The European Society of Cardiology
Respiratory fatigue in patients with acute cardiogenic pulmonary edema
a Servizio di Anestesia e Rianimazione I, IRCCS Policlinico S. Mattea, Pavia, Italy
b Cattedra di Anestesiologia e Rianimazione, Università degli studi di Pavia, Italy
c Dipartimento di Cardiologia, IRCCS Policlinico S. Mattea, Pavia, Italy
* Correspondence: IRCCS San Matteo Hospital P. le Golgi 2, 1-27100 Pavia, Italy. Tel.: +39-0382-422222/503477; fax: +39-0382-527992 (E-mail: a.braschi{at}smatteo.pv.it).
Abstract
AIMS: Evaluation of prevalence and features of respiratory fatigue (RF) in patients with acute cardiogenic pulmonary oedema (APE)
METHODS AND RESULTS: Eighteen patients out of 65 consecutive APE were enrolled. All were treated with CPAP delivered by helmet added to medical therapy. RF (defined as an arterial CO2 tension at admission higher than the expected) was diagnosed in nine patients. In these patients pH was lower (7.18 vs 7.35; P=0.0001), base excess more negative (–9.9 vs –3.7 mEq/l; P=0.005) and blood lactates more elevated (46.4 vs 20.8 mg/dl; P=0.013) than in non-fatigued patients; after 3 h of treatment no more differences were found between the two groups.
At admission RF patients had lower mean echocardiographic left ventricular ejection fraction (LVEF): 30.7±12.4% vs 39.1 ±12.8%. After 24 h LVEF increased significantly (P=0.0034) in RF patients, whereas didn't in non-fatigued ones (P=0.19).
CONCLUSIONS: About 50% of patients with APE present respiratory fatigue. These patients are characterized by a pH <7.3 at admission; they are likely to rapidly restore normal gas exchange when treated with CPAP, and to have their LVEF improved after APE resolution.
Keywords Respiratory fatigue; Acute pulmonary edema; Continuous positive airway pressure; CO2 removal; Alveolar ventilation
Introduction
Acute cardiogenic pulmonary edema (APE) is a common medical emergency. Because of improved technologies for respiratory support and effectiveness of early treatment with continuous positive airway pressure (CPAP),1–3 nowadays many patients start CPAP as first-line treatment:4 the rationale for this choice is the presence of pulmonary crepitations and hypoxemia, regardless to the presence of respiratory fatigue and impaired CO2 removal.
During acute pulmonary edema two main factors – arterial oxygen desaturation and inadequate cardiac output – may produce metabolic acidosis with increase of blood lactate levels. Initially, respiratory compensation counteracts this metabolic disturbance with hyperventilation and arterial carbon dioxide partial pressure (pCO2) reduction, so patients with acute pulmonary edema may have a normal or slightly alkaline blood pH in this phase.5–6 Later, respiratory fatigue may appear and the balance between ventilatory need (to keep a normal pH) and ventilatory capacity can be lost. Respiratory compensation of metabolic acidosis can be more or less effective according to the many factors that can influence arterial CO2 tension.7 Ipoxemia and a low pH are major stimuli to increase alveolar ventilation (but very low pH may actually depress respiration and increase arterial pCO2); moreover, stimulation of pulmonary proprioreceptors related to the organ congestion increases neural output to all inspiratory muscles.8 Edema impairs pulmonary mechanics by lowering compliance and raising airway resistance:9 direct consequence is an increased work of breathing, which may increase metabolic production of CO2 by the respiratory muscles.
Intense respiratory effort is a striking feature of acute pulmonary edema: when the work of breathing is greatly intensified, increased ventilation may be associated with such large increases in CO2 production from respiratory muscles that arterial pCO2 actually rises instead of falling. On the other hand, increased lactate is associated with muscle exhaustion and fatigue.10–11 Moreover, old age and cardiac insufficiency, as well as hypoxia, have been reported to limit the amount of lactic acid that can be accumulated before muscle exhaustion occurs.
This study had three objectives. First, to establish the prevalence of respiratory fatigue in patients affected by APE. Second, to find out clinical and instrumental markers of respiratory fatigue. Third, to evaluate the ability of our standard treatment (medical therapy and CPAP delivered by helmet) to reverse respiratory fatigue with the aim to avoid tracheal intubation and mechanical ventilation.
Patients
We evaluated 65 patients admitted to the cardiology emergency room from September 2001 to May 2002 because of APE.
