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MANAGEMENT OF SEVERE SEPSIS

MANAGEMENT OF SEVERE SEPSIS. Virginia Chung, MD Director, MICU Jacobi Medical Center. INTRODUCTION. Sepsis is a clinical syndrome that complicates severe infection and is characterized by systemic inflammation and widespread tissue injury.

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MANAGEMENT OF SEVERE SEPSIS

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  1. MANAGEMENT OF SEVERE SEPSIS Virginia Chung, MD Director, MICU Jacobi Medical Center

  2. INTRODUCTION • Sepsis is a clinical syndrome that complicates severe infection and is characterized by systemic inflammation and widespread tissue injury. • Tissues remote from the original insult display signs of inflammation, including vasodilation, increased microvascular permeability, and leukocyte accumulation. • Tissue injury due to activation of the inflammatory system may also complicate noninfectious disorders such as acute pancreatitis or trauma.

  3. TERMINOLOGY • In 1992, the ACCP/SCCM consensus panel defined the following terms: • Infection – microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms. • Bacteremia – presence of viable bacteria in the blood • SIRS (Systemic Inflammatory Response Syndrome) – is a widespread inflammatory response to a variety of severe clinical insults, manifested by 2 or more of the following:

  4. TERMINOLOGY SIRS • Temperature > 38ºC or < 36ºC • Heart rate > 90 beats/min • Respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg • WBC count > 12,000/mm3, <4,000/mm3, or > 10% immature forms • Sepsis – is the systemic response to an infection, i.e., SIRS + infection. • Severe Sepsis – sepsis associated with organ dysfunction, hypoperfusion, or hypotension.

  5. TERMINOLOGY • Organ Dysfunction Criteria: • Cardiovascular – SBP <= 90 mmHg or MAP <= 70 mmHg for at least 1 hour despite adequate volume resuscitation, or the use of vasopressors to achieve the same goals. • Renal – urine output < 0.5 ml/kg of body weight for 1 hour despite adequate volume resuscitation. • Pulmonary – PaO2/FiO2 <= 250 if other organ dysfunction present or <= 200 if the lung is the only dysfunctional organ. • Hematologic – platelet count < 80,000/mm3 or decreased by 50% over 3 days. • Metabolic – pH<= 7.30 or base deficit > 5.0 mmol/l AND plasma lactate > 1.5 x upper limit of normal. • CNS – acute alteration in mental status

  6. TERMINOLOGY • Septic Shock – • a subset of severe sepsis with hypotension despite adequate fluid resuscitation combined with perfusion abnormalities. • patients requiring inotropic or vasopressor agents may no longer be hypotensive by the time they exhibit organ dysfunction, but are nonetheless considered to be in septic shock. • form of vasodilatory or distributive shock resulting from a marked reduction in systemic vascular resistance; it is often associated with an increased cardiac output but some patients can present with decreased cardiac output due to sepsis-induced cardiac dysfunction.

  7. SIRS & SEPSIS Infection/Trauma Sepsis Severe Sepsis SIRS SIRS with a presumed or confirmed infectious process A clinical response arising from a nonspecific insult, including  2 of the following: • Temperature 38oC or 36oC • HR 90 beats/min • Respirations 20/min • WBC count 12,000/mm3or 4,000/mm3 or >10% immature neutrophils SIRS = Systemic Inflammatory Response Syndrome Adapted from: Bone RC, et al. Chest 1992;101:1644 Opal SM, et al. Crit Care Med 2000;28:S81

  8. Shock SEVERE SEPSIS Infection/Trauma Sepsis Severe Sepsis SIRS • Sepsis with 1 sign of organ failure • Cardiovascular (refractory hypotension) • Renal • Respiratory • Hepatic • Hematologic • CNS • Metabolic acidosis Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N England J Med 1999;340:207

  9. WORLDWIDE • Incidence of severe sepsis is 3.0 cases / 1,000 • 18 million cases of severe sepsis annually. • Kills approximately 1,400 people each day. • Leading cause of death in non-coronary ICUs • Number of cases of severe sepsis is growing at the rate of 1.5% per year. • This translates to an additional 1 million cases per year in the USA alone by 2020.

  10. RISK FACTORS • Factors potentially responsible for the growing incidence of severe sepsis and septic shock: • Increased awareness and sensitivity for the diagnosis. • Increased number of immunocompromised individuals: • HIV/AIDS • Increased use of cytotoxic and immunosuppressant agents • Malnutrition • Alcoholism • Diabetes Mellitus

  11. RISK FACTORS • Increased number of transplant recipients and transplantation procedures. • Increased use of aggressive invasive procedures in patient management and diagnosis. • Increased number of resistant microorganisms. • Increased number of elderly patients. • Increased number of institutionalized individuals.

