UMEM Educational Pearls - By Mike Winters

Since all of us are taking care of critically ill patients for longer periods of time, I think it is important to be familar with current critical care literature.  Often, we are the first "intensivist" a patient sees when they arrive to the hospital.  To keep us up to date, I am going to be sending out critical care literature updates every couple of weeks similar to Amal's cardiology updates.   Please email me with any questions, comments, or feedback.

Mike

Recent Articles from the 2008 Critical Care Literature

Hydrocortisone therapy for patients with septic shock.

Sprung CL, Annane D, Keh D, Moreno R, Singer M, et al. NEJM 2008;358:111-24.

            Corticosteroid therapy for patients with septic shock seems to change favor every couple of years.  In the first publication of the Surviving Sepsis Campaign Guidelines, steroids were given a favorable recommendation based largely upon the results of one multicenter, randomized, controlled trial. (Annane, et al. JAMA 2002;288:862-71) In this study, Annane reported a reduction in the likelihood of death in patients who did not respond to the corticotropin stimulation test and were given steroids (hydrocortisone and fludrocortisone).

            The current study is from the CORTICUS Study Group and is a multicenter, randomized, double-blind, placebo-controlled study conducted in 52 ICUs from March 2002 to November 2005.  Enrolled patients had to have clinical evidence of infection, a systemic response to infection, organ dysfunction attributable to sepsis, and the onset of shock within 72 hours (SBP < 90 mmHg despite fluids or vasopressors).  Patients were randomized to receive either hydrocortisone or placebo for 5 days.  Doses were then tapered over the next 6 days for a total duration of therapy of 11 days.  A lack of response to corticotropin was defined as an increase in cortisol of no more then 9 mcg/dL.  The primary end point of the study was the rate of death from any cause at 28 days in “non-responders”.  Some important secondary end-points included the rate of death at 28 days in “responders”, time to reversal of shock, duration of ICU and hospital stay, and rates of death at 1 year.

            Four-hundred ninety nine patients were enrolled in the study.  Of these, 233 were identified as “non-responders”.  In this group, 125 were randomized to receive hydrocortisone and 108 received placebo.  The demographic and clinical characteristics of patients in each group were similar.  Over 90% of patients in each group were vented and all were receiving vasopressors, the most common being norepinephrine.  With respect to the primary outcome, there was no significant difference in the rate of death at 28 days between the study groups.  For the secondary end points, there was also no significant difference in the rate of death in “responders”, duration of ICU or hospital length of stay, or death at 1 year.  The only difference that was found in those receiving hydrocortisone was a reduction in the time to reversal of shock.  Importantly, this did not translate into improved mortality.  Lastly, the authors reported an increase in new episodes of sepsis and septic shock in those receiving hydrocortisone but the absolute numbers are small.

            Things to Consider:  Investigators had planned to enroll 800 patients but stopped at 499 due to slow recruitment, termination of funding, and expiration of the study drug.  In addition, the mortality rate in the placebo group was lower than what would be expected.  As a result, the study is inadequately powered.  In contrast to the Annane study, enrollment of patients could be up to 72 hours after the onset of shock, raising the question of timing of steroids administration.  Furthermore, the majority of patients in this study were older, Caucasian males who required emergency surgery – not typical of the septic shock population at UMMC.  Importantly, patients who were receiving long-term corticosteroids within the past 6 months, or short-term steroids within the past 4 weeks, were excluded – the patients we would typically give stress dose steroids to during refractory shock. 

            Take Home Point: Although CORTICUS is underpowered, it is one of the largest trials to date on corticosteroids in patients with septic shock.  The results indicate that corticosteroid therapy in this patient population of “non-responders” had no effect on mortality.  Based upon this study, the latest version of the Surviving Sepsis Campaign Guidelines has downgraded their recommendation on corticosteroids.  It appears that the pendulum regarding steroids may now be swinging back in the negative direction.

Intensive insulin therapy and pentastarch resuscitation in severe sepsis.

Brunkhorst FM, Engel C, Bloos R, Meier-Hellmann A, Ragaller M, et al. NEJM 2008;358:125-139.