Exclusion criteria were chronic obstructive pulmonary disease, neurological diseases with impaired control of breathing, myopathy determining muscular weakness, indication to primary angioplasty, previous CPAP treatment and tracheal intubation, or O2 therapy by facial mask lasting more than 15 min. Among patients evaluated, 47 met the exclusion criteria (in 26 cases because of ongoing CPAP treatment); 18 patients (nine female) were enrolled.
Mean age±standard deviation (SD) was 75.3±15.8 years (yrs), range 22–90 yrs, median value 77 yrs. The cause of APE was myocardial ischemia in seven cases and uncontrolled hypertension in remaining 11 cases. Twelve patients were experiencing APE for the first time; history of myocardial infarction was present in 10 patients. All patients, at the beginning of the study period, were already in O2 therapy by face mask for no longer than 15 min.
Methods
All patients were treated with O2 supply and CPAP delivered by helmet in addition to medical therapy decided by on duty physician.
Helmet was chosen, instead of mask, as device for CPAP deliver in order to limit patient's discomfort and avoid discontinuation of non invasive ventilatory support.12 Occurrence of CO2 re-breathing was avoided by delivering high fresh gas flow (never less than 30 l/min) in order to wash out exhaled CO2 away from the closed volume inside the helmet. Levels of continuous positive airway pressure and inspired oxygen fraction were adjusted in order to maintain haemoglobin oxygen saturation more than 94%, and ranged from 6 to 12 cm H2O and from 0.3 to 0.7, respectively.
Blood analysis and echocardiography were performed within the first 30 min, immediately after the start of CPAP delivering, and 24 h later, once suspended CPAP release. Respiratory rate, non-invasive blood pressure, heart rate, transcutaneous pulse-oximetry and consciousness were strictly monitored. Arterial blood samples were taken at standardized intervals: early before CPAP administration, and then after 30 min, 1, 3, 6 and 12 h. The specimens of arterial blood were analysed for pH, CO2 tension (pCO2), oxygen tension (pO2), haemoglobin concentration (Hb), haemoglobin oxygen saturation (SpO2 %), bicarbonates and lactates concentration. Base excess (BE) and the ratio between arterial oxygen tension and inspired oxygen fraction (pO2/FiO2 ratio) were contextually calculated.
We defined respiratory competence the ability to maintain a near-complete respiratory compensation of metabolic acidosis, that is to maintain the expected arterial CO2 tension. Expected arterial CO2 tension (E-pCO2) was calculated from actual arterial bicarbonates concentration: .13–15 We indicated as D-pCO2 the difference between actual arterial CO2 tension and E-pCO2: patients whose D-pCO2 was more elevated then 2 mmHg were regarded to have respiratory fatigue (RF). The arterial blood sample performed at admission allowed us to divide patients entering the emergency department because of an episode of APE into two groups: patients having near-complete respiratory compensation (D-pCO2⩽2 mmHg, non-RF group) and patients whose respiratory compensation was incomplete or absent (D-pCO2>2 mmHg, RF group).
The study period was divided into two phases, each one of 3 h: phase 1 from beginning to third hour and phase 2 from third hour to sixth hour. Mean rate of variation during each phase of studied parameters was calculated as the difference between final and initial value, divided 3 h.
The results are reported as means±standard deviation (SD). The paired and impaired t test was used to analyse the intra and inter group differences when appropriate.
Study protocol was approved by our institution's ethics committee and informed consent was obtained from the patients or their next of kin.
Results
By means of the first arterial sample we were able to find out nine patients with impaired respiratory compensation of metabolic acidosis, that is having a value of D-pCO2 more than 2 mmHg. In these patients (RF group, n=9 pts) mean D-pCO2±SD was 15.7±12.9 mmHg whereas in non-fatigued patients (non-RF group, n=9 pts) was –1.1±1.8 mmHg (P=0.0014). The two groups did not significantly differ in terms of age (RF pts: 79.8±8.9 yrs; non-RF pts: 70.9±20.1; P=0.21), sex (five and four females in non-RF and RF group, respectively), or cause of acute pulmonary oedema (three and four ischemic patients in RF and non-RF group, respectively). Patients who had been previously suffered from a myocardial infarction and those who had been previously experienced an episode of APE were equally distributed into the two groups.
