William E. Hurford

Recommendations for end-of-life care in the intensive care unit: The Ethics Committee of the Society of Critical Care Medicine.

T hese recommendations are intended to provide information and advice for clinicians who deliver end-of-life care in intensive care units (ICUs). The number of deaths that occur in the ICU after the withdrawal of life support is increasing, with one recent survey finding that 90% of patients who die in ICUs now do so after a decision to limit therapy (1). Although there is significant variability in the frequency of withdrawal of life support both within countries (2) and among cultures (3), the general trend is international in scope (4). Nevertheless, most evidence indicates that patients and families remain dissatisfied with the care they receive once a decision has been made to withdraw life support (5). Although intensive care clinicians traditionally have seen their goals as curing disease and restoring health and function, these goals must now expand when necessary to also include assuring patients of a “good death.” Just as developments in knowledge and technology have dramatically enhanced our ability to restore patients to health, similar developments now make it possible for almost all patients to have a death that is dignified and free from pain. The management of patients at the end of life can be divided into two phases. The first concerns the process of shared decision-making that leads from the pursuit of cure or recovery to the pursuit of comfort and freedom from pain. The second concerns the actions that are taken once this shift in goals has been made and focuses on both the humanistic and technical skills that must be enlisted to ensure that the needs of the patient and family are met. Although both of these issues are critically important in end-oflife care, the decision-making process is not unique to the ICU environment and has been addressed by others (6 –11). These recommendations, therefore, do not deal primarily with the process that leads to the decision to forego lifeprolonging treatments but rather focus on the implementation of that decision, with particular emphasis on the ICU environment. This division of the process into two phases is necessarily somewhat artificial. Patients and families do not suddenly switch from the hope for survival and cure to the acceptance of death and pursuit of comfort. This process happens gradually over varying periods of time ranging from hours to weeks. Similarly, the forgoing of life-sustaining treatments rarely happens all at once and is likewise a stepwise process that parallels the shift in goals. Although acknowledging the relationship between the process of decision-making and the corresponding actions, these guidelines will focus on the latter. These recommendations are written from the emerging perspective that palliative care and intensive care are not mutually exclusive options but rather should be coexistent (12–14). All intensive care patients are at an increased risk of mortality and can benefit from inclusion of the principles of palliative care in their management. The degree to which treatments are focused on cure vs. palliation depends on the clinical situation, but in principle both are always present to some degree. Figure 1 illustrates a useful paradigm for the integration of palliative care and curative care over the course of a patient’s illness. Although many patients are best served by transfer to other environments (e.g., home, hospice, or ward) that may be more conducive to palliative care, some patients are so dependent on ICU technology at the end of life that transfer is not possible. For those who are expected to survive for only a short time after the removal of life-sustaining technology, transfer of the patient to a new environment with new caregivers is awkward and may disrupt the patient’s medical care. For these reasons, among others, intensive care clinicians must become as skilled and knowledgeable at forgoing life-sustaining treatments as they are at delivering care aimed at survival and cure.

Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome. Effects on pulmonary hemodynamics and oxygenation.

Background:Nitric oxide (NO) inhalation selectively decreases pulmonary artery hypertension and improves arterial oxygenation in patients with the adult respiratory distress syndrome (ARDS). In this study of patients with severe ARDS, we sought to determine the effect of inhaled NO dose and time on pulmonary artery pressure and oxygen exchange and to determine which patients with ARDS are most likely to show this response. Methods:Thirteen patients with severe ARDS (hospital mortality 67%) inhaled 0-40 parts per million (ppm) NO. Seven of these patients continued to breathe 2-20 ppm NO for 2-27 days. Results:Inhaling 5-40 ppm NO decreased mean pulmonary artery pressure in a dose-related fashion (from 34 ± 7 to 30 ± 7 mmHg at 20 ppm NO). Systemic arterial pressure did not change. The ratio of arterial oxygen tension to inspired oxygen fraction increased (from 126 ± 36 to 149 ± 38 mmHg) and the venous admixture decreased (from 31.2 ± 5.5 to 28.2 ± 5.2%) without a clear dose-response effect. During prolonged NO inhalation, 2-20 ppm NO effectively reduced mean pulmonary artery pressure (38 ± 7 vs. 31 ± 6 mmHg) and increased arterial oxygen tension (79 ± 10 vs. 114 ± 27 mmHg) without evidence of tachyphylaxis. The decrease of pulmonary vascular resistance during NO inhalation correlated with the level of pulmonary vascular resistance without NO (r=-0.72). The reduction of venous admixture correlated with the level of venous admixture without NO (r=-0.78). Conclusions:Long-term NO inhalation at low concentrations selectively decreases mean pulmonary artery pressure and improves arterial oxygen tension in patients with ARDS. The selective pulmonary vasodilation effect is most pronounced in ARDS patients with the greatest degree of pulmonary vasoconstriction.

