North American Survey of Vasopressor and Inotrope Use in Severe Sepsis and Septic Shock

Objective: The primary objective of this study was to characterize how vasopressor and inotropic agents are prescribed and administered in the hemodynamic management of sepsis. Secondary objectives were 1) to evaluate adherence with published guidelines to identify areas of deviation and 2) to describe pharmacists’ perceived incidence of adverse drug reactions (ADRs) of vasopressors and inotropes.
Design and setting: Web-based survey.
Patients and participants: Critical care pharmacists.
Interventions: An email invitation was sent to critical care pharmacists asking them to complete a web-based survey. The survey opened September 29, 2004 and closed March 4, 2005.
Measurements and results: Of 1065 pharmacists, 235 (22.1%) responded to the survey. Median hospital and ICU size were 451 and 20 beds, respectively. Primary types of ICUs included general (42.1%), medical (28.5%), surgical/trauma (18.3%), cardiac (9.8%), and other (1.3%). Independent of pulmonary artery catheter (PAC) use, the most common initial vasopressor choice in surgical/trauma ICUs was norepinephrine. In the other ICUs, the most common first-line agent was norepinephrine if a PAC was present and dopamine if a PAC was not present. The most common dosage regimen of vasopressin was a continuous infusion of 0.04 units/min (49.8%). The most commonly used inotrope was dobutamine. Respondents reported using inotropes either sometimes (48.1%) or rarely (34.0%), with therapy continuing 24–48 (54.5%) or 48–72 (26.0%) hours. Commonly associated agents with specifi c adverse effects included dopamine with tachycardia and norepinephrine with digital ischemia. Much variability was shown in drug concentrations and various dosages of vasopressors and inotropes between institutions.
Conclusions: Despite published guidelines, vasopressor and inotrope use in hemodynamic management of patients with sepsis and septic shock displayed much variability. Perceived incidence of ADRs for these agents also demonstrated inconsistency among respondents. National organizations need to develop recommendations for standardization of concentrations of continuous infusion medications in the ICU.


Airway Pressure Release Ventilation (APRV) for the Treatment of Severe Life-Threatening ARDS in a Morbidly Obese Patient

Airway pressure release ventilation (APRV) is a relatively new mode of ventilation that became commercially available in the United States in the mid-1990s. APRV differs fundamentally from that of conventional positive-pressure ventilation. Whereas conventional modes of ventilation begin the ventilatory cycle at a baseline pressure and elevate airway pressure to accomplish tidal ventilation, APRV commences at an elevated baseline pressure and follows with a deflation to accomplish tidal ventilation (Figure 1) [1]. The elevated baseline pressure facilitates oxygenation and lung recruitment while the timed releases aids in carbon dioxide removal. Advantages of APRV include lower airway pressures, lower minute ventilation, minimal adverse effects on cardio-circulatory function, ability to spontaneously breathe throughout the entire ventilatory cycle and decreased need for sedation. APRV is consistent with lung protection strategies that strive to limit lung injury associated with mechanical ventilation. APRV is a recognized mode of ventilation in trauma patients with acute respiratory distress syndrome (ARDS) [2]. However, its adoption in the medical ICU has been limited. We report the case of a morbidly obese patient who developed aspiration pneumonitis and severe life-threatening ARDS who was successfully managed with APRV.