Blood analyses
Arterial blood specimens obtained at admission revealed marked differences between the two groups (Table 1). In respiratory fatigued patients pH was significantly lower (7.18±0.1 vs 7.35± 0.03; P=0.0001), base excess (BE) more negative (–9.9±4.1 mEq/l vs –3.7±3.9; P=0.005) and blood lactates more elevated (46.4±24.1 mg/dl vs 20.8±12.9; P=0.013) than in non-RF patients. Arterial CO2 tension (pCO2) was higher in RF patients, but with borderline significance: 51±16 mmHg vs 38.9±6.2 (P=0.05). Neither haemoglobin oxygen saturation (81.5±10.5% in RF group vs 87.9±10.4% in non-RF group; P=0.21) nor pO2/FiO2 ratio (134.3 ±59.9 in RF pts, 182±129.7 in non-RF pts; P=0.33) differed significantly between the two groups at admission.
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After 3 h no differences were found between the two groups. In a single RF patient a persistent, moderate, respiratory impairment (D-pCO2=3.25 mmHg) was observed at 3 h. Similar results were obtained 6 h after admission (Fig. 1).
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) Respiratory fatigue group;
(
) non-respiratory fatigue group. The shown P values refer to differences between the two groups at admission. After 3 h of treatment no more significant differences were found between the groups.Rates of variation of studied parameters differed during the study period between the two groups (Table 2). Improvement of pH, decrease of pCO2 and decrease of D-pCO2 were significantly faster in fatigued than in non-fatigued patients during phase 1; the differences between the two groups attenuated during phase 2. Conversely, rate of increase of bicarbonates (and base excess) became significantly greater in fatigued than in non-fatigued patients during phase 2, mainly because the latter had already normal values of bicarbonates (and base excess) after 3 h of treatment.
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We found near perfect linear relationship between D-pCO2 and pH: the data obtained at 0, 3 and 6 h were well fitted (R2=0.92) by the linear equation pH=–0.01*D-pCO2+7.349. Instead poor relationships were found between pH and CO2 (R2=0.43) and between pH and bicarbonates (R2=0.28). Finally, a high linear relationship (R2=0.858) was noted between the values of D-pCO2 at admission and the pCO2 mean change rates during the first 3 h of treatment (Fig. 2).
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No differences were found in plasma concentrations of creatine phosphokinase (CK), CK-MB, myoglobin, troponin I and glutamic-oxaloacetic transaminase between the two groups. Levels of creatinine resulted slightly elevated in both groups of patients (1.58 ±0.88 mg/dl in RF and 1.22±0.5 in non-RF patients; P=0.33).
Natremia, kalemia, glycemia and white blood cells count did not differ between patients with and without respiratory fatigue. At admission, a significantly lower haemoglobin concentration was found in RF patients (11.1±2.1 g/dl vs 13.6±2.6; P=0.044).
Vital parameters
Respiratory rate (RR) significantly decreased during phase 1 both in RF patients (from 32.9±4.5 to 24.2±9.8; P=0.022) and in non-RF patients (from 32.3±5.2 to 26.4±9.5; P=0.029). There were no differences in RR between the two groups at any time during the study period. At admission respiratory fatigued patients had lower blood pressure, both systolic (137.2±34.7 mmHg vs 177.2±6.5; P=0.03) and diastolic (78.3±18.2 mmHg vs 101.7±20.3; P=0.02) than non-fatigued patients. At third hour systolic blood pressure values became similar between the two groups (125.5±28 mmHg vs 132.6±24.1; P=0.57). On the contrary, diastolic arterial pressure remained lower in RF than in non-RF patients at third how (69.4±14.5 vs 82.2±10.3 mmHg, respectively; P=0.047), and became similar between the two groups only after six hours (71.7±16.8 vs 74.1±12.5 mmHg).
Heart findings
Sinus rhythm was present in 15 patients; three patients showed atrial fibrillation (all in RF group). Heart rate (HR) was higher in RF group (126.7±30 bpm vs 101±20.3; P=0.049) at admission, not in the subsequent controls. In respiratory fatigued patients HR significantly decreased both from admission to third hour (126.7 ±30 bpm vs 96.7±25.4; P=0.0007) and from third hour to sixth hour (P=0.02); non-fatigued patients significantly decreased HR just during phase 1 (from 101±20.3 bpm to 84.9±13.3; P=0.0015).
At admission, once supported with CPAP, fatigued patients had also slightly lower mean echocardiographic left ventricular ejection fraction (Fig. 3) in comparison with non-RF patients (30.7±12.4% vs 39.1 ±12.8%), but this difference did not reach statistical significance (P=0.1). After 24 h, once CPAP had been discontinued in all patients, similar values of mean LVEF were recorded in the two groups (39.3±11.9% in RF patients vs 41.9±13.3% in non-RF patients; P=0.73). LVEF did not change significantly in non-fatigued patients at 24 h (P=0.19), while in patients presenting respiratory fatigue at admission it increased significantly (P=0.0034).