            The concept of “tight glucose control” in critically ill patients primarily began with the Van de Berghe study in 2001.  In this study, investigators found a reduction in mortality in critically ill patients whose glucose was maintained between 80 – 110 mg/dL. (Van de Berghe G, et al. NEJM 2001;345:1359-67.)  The benefit was primarily seen in cardiac surgery patients who had multiple organ failure from sepsis.  Furthermore, these patients were given a high glucose challenge immediately after surgery – not a common practice.  More recently, the same investigators evaluated MICU patients who had not undergone surgery nor received a glucose challenge.  (Van de Berghe G, et al. NEJM 2006;354-449-61.)  In this latter study there was no benefit to intensive insulin therapy.

            The current study is a multicenter, randomized, open-label study of both intensive insulin therapy and hydroxyethyl starch in patients with severe sepsis.  The study was conducted from April 2003 to June 2005 in 18 multidisciplinary ICUs at academic tertiary hospitals in Germany.  The study was designed to detect a decrease in mortality from 40% to 30% at 28 days.  Enrolled patients had to have the onset of severe sepsis or septic shock either 24 hours before ICU admission or less than 12 hours after ICU admission.  The primary end points were the rate of death from any cause at 28 days and morbidity.  Since we do not use HES in the ED for volume resuscitation, I will focus on intensive insulin therapy.

            The insulin arm of the study compared intensive insulin therapy to conventional insulin therapy.  In the conventional group, insulin was given when glucose values were > 200 mg/dL, with the goal of maintaining glucose between 180 – 200 mg/dL.  In the intensive insulin group, insulin was given when glucose values were > 110 mg/dL, with the goal of maintaining glucose between 80 – 110 mg/dL.  Treatment ended at either discharge from the ICU, death, or a total of 21 days of therapy were reached.

            Five hundred thirty seven patients were enrolled, 290 in the conventional insulin group and 247 in the intensive insulin group.  Baseline patient characteristics including age, pre-existing co-morbidities, sites of infection, lab values, and hemodynamic variables were similar between the groups.  Total nutritional intake, including glucose, was similar in both groups.  Interestingly, the majority of patients had nosocomial acquired infections and over 60% in both groups were given hydrocortisone.  Overall, there was no significant difference in the rate of death between the intensive and conventional insulin therapy groups.  Furthermore, there was no significant difference in morbidity between the two groups.  As one might expect, there was significantly more hypoglycemic episodes in the intensive insulin therapy group (17% vs. 4.1%).  Although no deaths were attributable to hypoglycemia, there were more “life threatening” episodes of hypoglycemia in the intensive insulin group.  As a result of the increase in hypoglycemic episodes the study was stopped early.

            Take Home Point:  In this patient population with severe sepsis, intensive insulin therapy, using a continuous infusion, to maintain glucose between 80 – 110 mg/dL did not improve mortality.  It did, however, result in significantly more hypoglycemic episodes (glucose < 40 mg/dl).  Many EDs across the country are now developing and implementing sepsis protocols primarily based upon the SSC Guidelines.  Based upon this study, intensive insulin therapy may not be a necessary component to the ED management of patients with severe sepsis or septic shock.

D-Dimer in the Critically Ill

• Diagnosis of VTE in the critically ill can be challenging and these patients are at high risk for the disease
• Only 3.6% - 16% of critically ill patients have a negative d-dimer, regardless of the presence or absence of VTE
• Even in patients with low pretest probability, d-dimer in the critically ill is of limited utility

Crowther MA, et al. Neither baseline tests of molecular hypercoagulability nor D-dimer levels predict deep venous thrombosis in critically ill medical-surgical patients. Intensive Care Med 2005;31(1):48-55.