Pulmonary Vasoconstriction and Hypertension in Mice With Targeted Disruption of the Endothelial Nitric Oxide Synthase (NOS 3) Gene

NO, synthesized in endothelial cells by endothelial NO synthase (NOS 3), is believed to be an important endogenous pulmonary vasodilator substance that contributes to the normal low pulmonary vascular resistance. To selectively investigate the role of NOS 3 in the pulmonary circulation, mice with targeted disruption of the NOS 3 gene were studied. Pulmonary hemodynamics were studied by measuring pulmonary artery pressure, left ventricular end-diastolic pressure, and lower thoracic aortic flow by using a novel open-chest technique. Transient partial occlusion of the inferior vena cava was used to assess the pulmonary artery pressure-flow relationship. Tension developed by isolated pulmonary artery segments after acetylcholine stimulation was measured in vitro. The histological appearance of NOS 3-deficient and wild-type murine lungs was compared. NOS 3-deficient mice (n = 27), when compared with wild-type mice (n = 32), had pulmonary hypertension (pulmonary artery pressure, 19.0 +/- 0.8 versus 16.4 +/- 0.6 mm Hg [mean +/- SE]; P < .05) that was due to an increased total pulmonary resistance (62 +/- 6 versus 33 +/- 2 mm Hg.min.g.mL-1; P < .001). In vitro, acetylcholine induced vasodilation in the main pulmonary arteries of wild-type but not NOS 3-deficient mice. The morphology of the lungs of NOS 3-deficient mice did not differ from that of wild-type mice. We conclude that NOS 3 is a key enzyme responsible for providing basal pulmonary NO release. Congenital NOS 3 deficiency produces mild pulmonary hypertension in mice.

Inhaled Nitric Oxide Basic Biology and Clinical Applications

A REMARKABLY exciting field of research has developed since nitric oxide (NO) was identified in 1987 as a key endothelium-derived relaxing factor (EDRF). The awarding of the 1998 Nobel prize in physiology or medicine to three seminal researchers in the field of NO biology provided the most recent evidence for the emerging prominence of this area of study. The understanding of the roles of NO in the cardiovascular, immune, and nervous systems; the isolation and localization of NO synthases (NOS); the manipulation of the genes for NOS, including their cloning and selective transfer or knock-out; and the therapeutic use of inhaled NO gas have revolutionized many fields of physiologic research and are influencing clinical therapy. Many insights into the mechanisms of action of NO have been gained. Since the reported applications of inhaled NO in the laboratory and in adult patients with primary pulmonary hypertension in 1991, hundreds of studies have been conducted to determine the clinical applicability of inhaled NO. In subgroups of severely ill and hypoxic children and adults, inhaled NO improves arterial oxygenation and selectively decreases pulmonary arterial hypertension (PAH). NO inhalation therapy, in combination with conventional or high-frequency oscillatory ventilation, can reduce the need for extracorporeal membrane oxygenation (ECMO), an expensive and invasive procedure in newborn patients with hypoxic respiratory failure. However, it remains uncertain whether NO inhalation improves survival rates in adults or children with severe lung injury. New applications for NO inhalation have been discovered. Recent studies indicate that inhaled NO may decrease intestinal ischemia–reperfusion injury and may be useful to treat thrombotic disorders. By increasing the oxygen affinity of sickle cell hemoglobin, inhaled NO may prevent or treat sickle cell crisis. This article reviews the relevant physiologic effects, therapeutic uses, side-effects, and toxicity of NO inhalation. The first portion of this article concentrates on the chemistry, biochemistry, toxicology, and biology of NO; the second portion summarizes the results of NO inhalation studies to date in experimental settings and the results of clinical studies in newborns, children, and adults.