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) RF group after 24 h; (
) non-RF group after 24 h. Respiratory fatigued patients showed significantly improvement of left ventricular systolic function after APE resolution, reaching values similar to those of non-respiratory fatigued patients. See text for P values.Therapy
Decisions about medical treatment were totally independent from our study protocol and therapy was exclusively decided by on duty physician. All patients received diuretic therapy (Furosemide) and all except three RF patients received nitrates. Three RF patients were treated with continuous venous infusion of Dopamine, Norepinephrine and dobutamine, respectively. Catecholamines administration started after at least 1 h after admission and was stopped within 12 h in all cases.
Discussion
Respiratory fatigue during APE: definition, detection, and features
The ventilatory control system provides the compensation for metabolic acid–base disturbances and the response is usually prompt. The changes in ventilation are mediated by H+-sensitive chemoreceptors located in the carotid body and in the lower brainstem: a metabolic acidosis excites these chemoreceptors and initiates a prompt increase in ventilation and a decrease in arterial .16,17 When these ventilatory responses are effective, the arterial pCO2 fit with the expected value as defined according to the previously described equation (see Methods). We excluded from the study patients affected by conditions known to determine impaired respiratory ability to counteract metabolic acidosis other than respiratory muscles fatigue: for this reason, whenever we measured an arterial pCO2 value higher than the expected, we thought to be in presence of respiratory fatigue.
In our study a near perfect linear relationship joined pH and D-pCO2; furthermore, the fitting equation of our experimental data indicated 7.349 as the pH value corresponding to full respiratory compensation of metabolic acidosis (pH associated with D-pCO2 equal to zero). These results imply that in patients affected by APE blood pH is determined by the amount of respiratory compensation and that compensatory responses limit rather than prevent changes in pH (compensation is not synonymous with correction).18
A judgement on ventilatory performance based on respiratory pattern, such as the presence of a rapid-shallow breathing, is of uncertain reliability.19–20 During APE various conditions other than respiratory fatigue, like hypoxemia, agitation and chest pain, when present, could influence patient's way of breathing: actually, we did not find an higher RR in respiratory fatigued than in non-fatigued patients.
The inability to maintain nearly normal pH by means of an increase of ventilation derives from a disproportion between ventilatory need (seriousness of metabolic acidosis, CO2 production) and ventilatory performance (function of work of breathing and respiratory muscles status). Not surprisingly, in respiratory fatigued patients base excess was more negative and blood lactates more elevated than in non-fatigued patients: an heavier metabolic acidosis imposes greater ventilatory burden and depresses respiratory muscle function.
Interestingly, arterial pCO2 resulted just slightly elevated in fatigued subjects, and pCO2 value did not discriminate patients with and without respiratory fatigue: among subjects presenting at admission a pCO2 more than 42 mmHg (median value of our population), only five were fatigued whereas four showed D-pCO2 value lower than 2 mmHg. A value of pH lower than 7.3 was instead able to elicit all (and only) the fatigued patients.
CPAP and respiratory performance
The administration of CPAP is known to greatly speed up the improvement of pulmonary gas exchange:1–4,21–24 hypoxemia resulting from alveolar collapse or liquid filling often responds to alveolar recruitment and maintenance of lung unit patency with positive end-expiratory airway pressure (PEEP). The effect of PEEP on work of breathing (WOB) and ventilatory performance is instead not univocal: alveolar recruitment tends to reduce WOB, but overdistention may decrease lung compliance and increase the elastic workload. Theoretically, CPAP may impair CO2 removal by distending alveolar units and increasing pulmonary capillary vessels resistance, hence increasing dead space ventilation. Moreover, chest distension limits the ability of the inspiratory muscles to perform work by placing them on a disadvantageous portion of their length-tension relationship and altering muscle geometry. On the other hand, PEEP may facilitate the transfer of inspiratory effort to the expiratory muscles, owing a redistribution of respiratory workload from inspiratory to expiratory muscles. Indeed, spontaneously breathing patients may actively oppose PEEP and the increase in end-expiratory lung volume by active exhalation. Active expiration to a volume lower than the equilibrium position that corresponds to the PEEP applied stores potential energy: as the expiratory muscle relax, the outward recoil of the chest wall then provides an inspiratory boost. In this way, CPAP may provide a mechanism by which the fatigued patient can use the expiratory muscles to share the inspiratory workload.