Case report
A 25 year-old African-American male presented to hospital for ophthalmic surgery for retinal detachment of his right eye. His past medical history was signifi cant for asthma, morbid obesity (BMI of 53.2 kg/m2), and obstructive sleep apnea. During anesthesia his airway was “secured” with a laryngeal mask (LMA). In the immediate post-operative period, he developed respiratory distress which was treated with supplemental oxygen as well as methylprednisolone, furosemide, and nebulized bronchodilators. He was transferred to the medical intensive care unit (MICU) with respiratory distress, progressive hypoxemia and hypotension requiring fl uid resuscitation and endotracheal intubation (approximately 6 hours after surgery) with assisted mechanical ventilation. On presentation to the ICU his temperature was 98oF, heart rate 120 beats per minute, blood pressure 90/60 mmHg, respiratory rate 30 breaths per minute with an oxygen saturation of 88% on a rebreathing mask. Physical examination was notable for morbid obesity, coarse breath sounds on lung auscultation and bilateral lower extremity pitting edema. On admission white blood cell was 31x109/l with 90% neutrophils, creatinine was 2.1 mg/dl and lactate was 6.7 mmol/l (67.4 mg/dl). Arterial blood gas analysis on assistcontrolled ventilation with a tidal volume 750 ml (9 ml/kg ideal body weight of 80kg), respiratory rate of 20/minute, PEEP of 5 cmH2O and FiO2 of 1.0 was pH 7.22, PaCO2 58 mmHg and PaO2 of 82 mmHg with an oxygen saturation of 94%. The chest radiograph revealed diffuse bilateral alveolar airspace disease (Figure 2). The presumptive diagnosis was acid aspiration pneumonitis causing ARDS (Mendelsohn’s syndrome) [3]. The patient developed progressive hypoxia despite increasing PEEP to 16 cmH2O with repeat blood gas analysis demonstrating a pH of 7.21, PaCO2 of 49 mmHg, PaO2 of 50 mmHg with an oxygen saturation of 84%. At this point the patient was switched to APRV (Puritan-Bennett 940® ventilator) with the following settings: PEEP-high 35 cmH2O, PEEP-low 5 cmH2O, release rate of 12/minute, time-low of 0.8 s, pressure support of 5 cmH2O above PEEP-high and a FiO2 of 100%. Within hours of changing to APRV we noted signifi cant improvement in oxygenation, a decrease in dead space ventilation ratio from 0.7 to 0.46 (NICO® Vd/Vt) with minimal change in PaCO2. Repeat chest radiograph was markedly improved (Figure 3). The change in the PaO2/FiO2 and PaCO2 over time is illustrated in Figure 4. A transthoracic echocardiogram demonstrated normal cardiac size and function while lower extremity venous Doppler examination was normal. Additional treatment included a hydrocortisone infusion at 10 cc/hr (for 7 days followed by a steroid taper), enoxaparin at prophylactic dose (40 mg SC daily) and enteral nutrition (Oxepa, Ross/Abbott Laboratories, Chicago, IL). Vancomycin and piperacillin/tazobactam initiated for treatment of presumed sepsis were discontinued once the mini-bronchoalveolar lavage and all other cultures were negative. The patient had a prolonged stay in ICU, being liberated from mechanical ventilation after 13 days of APRV. The remainder of his hospital course was uneventful; he was discharged after 20 days of hospitalization.

Discussion
ARDS is a frequent cause of admission to the ICU. The current standard ventilatory mode for patients with ARDS is volume-controlled ventilation using a low-tidal volume lung protective strategy (6 ml/kg ideal body weight) [4]. In a subset of patients with severe ARDS such a ventilatory strategy may be unable to maintain adequate arterial oxygenation and ventilation. APRV has been used in trauma patients as a rescue mode to improve oxygenation in patients failing assist-control mode [2]. There is limited data on the use of APRV in medical patients with severe ARDS. APRV may be particularly useful in patient with morbid obesity. We believe that the use of APRV in our patient was a life saving intervention. APRV, fi rst described by Stock and Downs in 1987 [5], is a time-triggered, pressure-limited, time-cycled mode of ventilation that allows unrestricted spontaneous breathing throughout the entire ventilatory cycle. The patient’s spontaneous breaths are unrestricted and independent of the ventilator cycle. APRV helps to meet the goals of ARDS management by maximizing alveolar recruitment [6] while limiting the transalveolar pressure gradient and barotrauma. APRV is very well tolerated by patients allowing minimal sedation with spontaneous breathing which improves V/Q mismatching and cardiac performance [7,8]. The reduced need for sedative agents as compared to other modes of advanced ventilation is a very important attribute of APRV, as the use of sedative agents has been liked to prolonged ICU stays, delirium and ncreased risk of complications. Morbid obesity has signifi cant effects on the respiratory system which impacts the ventilatory management of these patients. The expiratory reserve volume (ERV) declines signifi cantly with increasing BMI. The fall in ERV is presumably due to small airway closure particularly in the dependent areas of the lung. The vital capacity (VC), total lung capacity (TLC) and functional residual volume (FRV) are generally maintained in otherwise normal individuals with mild to moderate obesity but are reduced by up to 30% in morbidly obese patients [9-10]. In addition, the mechanical effect of obesity causes a decrease in chest wall compliance. The effects of obesity on the respiratory system are compounded in patients with acute lung injury, consequently the standard approach to ventilatory support with low-tidal volumes may result in severe lung derecruitment and inadequate ventilation. APRV may be the ideal ventilatory mode in obese patients with severe ARDS as the increased mean alveolar pressure with short release time will recruit collapsed lung while preventing over-distension of ventilated alveoli. In our institution, we use a step-wise strategy to liberate patients from mechanical ventilation when on the APRV mode. First we decrease FiO2 followed by the PEEP-high. Should the patient tolerate the decrease in FiO2 and PEEP-high, we then increase time-low with further reductions in the PEEP-high until we reach a CPAP (PEEP-low) of 5 cmH2O. At this point we increase the pressure support to 10 cmH2O followed by extubation if the patient is comfortable on these settings. It is very important to stress that the PEEPhigh should be reduced in increments of no greater than 3 cmH2O at an interval no more frequently than every 8-12 hours. Severe (and irreversible) derecruitment may occur if PEEP-high is weaned to rapidly.
In summary, we believe that APRV should be considered in patients with severe ARDS who tolerate low-tidal volume assist controlled ventilation poorly. APRV may be particularly useful in the management of obese patients with ARDS.