  12. Sepsis 400,000 7-17% Severe Sepsis 300,000 20-53% Septic Shock 53-63% MORTALITY Incidence Mortality Approximately 200,000 patients including 70,000 Medicare patients have septic shock annually Balk, R.A. Crit Care Clin 2000;337:52

  13. WHAT CAN WE DO AS HEALTHCARE PROVIDERS TO IMPROVE THESE MORTALITY STATISTICS ?

  14. IHI / SSC • To expedite Quality Improvement (QI) in health care, the Institute for Healthcare Improvement (IHI) launched the 100,000 Lives Campaign in December 2004. • This is a national initiative with a goal of saving 100,000 lives among patients in hospitals through improvements in the safety and effectiveness of health care by June 18, 2006. • A “life saved” is defined as a patient successfully discharged from a hospital who, absent the changes achieved through the campaign, would not have survived. • All 5,759 hospitals in the U.S. have been invited to join this campaign. The Health and Hospitals Corporation (HHC) with its 11 acute care hospitals (incl. Jacobi and NCB) are participants

  15. IHI / SSC • IHI Campaign Interventions: • Deploy Rapid Response Teams (RRT/MET) • Deliver Reliable Evidence-Based Care for Acute MI • Prevent Adverse Drug Events Through Medication Reconciliation. • Prevent Central Line Infections. • Prevent Surgical Site Infections. • Prevent Ventilator-Associated Pneumonia

  16. IHI / SSC • At the same time, the Critical Care community formed a working group, launched the Surviving Sepsis Campaign (SSC), and published their “Guidelines for Management of Severe Sepsis and Septic Shock” in the March 2004 issue of Critical Care Medicine. (Recently updated Jan 2008) • IHI and the SSC working group have since teamed up to “wage war” on sepsis; their goal is to “achieve a 25% reduction in sepsis mortality by 2009”. • To implement these evidence-based guidelines, 3 core strategies are recommended: • Model for improvement : Plan-Do-Study-Act (PDSA) cycles • Using “Bundles” to simplify the complex process of caring for patients with severe sepsis by grouping specific management elements together. • Enhancing reliability of the bundled elements.

  17. SEVERE SEPSIS BUNDLES • A “bundle” is a group of interventions related to a specific disease process that, when executed together, result in better outcomes than when implemented individually. The elements of the bundle are based upon evidence-based practice and should be considered generally accepted practice. • There are 2 different Severe Sepsis Bundles. Each bundle articulates objectives to be accomplished within specific timeframes: • Severe Sepsis Resuscitation Bundle • Severe Sepsis Management Bundle

  18. Resuscitation Bundle • Describes 7 tasks that should begin immediately, but must be accomplished within the first 6 hours of presentation for patients with severe sepsis, septic shock, or a lactate > 4 mmol/l. • 1. Measure serum lactate – hyperlactatemia is typically present and may be secondary to anaerobic metabolism due to hyperperfusion; obtaining a level is essential to identifying tissue hypoperfusion in patients who are not yet hypotensive, but who are at risk for septic shock.

  19. Resuscitation Bundle • 2. Blood Cultures Obtained Prior to Antibiotic Administration – 30-50% of these patients will have positive blood cultures; best hope of identifying the organism causing severe sepsis. Two or more blood cultures are recommended. • In patients with suspected catheter-related infection, blood cultures should be drawn simultaneously through the catheter hub and from a peripheral site. If the same organism is recovered and the culture drawn from the line is positive much earlier than the peripheral culture, then it is likely that the catheter is the source of infection.

  20. Resuscitation Bundle • 3. Improve Time to Broad-Spectrum Antibiotics – early administration of appropriate antibiotics reduces mortality in patients with Gram(+) and Gram(-) bacteremias. Therefore, broad-spectrum antibiotics should be given within 3 hours from time of presentation to the E.D. or within 1 hour for ward patients transferred to the ICU. 2008: 1 hour. • Major sources of infection in severe sepsis or septic shock are pneumonia and intra-abdominal infections; other sources accounting for < 5% of cases. • Choice of antibiotics should be guided by the susceptibility patterns of likely pathogens in the community or hospital as well as any specific knowledge about the patient. The regimen should cover all likely pathogens since there is little margin for error in critically ill patients. Re-evaluate at 48-72 hours.