Physiologic Determinants of the Response to Inhaled Nitric Oxide in Patients with Acute Respiratory Distress Syndrome

Background:The response to inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS) varies. It is unclear which patients will respond favorably and whether the initial response persists over time. The authors defined a clinically useful response to inhaled NO as an incre

The right ventricle and critical illness: a review of anatomy, physiology, and clinical evaluation of its function.

This paper reviews right ventricular anatomy and physiology in the critically ill patient. The role of right ventricular function during acute pulmonary artery hypertension and the effect of acute myocardial injury upon right ventricular performance are examined. Clinical methods of assessing right ventricular function at the bedside in acutely ill patients are critically reviewed.

A quality improvement study of the placement and complications of double-lumen endobronchial tubes.

To assess the complications of conventional and fiberoptic endobronchial intubations using reusable (Leyland, London) and disposable (Rüsch, Waiblinger, Germany; Sheridan, Argyle, NY) double-lumen tubes (DLTs), endobronchial intubations occurring over a 12-month period were prospectively studied at this hospital. Residents working with staff anesthesiologists placed either left or right reusable (Leyland) or disposable (Rüsch or Sheridan) DLTs. The DLT used, the use of fiberoptic bronchoscopy (FOB), findings at FOB if used during the intubation or operation, and complications occurring during the case (SpO2 < 90%, peak inflation pressure > 40 cm H2O, air trapping, poor lung isolation, and airway trauma) were recorded. Two hundred thirty-four intubations were analyzed (102 right, 132 left; 70 Leyland reusable DLTs, 66 Rüsch disposable tubes, and 98 Sheridan tubes). Physical signs alone were used to confirm tube position more frequently when Leyland tubes were placed compared with disposable tubes (79% v 39%, P < 0.0001). Rüsch and Sheridan DLTs had similar rates of conventional placement. Nineteen percent of reusable tubes and 44% of disposable tubes required position adjustments using FOB during the initial intubation (P = 0.0002). Disposable tubes also more commonly required readjustment using FOB during the operation (30% v 7%, P < 0.0005). Complications occurred in 42/234 patients (18%). The frequency of specific complications was: decreased SpO2, 9%; increased airway pressures, 9%; poor lung isolation, 7%; air trapping, 2%, and airway trauma, 0.4%. Right-sided Sheridan DLTs had a statistically higher incidence of malposition, resulting in poorer lung isolation.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial Perfusion as Assessed by Thallium-201 Scintigraphy during the Discontinuation of Mechanical Ventilation in Ventilator-dependent Patients

Patients who cannot be separated from mechanical ventilation (MV) after an episode of acute respiratory failure often have coexisting coronary artery disease. The authors hypothesized that increased left ventricular (LV) wall stress during periods of spontaneous ventilation (SV) could alter myocardial perfusion in these patients. Using thallium-201 (201TI) myocardial scintigraphy, the authors studied the occurrence of myocardial perfusion abnormalities during periods of SV in 15 MV-dependent patients (nine women, six men; aged 71 +/- 7 yr, mean +/- SD). Fourteen of these patients were studied once with 201TI myocardial scintigraphy during intermittent mechanical ventilation (IMV) and again on another day, after at least 10 min of SV through a T-piece. One patient was studied during SV only. Thirteen of 14 of the patients (93%) studied during MV had abnormal patterns of initial myocardial 201TI uptake, but only 1 patient demonstrated redistribution of 201TI on delayed images. The remainder of the abnormalities observed during MV were fixed defects. SV produced significant alterations of myocardial 201TI distribution or transient LV dilation, or both, in 7 of the 15 patients (47%). Four patients demonstrated new regional decreases of LV myocardial thallium concentration with redistribution of the isotope on delayed images. The patient studied only during SV also had myocardial 201TI defects with redistribution. Five patients (3 also having areas of 201TI redistribution) had transient LV dilation during SV.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of myocardial ischemia with failure to wean from mechanical ventilation.