• The use of central venous pressure as a monitor of volume status remains very controversial in the critical care literature
• Remember that CVP can be affected by many conditions
• Important conditions that affect the accuracy of CVP include: 
  • right ventricular disease
  • tricuspid valve disease
  • pericardial disease
  • changes in intrathoracic pressure (PEEP, positive pressure ventilation) 
  • arrhythmias
  • reference level of the transducer

Spontaneous Pneumomediastinum

• Spontaneous pneumomediastinum is largely a benign disease typically seen in young males ages 18-21 years
• It is typically caused by activities that increase alveolar pressure such as coughing, sneezing, vomiting, inhalational drug use, and Valsalva maneuver
• The most common symptoms include chest pain and dyspnea; chest pain is usually centrally located, may radiate to the neck, and may be worse with inspiration
• CT scan is the "gold standard"; CXR is a good place to start but it is normal in up to 30% of cases
• The vast majority of patients do not require admission or supplemental O₂
• Advise patients to avoid strenuous activity until after symptom resolution (typically takes about 2 weeks)
• Any patient with a fever, elevated WBC count, hemodynamic instability, severe dysphagia or odynophagia should first be evaluated for infectious mediastinitis or esophageal perforation (spont. pneumomediastinum is a diagnosis of exclusion in these patients)

Invasive Arterial Pressure Monitoring - Complications

In critically ill patients with hemodynamic instability we often place arterial catheters to continuously monitor mean arterial pressure.  Since we frequently use the radial artery for cannulation, it is important to know the complications associated with these catheters.  Scheer et al performed, perhaps, the largest review of complications of peripheral arterial catheters.  The results:

• Radial arterial catheters
  • 19,617 cannulations reviewed
  • temporary occlusions - 19.7%
  • hematoma - 14.4%
  • serious ischemic damage - 0.09%
  • pseudoaneurysm - 0.09%
  • sepsis - 0.13%

Pearl: Although permanent ischemic damage is rare, when placing a radial artery catheter use the non-dominant hand.

Scheer BV, Perel A, Pfeiffer UJ. Clinical review: Complications and risk factors of peripheral arterial catheters used for haemodynamic monitoring in anaesthesia and intensive care medicine. Crit Care 2002;6:198-204.

Pitfalls in pulse oximetry in the critically ill

• Pulse oximeters are calibrated by manufacturers using data collected from healthy volunteers
• In general, pulse oximeters are accurate  within +/- 2% for sats > 70%
• In the critically ill, however, the accuracy of pulse oximetry diminishes when sats drop below 90%
• Also, there may be a significant lag time between a hypoxic event and the actual display of the event - most commonly seen in low flow states, hypotension, mild hypothermia, and when using vasoactive medications
• Prolonged lag times are more common with finger probes
• Pitfall - pulse oximetry does not provide any assessment regarding ventilation (P_aCO₂) or acid-base status (pH) - it is simply an estimate of arterial oxgyen saturation
• Pearl: anemia does not affect the accuracy of pulse oximetry

Mean Arterial Pressure

• Arterial pressure is the input pressure for organ perfusion
• Mean arterial pressure (MAP) is the best physiologic estimate of perfusion pressure
• MAP is less subject to measurement variability than SBP and DBP
• MAP remains relatively constant when measured at different sites throughout the arterial circuit
• MAP of 60 mmHg is considered the autoregulatory threshold below which perfusion becomes compromised
• Goal: maintain MAP > 65 mmHg
• There is no proven value to achieving a MAP higher that 65 mmHg.  In fact, there is some literature to support that if you try and drive the MAP higher, patients do worse

Pulmonary Hypertension Pearls

We are beginning to see more and more patients with pulmonary hypertension (PAH),  many of whom are on continuous IV infusions of new medications.  With that in mind, here are a few pearls:

• The most common causes of rapid deterioration in patients with PAH are: catheter occlusion/pump malfunction, pneumonia, indwelling catheter infection, RV ischemia, PE, and GI bleeding
• Hypotension is usually due to worsening RV failure and less likely to hypovolemia
• If a catheter occlusion or pump failure is found, the drug should be restarted as soon as possible through an alternative access (including peripheral)
• Calcium channel blockers, a prior treatment for PAH, are no longer indicated and should not be given