  21. Resuscitation Bundle • 4. Treat Hypotension and/or Elevated Lactate with fluids – patients may experience ineffective arterial circulation due to vasodilatation or impaired cardiac output; poorly perfused tissue beds result in global tissue hypoxia leading to an elevated serum lactate level. • Lactate > 4 mmol/l or 36 g/dl is correlated with increased severity of illness and poorer outcomes even if hypotension is not yet present. • Initial administration of at least of 20 ml/kg of crystalloid as a fluid challenge/bolus should be given ASAP to these patients; boluses should be repeated as necessary.

  22. Resuscitation Bundle • Fluid Challenge – describes the initial volume expansion period in which the patient response is closely monitored; 4 componenets are: • 1. Fluid type – crystalloid vs. colloid • 2. Infusion rate – 500-1,000 ml over 15-30 minutes • 3. End points – MAP > 65 or 70 mmHg, hr < 110 beats/min • 4. Safety limits – pulmonary edema • Crystalloid vs. Colloid – the volume of distribution for crystalloids is much larger than for colloids, hence a larger volume of crystalloids will be required to achieve the same goals and could result in more edema.

  23. A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit The SAFE (Saline versus Albumin Fluid Evaluation) Study Investigators NEJM 2004; 350: 2247-56

  24. SAFE STUDY • Multicenter, randomized, double-blind trial comparing the effect of fluid resuscitation with 4% albumin versus normal saline on 28-day mortality in the 16 ICUs in Australia & New Zealand. • 7,000 patients age 18 or older were randomized. • 3 were mistakenly randomized twice, leaving 6,997 patients in the study; 3,497 received 4% albumin and 3,500 received NS. • Results: 726 deaths in the albumin group and 729 in NS group (relative risk of death 0.99; p=0.87); additionally, there was no significant differences in ICU days, hospital days, mechanical ventilation days, renal-replacement therapy days, or development of new single or multiorgan failures.

  25. Resuscitation Bundle • End Points of Fluid Resuscitation – for refractory hypotension not responding to fluids or lactate > 4 mmol/l, patients should now enter the Early Goal Directed Therapy (EGDT) phase of the Resuscitation Bundle where central venous pressure (CVP) >= 8-12 mmHg and central venous saturation (ScvO2) >=70% are the goals. • Rivers, et al., demonstrated a 34% reduction in hospital mortality for the patients in the EGDT group versus those in the standard therapy group. • The degree of intravascular volume deficit in septic patients varies; with venodilation and ongoing capillary leak, most patients require aggressive fluid resuscitation during the first 24 hours of management.

  26. Resuscitation Bundle • 5. Apply Vasopressors for Ongoing Hypotension (Shock) – when an appropriate fluid challenge fails to restore an adequate arterial pressure and organ perfusion, therapy with vasopressors should be started; vasopressors may be required transiently to sustain life even when hypovolemia has not been corrected or when a fluid challenge is in progress. • MAP (mean arterial pressure) >= 65 mmHg • Place arterial catheter for continuous blood pressure measurements; ABGs, lactates readily available

  27. Resuscitation Bundle • Choice of Vasopressors: either norepinephrine or dopamine is the first-choice vasopressor agent to correct hypotension in septic shock; epinephrine and phenylephrine should not be used as first-line vasopressors because they decrease splanchnic blood flow significantly • Vasopressin can be added when patients are still in shock despite adequate fluid resuscitation and high-dose conventional vasopressors.

  28. Vasopressors • Dopamine – natural precursor of NE and Epi and possesses several dose-dependent pharmacologic effects. • Low doses (< 5 mcg/kg/min) – stimulates dopaminergic DA1 receptors in the renal, mesenteric, and coronary beds, resulting in vasodilation. • Intermediate doses (5-10 mcg/kg/min) – β-adrenergic effects predominate, resulting in an increase in cardiac contractility and heart rate • High doses (>10 mcg/kg/min) – α-adrenergic effects predominate, leading to arterial vasoconstriction and an increase in blood pressure. • Systemic hemodynamic effects of dopamine in septic patients : increases MAP primarily by increasing cardiac index with minimal effects on SVR; SV increases more than heart rate. • Very high doses (>20 mcg/kg/min) – increases heart rate and right heart pressures; consider alternative agent.

  29. Vasopressors • Norepinephrine (NE) – is a potent α-adrenergic agonist with some β-adrenergic agonist effects; increases MAP due to vasoconstrictive effects, with little change in heart rate or cardiac output, leading to increased SVR. • In open label trials, NE was shown to increase MAP in hypo-tensive patients resistant to fluid resuscitation and dopamine. • In the past, there was concern that NE may have negative effects on splanchnic and renal blood flow leading to regional ischemia; however, recent experience does not support this. • In hyperdynamic septic shock, NE markedly improves MAP and glomerular filtration; after restoration of systemic hemodynamics urine output increases and renal function improves in most patients.