OBJECTIVE To determine if myocardial ischemia, as detected by continuous electrocardiographic monitoring, is correlated with continued ventilator dependence in patients who have had difficulties weaning from mechanical ventilation. DESIGN A prospective, observational study. SETTING A university, tertiary care hospital. PATIENTS Seventeen medical and postsurgical patients (age 70 +/- 9 yrs; range 54 to 84) who had received mechanical ventilation for 5 to 67 days at the time of entry into the study. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Patients wore a calibrated, frequency-modulated, two-channel electrocardiographic recorder with two bipolar chest leads attached to exploring electrodes for 24 hrs. We recorded the following data: a) electrocardiographic evidence of myocardial ischemia; b) eventual separation from mechanical ventilation; c) whether the patient survived to be discharged from the hospital; d) duration of tracheal intubation and mechanical ventilation; and e) length of hospital stay. The key outcome variable tested was successful weaning, which was defined as breathing without mechanical ventilatory assistance on discharge from the hospital. Six (35%) of 17 patients had electrocardiographic evidence of myocardial ischemia at the time of entry into the study. The presence of ischemia was associated with failure to wean from mechanical ventilation (p < .05; relative risk 3.05). CONCLUSIONS Myocardial ischemia (as detected by a 24-hr, continuous Holter monitor) occurs frequently in ventilator-dependent patients. The occurrence of ischemia was associated with failure to wean from mechanical ventilation in this patient population.

Inhaled Nitric Oxide Increases Coronary Artery Patency After Thrombolysis

BACKGROUND Nitric oxide (NO) and nitrosovasodilators that release NO inhibit platelet aggregation. The antithrombotic effect of intravenously infused nitrosovasodilators is usually accompanied by systemic vasodilation. Inhaled NO is a pulmonary vasodilator that does not produce systemic hemodynamic effects. This study examines the antithrombotic effect of inhaled NO in a canine model of platelet-mediated coronary artery reocclusion after thrombolysis. METHODS AND RESULTS In 25 anesthetized dogs, a segment of the left anterior descending coronary artery was traumatized and a high-grade stenosis created. Thrombus was injected at this site, and tissue plasminogen activator was administered, producing cyclic flow variations (CFVs) in 24 of 25 dogs. CFV frequency was unchanged in dogs not breathing NO but decreased by 35 +/- 9% (P < .05) and 53 +/- 7% (P < .01) while dogs breathed 20 and 80 parts per million (ppm) NO, respectively. The coronary artery patency ratio (fraction of time during which the coronary artery was patent; CAPR) was unchanged in dogs not treated with NO but increased from 51 +/- 7% to 64 +/- 8% while breathing 20 ppm NO (P < .01) and from 49 +/- 3% to 75 +/- 7% while breathing 80 ppm NO (P < .01). The increased CAPR during 80 ppm NO administration persisted during a 45-minute posttreatment period (70 +/- 7%, P < .05 versus baseline). NO inhalation did not change systemic hemodynamics. In a pharmacological model of coronary vasoconstriction, inhaled NO did not reverse the effect of the thromboxane A2 agonist U-46619. In vitro ADP-induced platelet aggregation was inhibited by NO gas. CONCLUSIONS Inhaled NO at concentrations of 20 and 80 ppm increases coronary patency and decreases CFV frequency in a canine model of platelet-mediated coronary reocclusion after thrombolysis without producing systemic hemodynamic effects.