective trial comparing

traditional ventilator strategies for ARDS

(large tidal volume: 12 mL/kg of ideal

body weight) with a low tidal volume

(6  mL/kg of ideal body weight). This

2221Approach to the Patient with Critical Illness CHAPTER 300

study showed a dramatic reduction in mortality rate in the low-tidalvolume group from that in the high-tidal-volume group (31% vs

39.8%). Other studies have suggested that large tidal volumes may lead

to ARDS in patients who initially do not have this problem. Prone positioning has been shown to improve survival in those with severe ARDS

and has been more broadly applied in many centers in COVID-19

ARDS. Select patients may benefit from neuromuscular blockade in

ARDS. In addition, a “fluid-conservative” management strategy (maintaining a low central venous pressure [CVP] or pulmonary capillary

wedge pressure [PCWP]) is associated with fewer days of mechanical

ventilation than a “fluid-liberal” strategy (maintaining a relatively high

CVP or PCWP) in ARDS in those patients who have been resuscitated

from shock. There is growing interest in avoiding intubation in patients

with ARDS by the use of a variety of devices, such as masks, high-flow

oxygen delivery systems, and helmets for respiratory support; however,

this is tempered by concern that higher tidal volumes during spontaneous breathing with these devices could result in progression of

preexisting lung injury.

■ TYPE II RESPIRATORY FAILURE: HYPERCAPNEIC

RESPIRATORY FAILURE

This type of respiratory failure is a consequence of alveolar hypoventilation and results from the inability to eliminate carbon dioxide effectively. Mechanisms are categorized by impaired central nervous system

(CNS) drive to breathe (colloquially termed, “won’t breathe”), impaired

strength with failure of neuromuscular function in the respiratory system, and increased load(s) on the respiratory system (with the latter two

colloquially termed, “can’t breathe”). Reasons for diminished CNS drive

to breathe include drug overdose, brainstem injury, sleep-disordered

breathing, and severe hypothyroidism. Reduced strength can be due

to impaired neuromuscular transmission (e.g., myasthenia gravis,

Guillain-Barré syndrome, amyotrophic lateral sclerosis) or respiratory

muscle weakness (e.g., myopathy, electrolyte derangements, fatigue).

The overall load on the respiratory system can be subclassified into

resistive loads (e.g., bronchospasm), loads due to reduced lung compliance (e.g., alveolar edema, atelectasis, intrinsic positive end-expiratory

pressure [auto-PEEP]—see below), loads due to reduced chest wall

compliance (e.g., pneumothorax, pleural effusion, abdominal distention), and loads due to increased minute ventilation requirements (e.g.,

pulmonary embolus with increased dead-space fraction, sepsis).

The mainstays of therapy for hypercapnic respiratory failure are

directed at reversing the underlying cause(s) of ventilatory failure.

Noninvasive positive-pressure ventilation with a tight-fitting facial or

nasal mask, with avoidance of endotracheal intubation, may stabilize

these patients in certain circumstances. This approach has been shown

to be beneficial in treating patients with exacerbations of chronic

obstructive pulmonary disease; it has been tested less extensively in

other kinds of respiratory failure but may be attempted nonetheless

with close monitoring in the absence of contraindications (hemodynamic instability, inability to protect the airway, respiratory arrest, significant airway secretions, significant aspiration risk). There has been

reticence in some centers to use noninvasive ventilation in COVID-19

patients due to increased risk of virus aerosolization and transmission

to health care workers.

■ TYPE III RESPIRATORY FAILURE:

LUNG ATELECTASIS

This form of respiratory failure results from lung atelectasis. Because

atelectasis occurs so commonly in the perioperative period, this form

is also called perioperative respiratory failure. After general anesthesia,

decreases in functional residual capacity lead to collapse of dependent

lung units. Such atelectasis can be treated by frequent changes in position, chest physiotherapy, upright positioning, and control of incisional

and/or abdominal pain. Noninvasive positive-pressure ventilation may

also be used to reverse regional atelectasis.

■ TYPE IV RESPIRATORY FAILURE:

METABOLIC DEMANDS

This form most often results from hypoperfusion of respiratory muscles in patients in shock. Normally, respiratory muscles consume <5%

of total cardiac output and oxygen delivery. Patients in shock often

experience respiratory distress due to pulmonary edema (e.g., in cardiogenic shock), lactic acidosis, and anemia. In this setting, up to 40%

of cardiac output may be distributed to the respiratory muscles. Intubation and mechanical ventilation can allow redistribution of the cardiac

output away from the respiratory muscles and back to vital organs

while the shock is treated. In addition, other causes of significant metabolic acidosis might require ventilatory support while reversal of the

underlying cause of the acidosis is addressed.

CARE OF THE MECHANICALLY

VENTILATED PATIENT

Mechanically ventilated patients frequently require sedatives and analgesics. Opiates are the mainstay of therapy for analgesia in mechanically

ventilated patients. After adequate pain control has been ensured, additional indications for sedation include anxiolysis; treatment of subjective

dyspnea; reduction of autonomic hyperactivity, which may precipitate

myocardial ischemia; and reduction of total O2

 consumption (Vo2

).

Nonbenzodiazepine sedatives are preferred because benzodiazepines

are associated with increased delirium and worse patient outcomes.

The neuromuscular blocking agent cisatracurium is occasionally

used to facilitate mechanical ventilation in patients with profound

ventilator dyssynchrony despite optimal sedation, particularly in the

setting of severe ARDS. Use of these agents may result in prolonged

weakness—a myopathy known as the postparalytic syndrome. For

this reason, neuromuscular blocking agents typically are used as a

last resort when aggressive sedation fails to achieve patient–ventilator

synchrony. Because neuromuscular blocking agents result in pharmacologic paralysis without altering mental status, sedative-induced

amnesia is mandatory when these agents are administered.

Amnesia can be achieved reliably with propofol and benzodiazepines such as lorazepam and midazolam. Outside the setting of

pharmacologic paralysis, few data support the idea that amnesia is

mandatory in all patients who require intubation and mechanical ventilation. Because many of these critical patients have impaired hepatic

and renal function, sedatives and opiates may accumulate when given

for prolonged periods. A nursing protocol–driven approach to sedation

of mechanically ventilated patients or daily interruption of sedative

infusions paired with daily spontaneous breathing trials has been

shown to prevent excessive drug accumulation and shorten the duration of both mechanical ventilation and ICU stay (see below).

(See also Chap. 302) Whereas a thorough understanding of the

pathophysiology of respiratory failure is essential for optimal patient

care, recognition of a patient’s readiness to be liberated from mechanical ventilation is likewise important. Several studies have shown that

Pressure, cmH2O

0

500

Alveoli

15

Lower inflection

point

Upper inflection

point

Volume, mL

30 45

250

C

D

B

A

FIGURE 300-5 Pressure-volume relationship in the lungs of a patient with acute

respiratory distress syndrome (ARDS). At the lower inflection point, collapsed

alveoli begin to open and lung compliance changes. At the upper deflection point,

alveoli become overdistended. The shape and size of alveoli are illustrated at the

top of the figure.