  30. Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Russell, JA, MD, et. al., for the VASST Investigators NEJM, 2008, 358:877-887.

  31. VASST • Multicenter, randomized, double-blind trial, comparing the use of NE alone to NE plus vasopressin at 0.03units/min. on 28 day mortality. • 27 centers in Canada, Australia, and USA participated between July 2001 and April 2006. • Inclusion criteria: age>16 with septic shock – hypotension despite fluid resuscitation requiring >= 5 mcg/min NE. • Less severe septic shock : NE 5-14 mcg/min • More severe septic shock : NE >=15 mcg/min • Of 6229 screened, 802 were randomized : • 396 NE ; 406 vasopressin • Pts were very ill with mean APACHE II scores of 27 and > 3 organ dysfunction

  32. VASST • Results: No significant difference in the primary outcome – rate of death from any cause, 28 days after start of the infusions- between the VP and the NE group (35.4 vs 39.3%, p=0.26) • Similarly, there was no difference in 90-day mortality either (43.9 vs 49.6%, p=0.11) • Sub-group analysis: less severe septic shock pts who received VP had lower mortality at 28-days (26.5 vs 35.7%, p=0.05) and at 90-days (35.8 vs 46.1%, p=0.04) • Investigators had hypothesized that beneficial effects of VA would be more pronounced in the more severe septic shock group

  33. Resuscitation Bundle • 6. Maintain Adequate Central Venous Pressure – in the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/l (36 mg/dl) achieve CVP >= 8-12 mmHg. • Patients should receive the initial minimum of 20 ml/kg fluid challenge prior to placement of a Central Venous Catheter (CVC) and attempts to optimize CVP. • For patients who are hypovolemic and anemic with a Hct < 30, consider transfusing packed RBCs; blood is a better volume expander and increases oxygen carrying capacity. • In mechanically ventilated patients, a higher target CVP > 12 mmHg is recommended because positive pressure ventilation causes increases in intrathoracic pressures and decreases venous return.

  34. Resuscitation Bundle • 7. Maintain Adequate Central Venous Oxygen Saturation (ScvO2) – in the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/l (36 g/dl) achieve a ScvO2 > 70% OR a mixed venous oxygen saturation (SvO2) via PA catheter > 65%. • Strategies to achieve target ScvO2: • If the CVP > 8 mmHg and Hct < 30, transfuse PRBCs to increase oxygen carrying capacity and hence oxygen delivery to the tissues. • If the patient has underlying cardiac dysfunction or has developed sepsis-induced cardiac dysfunction, then add an inotrope (dobutamine) provided the patient has been fluid resuscitated and transfused (if indicated). Increasing cardiac output increases oxygen delivery to the tissues. • 2008 : option of transfusing first or go directly to inotropes

  35. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock Rivers, E., M.D., M.P.H., Nguyen, B., M.D., et. al., for the Early Goal-Directed Therapy Collaborative Group; NEJM, 2001, 345:1368-1377.

  36. EGDT • Randomized, controlled, predominantly blinded study in an E.D. of an 850-bed tertiary referral center (Henry Ford Hospital, Detroit, MI) over a 3-yr period (3/1997-3/2000). • Enrollment criteria: 2 of 4 SIRS criteria with a SBP < 90 mmHg after a 20-30 ml/kg fluid challenge or a blood lactate level > 4 mmol/l (36 g/dl). • Patients either received 6 hours of standard therapy or 6 hours of goal-directed therapy before admission to the ICU; clinicians subsequently involved in the care of the study patients were blinded to the treatment arm of the study. • Control group followed an existing protocol for hemodynamic support: CVP 8-12 mmHg, MAP > 65 mmHg, urine output > 0.5 ml/kg/hr; 500 ml fluid boluses and vasopressors were used.

  37. EGDT • Treatment group had the same aims as the control group PLUS they had to achieve a central venous oxygen saturation (ScvO2) > 70%: • If the ScvO2 < 70 % and • Hct < 30, transfuse PRBCs • MAP > 90 mmHg, give vasodilators until MAP <= 90 mmHg • If CVP, Hct, and MAP were in the optimal range and ScvO2 still < 70%, start dobutamine 2.5 mcg/kg/min (inotrope) and titrate it up by 2.5 mcg/kg/min every 30 min until ScvO2 > 70% or a maximum dose of 20 mcg/kg/min is reached. The dose was decreased or d/c’ed if MAP < 65 mmHg or hr > 120 beats/min • Finally, to decrease O2 demand, sedate and mechanically ventilate the patient.