Recovery from respiratory fatigue
Our working hypothesis was that negative effects of CPAP on ventilatory performance may occur when normal lungs are forced to assume an end expiratory volume greater than normal, whereas no adverse effects could occur when PEEP is used to restore normal alveolar recruitment and lung unit patency, that is when is applied to patients suffering from APE. Actually, in our study all respiratory fatigued patients greatly improved during the first 3 h of treatment: they significantly decreased both arterial pCO2 and respiratory rate, hence they increased alveolar ventilation and at the same time improved their respiratory pattern (wider tidal volume at lower frequency). Furthermore, 3 h of treatment were enough to reduce D-pCO2 to normal values in all (but one) patients with respiratory fatigue at admission. In these patients the improvement of D-pCO2 (and hence of pH) can derive from an increase of expected pCO2 (improvement of metabolic acidosis) and/or a decrease of arterial pCO2 (improvement of alveolar ventilation). Respiratory fatigued subjects quickly decreased D-pCO2 during phase 1 of our study period, and about 75% of this reduction was achieved by rapidly decreasing pCO2. The same patients showed a much lower rate of D-pCO2 improvement during phase 2, while pCO2 did not changed significantly: respiratory compensation was already reached by virtually all patients, and further D-pCO2 reduction was due to residual, and gradual, improvement of metabolic acidosis.
Interestingly, pCO2 mean change rate from admission to third hour was a function of D-pCO2 value at admission: this result suggests that our standard treatment of APE was able to rapidly reverse respiratory fatigue, allowing these patients, in few hours, to completely overcome the imbalance between ventilatory need and ability, whatever the initial degree of respiratory impairment.
Respiratory fatigue and systolic dysfunction
Owing to the need of early CPAP support to our patients, we were unable to perform echocardiography before starting administration of CPAP; conversely, echocardiographic evaluation at 24 h was performed in patients who had already stopped CPAP treatment.
PEEP application may induce a drop in cardiac index caused by reduction in ventricular filling due to decreased venous return, whereas ventricular compression facilitates ventricular emptying during systole: partial transmission of positive intrathoracic pressure across the ventricles chambers will decrease the transmural pressure during systole and this decrease ventricular afterload. PEEP induced decreases in stroke volume (and in cardiac index) that may occur in patients suffering from APE are therefore primarily due to a significant decrease in ventricular preload, whereas left ventricular ejection fraction normally increases.25–27
In our study, respiratory fatigued patients showed lower LVEF than non fatigued patients, together with higher heart rate and lower blood pressure. Overall, this pattern indicates a depressed left ventricular systolic performance during the APE, with a significant improvement when APE resolved. Left ventricular systolic function appeared moderately compromised during acute heart insufficiency in non fatigued patients and remained so 24 h later after APE resolution. This evolutionary behaviours of the LV systolic function partially confirms the findings reported recently by Gandhi et al.28 showing values of LVEF roughly similar during APE and 2–3 days after in a group of patients with hypertensive APE. About half patients examined in that study had normal LVEF (>50%) either during APE or afterwards. The authors concluded that a diastolic ventricular failure was predominant during APE in their cases. This was not the case in our population. Actually in our fatigued patients LVEF was markedly depressed during APE, and this was associated with markedly elevated heart rate and borderline blood pressure. It is noteworthy that the depression of left ventricular systolic function could have been underestimated because of a PEEP induced increase in LVEF during echocardiographic study performed in the course of APE. Such a pattern suggest a strong adrenergic activation with an impaired contractile ventricular function. The subsequent increase in LVEF, after APE resolution, support a pathophysiologic role of the ventricular systolic insufficiency. Whether such a role was casual in APE occurrence or secondary to the biological disorder determined by the acidosis, hypoxia and respiratory distress, could not be determined. On the other hand the absence of significant changes of LVEF in non-fatigued patients during and after APE resolution may suggest a non primary role of the left ventricular contractile function in the occurrence and progression of the APE in these patients.
Actually cardiac and respiratory impairment may be tightly related during acute pulmonary oedema, probably worsening each other. Cardiac dysfunction may facilitate appearance of muscle fatigue by decreasing oxygen delivery and determining metabolic acidosis; on the other hand, respiratory fatigue – impairing ventilatory compensation – contributes to a further decrease of pH: acidemia is known to decrease myocardial contractility, probably by means of pH-induced alteration of sarcolemmal Ca2+ transport and myofilament Ca2+ sensitivity.29
Conclusions
Respiratory muscle fatigue can play an important role in the clinical evolution of APE and can be a precipitating factor for an unfavourable outcome. Accordingly, the evolving techniques of respiratory support may be an essential component of the therapeutic strategy and further studies on the pathophysiology of muscle fatigue in APE may help in optimising the therapeutic approach to acute cardiac failure.
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