Adrenal Insufficiency in the Critically Ill

• Adrenal insufficiency (AI) is estimated to occur in up to 30% of critically ill patients
• The most common causes of AI in the critically ill are SIRS and sepsis
• In most cases of critically ill patients, AI is functional (i.e relative) - the adrenal response is insufficient to respond to the degree of stress
• Diagnostic clues include hyponatremia, hyperkalemia, hypoglycemia (rare), and hemodynamic instability despite IVFs and vasopressors
• Although still controversial, most feel that AI is present in critically ill patients with either a basal cortisol < 15 mcg/dl, an increase in < 9 mcg/dl after ACTH stimulation, or a random cortisol < 25 mcg/dl
• IV hydrocortisone, methylprednisolone, and dexamethasone are the 3 glucocorticoids most commonly administered
• Hydrocortisone is usually the preferred agent because it is the synthetic equivalent of cortisol (and has both glucocorticoid and mineralocorticoid activity)

Critical Care Monitoring - End-Tidal CO₂

• End-tidal CO₂ (ETCO₂) monitoring is used to verify ETT placement, monitor procedural sedation, traumatic brain injury, and to estimate prognosis during cardiopulmonary resuscitation
• ETCO₂ concentration typically underestimates P_aCO₂ by 4-5 mmHg in healthy non-intubated patients
• This relationship is less reliable in critically ill patients secondary to shunt, altered alveolar dead space, and inadequate ventilation
• While a low ETCO₂ value is less useful in the critically ill, a high value almost always correlates with an equal or higher P_aCO₂ value
• This can be useful when monitoring conditions such as status asthmaticus, CHF, or increased ICPs in which a high ETCO₂ may signal the need for additional aggressive treatment

Unilateral Pulmonary Edema

• unilateral pulmonary edema is a well recognized and well documented entity
• although there are several causes, the most likely scenarios for EPs are severe mitral valve insufficiency, aortic dissection (with compression of the pulmonary artery), airway obstruction, and heroin use
• even though radiology will read the xray as likely pneumonia, if the story/exam fit with edema then treat as such

Massive hemoptysis

• Massive hemoptysis is defined by most as the expectoration of > 600 ml in 24 hrs
• Chronic lung inflammatory disease and bronchogenic CA are the most common causes in the US
• TB remains the most common cause worldwide
• The bronchial artery causes approximately 90% of cases
• Get a STAT portable and place the patient in the lateral decubitus position toward the affected side (this is theorectical and has not been proven)
• Options for bleeding control can include endobronchial tamponade methods(pulmonary), bronchial artery embolization (interventional radiology), and emergent surgical resection (surgery)
• Bronchial artery embolization is now the most successful non-surgical treatment of massive hemoptysis

Acute Liver Failure

• Acute liver failure (ALF) is defined as the onset of encephalopathy and coagulopathy within 26 weeks of jaundice in a patient without prior history of liver disease
• ALF has an extremely high mortality
• The most common cause of ALF include Tylenol, HSV, autoimmune hepatitis, HBV, and acute fatty liver of pregnancy/HELLP
• Complications EPs are likely to see/manage include hepatic encephalopathy, infection, circulatory dysfunction, bleeding, and seizures
• Fungal infections may be present in one-third of patients with ALF (Candida)
• Non-convulsive seizure activity occurs in a high proportion of patients with ALF and encephalopathy - consider EEG for severly encephalopathic patients and those with a sudden deterioration in neuro status

Stravitz RT, et al. Intensive care of patients with acute liver failure. Crit Care Med 2007;35:2498-2508.

A few days ago Dr. Jump and I had a case of an acute variceal hemorrhage.  Dr. Bond already sent out a great pearl earlier in the year highlighting the importance of octreotide in acute variceal bleeding.  In fact, octreotide alone can result in cessation of hemorrhage in up to 80% of patients.  To add onto Dr. Bond's pearl:

• Don't forget about antibiotics in acute variceal hemorrhage
• These patients have a relatively high incidence of bacteremia, which leads to worse outcomes
• Antibiotics have been shown to decrease infection rates and are associated with decreased rebleeding and the need for transfusions
• A 3rd generation cephalosporin is currently the recommended antibiotic of choice