Rhino-Orbital-Cerebral Mucormycosis in a Critically Ill Patient

A 54 year-old Caucasian gentleman with history of diabetes presented to emergency department with complaints of facial swelling for one week and left orbital pain of one day duration. The patient underwent computed tomography (CT) scan of head with intravenous contrast which revealed infl ammation of left medial rectus muscle and cellulites of medial left orbital coronal space deep to and surrounding the medial rectus muscle with some lateral deviation of the left eye. In addition, left maxillary sinus disease was noted. A tooth in the left maxilla with a fluid collection associated with its root communicating to the left maxillary sinus suspicious for tooth abscess related to sinus disease (Figure 1). The patient’s white blood cells on presentation was elevated and his blood sugar was 597 mg/dL with a chemistry showing an anion gap of 34 and serum ketones. The patient was hypotensive with a systolic blood pressure of 70 mmHg and was admitted into the intensive care unit. After few hours of volume resuscitation the patient was taken to the operating room for orbital cellulites secondary to possible mucormycosis. Extensive surgical debridement ensued and emergent decompression of the left eye performed. The patient was started on liposomal amphotericin-B, and hyperbaric oxygen therapy. His course was further complicated by the development of brain abscess and cerebritis (Figures 2 and 3). The patient underwent bifrontal craniotomy with the evacuation of abscess, ablation of right frontal sinus and intracranial repair of skull base and dural defect. The patient post operative course was uneventful and patient was discharged home with no neurological deficit.
Rhinocerebral mucormycosis is recognized as a potentially aggressive and commonly fatal fungal infection. Mucormycosis is a rare opportunistic necrotizing infection within the class Zygomycetes and the order mucorales. Mucormycosis is commonly seen in patients with diabetes, hemochromatosis, burns, leukemia, lymphoma, HIV and other immunocompromised status. Clinical course of the infection typically begins with the symptoms of sinusitis or rhinitis with mucosal ulceration or necrosis. The infection disseminates to the orbit and cerebrum by direct extension as in our patient, or it may spread by vessels such as those of cavernous sinus. Imaging and early surgical debribement is essential in management of these patients.


Hypertensive Emergencies: Time for Guidelines

Hypertension remains the “silent killer”. Over 72 million Americans suffer from this condition and it is estimated that as many as 1 billion people worldwide may have it [1]. Critical care clinicians are likely to encounter patients with this malady. Indeed, one percent of patients with essential hypertension (HTN) will develop at some point in their life a hypertensive crisis [2].
What is more concerning, is the fact that the mortality from acute severe HTN remains high. The author participated in a multicenter registry to be published in the next few months. In this registry (studying the treatment of acute hypertension or STAT), an alarming number of patients were readmitted within one month of their initial admission for another hypertensive crisis. Moreover, these patients had an in-hospital mortality that exceeded that of congestive heart failure.
In this issue of Critical Care and Shock, Benson et al, in a large web-based survey, assessed the patterns of drug utilization and management in patients with acute HTN [3]. This original investigation yielded results which are quite interesting and distressing. As the authors indicate, no national practice guidelines exist in the United States for the treatment of patients with acute severe HTN. The authors characterized the utilization patterns of intravenous antihypertensive agents among physicians and clinical pharmacists members of the Society of Critical Care Medicine (SCCM) and the American College of Clinical Pharmacy (ACCP).
Looking at the patterns of utilization we can infer that despite advances in the understanding and management of this illness, many clinicians continue to utilize agents with poor safety profi les. A remarkably high number of them use sodium nitroprusside in this setting. This is disconcerting as 44 percent of the fractional weight of this agent is cyanide and the therapeutic spectrum is very narrow [4]. Moreover, 36% of respondents had seen patients with cyanide or thiocyanate-induced toxicity [3]. So, why do we still use agents that are potentially lethal?
In many instances, and in many countries, the lack of other intravenous antihypertensive agents is the primary concern. However, in Western countries, where other agents are available (i.e., nicardipine, clevidipine, labetalol) misinformation and lack of knowledge are the primary reasons for clinicians to utilize these dangerous agents. In the author’s personal experience there are many options for clinicians to utilize in cases of acute severe HTN in a variety of settings [5].
The article by Benson and coworkers reminds us for the need of national practice guidelines in the fi eld of acute HTN. This illness is likely to remain a common cause of long-term disability and still an exceedingly high mortality in acute care medicine.