• Acute chest syndrome (ACS) is the leading cause of death in sickle cell patients
• ACS is defined by the presence of a new infiltrate and one of the following: chest pain, wheezing, fever, tachypnea, or cough
• Early and aggressive therapy is needed to minimize mortality
• Up to 50% of patients develop respiratory failure
• Treatment
  • Broad spectrum antibiotics - including a macrolide
  • Pain control to reduce hypoventilation
  • Early use of blood transfusion to improve O2 carrying capacity
  • Incentive spirometry
  • Bronchodilators if wheezing present
  • Hematology consult

• It is traditionally taught that in hypotensive patients the presence of a carotid pulse corresponds to a SBP of 60-70 mmHg, a femoral pulse with a SBP of 70-80 mmHg, and a radial pulse with an SBP of at least 80 mmHg
• These physical exam estimates of BP have been shown to poorly correlate with the patient's actual BP
• Similarly, non-invasive measurements of BP (automated cuff) in patients with hypotension may either overestimate or underestimate SBP by as much as 20 mmHg
• Since physical exam estimates and non-invasive measurements are inaccurate in low-flow states, utilize invasive arterial monitoring
• Radial and femoral artery sites have been found to produce results that are clinically interchangeable

Critical Care Pearls for Traumatic Brain Injury

• Avoid hypotension and hypoxia - SBP < 90 and/or PaO2 < 60 are associated with significant increases in morbidity and mortality
• Hypertonic saline remains controversial - a recent large, controlled trial did not show any early or long-term benefit
• ICP monitoring routinely recommended in patients with GCS < 8 - they have a 60% chance of increased ICP
• Maintain ICP < 20 mmHg and CPP > 60
• Supportive care
  • Elevate the head of bed > 30 degrees, if possible
  • Control fever
  • Provide analgesia and sedation
• Ventilator management - keep PaCO2 between 30-35 mmHg
• Surgery - last resort to controlling increased ICP
  • Decompressive craniotomy
  • Decompressive laparotomy

• Binding of vasopressor agents to their receptors is influenced by pH (and temperature and concentration)
• Acidic conditions have been shown to alter receptor numbers on cell surfaces as well as alter binding affinity
• Overall, pH values > 7.15 do not have an appreciable clinical effects on vasopressors
• At pH values < 7.1 reductions in effectiveness become apparent
• Routine administration of bicarbonate remains controversial
• Aggressively search for and treat the underlying cause of the acidosis

Hyperammonemia in the Critically Ill

• Patients with acute hyperammonemia have significant morbidity and mortality 
• Fulminant hepatic failure is the most common cause of acute hyperammonemia in adult ICUs
• Other causes include TPN, GI hemorrhage, steroid use, trauma, multiple myeloma, infection with urease-splitting organisms, and drugs (salicylates, valproate) 
• Cerebral edema, intracranial hypertension, seizures, and herniation are the most significant effects
• Initial management should focus on treating intracranial hypertension - mannitol, hypothermia, N-acetylcysteine have been used
• Lactulose has not been shown to reduce mortality in acute hyperammonemia but is unlikely to be harmful

Clay AS, Hainline BE. Hyperammonemia in the ICU. Chest 2007;132:1368-1378.

[RESENT - STILL FIXING CODE - THESE TEST EMAILS SHOULD CEASE SHORTLY... SORRY FOR THE INCONVENIENCE]

• Abdominal compartment syndrome (ACS) is increasingly identified in the critically ill medical patient population
• ACS is defined as a sustained intra-abdominal pressure > 20 mmHg associated with new organ dysfunction
• Primary organs adversely affected by ACS include cardiac, pulmonary, GI, and renal
• To date, associated mortality rates have ranged from 27% to 50%
• Risk factors for ACS include:
  • massive fluid resuscitation ( >10 L crystalloid in 24 hours)
  • massive transfusion ( > 10 U PRBCs in 24 hours)
  • severe sepsis or septic shock from any cause
  • mechanical ventilation
  • PEEP > 10 cm H20
• Intravesicular (bladder) pressures are currently the standard monitoring modality
• Decompressive laparotomy is the current standard for management of ACS