  38. EGDT • Results: 263 patients randomized – 133 received standard therapy and 130 received EGDT; Temp, hr, urine output, BP, CVP were measured cont. for 6 hours, then q 12h for 72 hrs. • During the initial 6 hours, the EGDT group received more IV fluids, red cell transfusions, and inotropic therapy than the control group. • During the subsequent 66 hours, the control group received more transfusions, more vasopressors, and had a greater requirement for mechanical ventilation and PA catheterization. • This showed that the control group was relatively under-resuscitated initially. • In-hospital mortality was significantly higher in the control group than in the EGDT group – 46.5 % versus 30.5% (p=0.009).

  39. Resuscitation Bundle • To summarize, for patients presenting with severe sepsis, septic shock, or lactate > 4 mmol/l, the following 7 tasks need to be accomplished within the first 6 hours of presentation: • 1. Measure serum lactate. • 2. Obtain blood cultures prior to antibiotic administration. • 3. Improve time to broad-spectrum antibiotics (< 3(1) hrs). • 4. Treat hypotension and/or elevated lactate with fluids. • 5. Apply vasopressors for ongoing hypotension. • 6. Maintain adequate CVP (>= 8 mmHg). • 7. Maintain adequate ScvO2 (>= 70%).

  40. Management Bundle • Describes 4 tasks that must be completed within 24 hours of presentation for patients with severe sepsis, septic shock, and/or lactate >4 mmol/l. • 1. Administer Low-Dose Steroids by a Standard Policy – IV corticosteroids (hydrocortisone 200-300 mg/day, for 7 days in 3-4 divided doses) are recommended in patients with septic shock who despite adequate fluid replacement require vasopressor therapy to maintain adequate blood pressure. • The use of fludrocortisone in addition to low-dose hydrocortisone is considered optional. Absolute primary adrenal insufficiency is rare in septic shock (0-3%).

  41. Management Bundle • In refractory septic shock, the prevalence of Relative Adrenal Insufficiency (RAI) may be as high as 50-75%. RAI is present when the increase in serum cortisol level is < 9 mcg/dl, 30-60 min after a 250- mcg ACTH stimulation. • Low dose CorticoSteroids (CS)promote shock reversal. Their effects on vascular tone were recognized well before their anti-inflammatory properties. In patients with septic shock, low dose CS significantly reduces nitrite/nitrate plasma concentrations, indicating inhibition of NO formation. • Median time to cessation of vasopressors in one study decr. from 13 to 4 days and 7 to 3 days in another. Another study showed that MAP and SVR increased and HR, CI, and NE requirement decreased with the use of low-dose CS.

  42. Effect of Treatment with Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock Annane, D., Sebille, V., Charpentier, C., et al., JAMA, 2002; 288: 862-871

  43. Low Dose CS • Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 ICUs in France from 1995-1999. • 1326 pts were assessed for eligibility; 1026 were ineligible; 300 randomized to receive either hydrocortisone 50 mg IV q6h and fludrocortisone 50 mcg po qd or matching placebos for 7 days. • Corticotropin test was performed in all patients; RAI was defined as a response of 9 mcg/dl or less. RAI pts were deemed Nonresponders while those who had a >9 mcg/dl increase were Responders.

  44. Low Dose CS • Mortality rates: • All patients – there was no significant effect of CS on 28-day, ICU, hospital, and 1-year mortality rates. • Responders (>9 mcg/dl incr.) – there was no significant effect of CS on 28-day, ICU, hospital, and 1-year mortality rates. • Nonresponders (<= 9 mcg/dl incr.) – • 28 days : placebo 73 (63%) CS 60 (53%) deaths p=.04 • ICU: placebo 81 (70%) CS 66 (58%) deaths p=.02 • Hospital: placebo 83 (72%) CS 70 (61%) deaths p=.04 • 1-year: placebo 88 (77%) CS 77 (68%) deaths p=.07

  45. Low Dose CS • Median Time-to-Vasopressor-Therapy Withdrawal – • All patients – 9 days (placebo) , 7 days (CS) , p=.01 • Responders – 7 days (placebo) , 9 days (CS) , p=.49 • Nonresponders – 10 days (placebo) , 7 days (CS) , p=.001 • No significant differences between the 2 groups in the rates of adverse events related to CS (infection, GI bleed, psychiatric d/o). • Conclusion: in pressor-dependent septic shock, administer low dose CS and fludrocortisone for 7 days in those with RAI.

  46. Hydrocortisone Therapy for Patients with Septic Shock Sprung, CL, MD, Annane, D, MD, et. al., for the CORTICUS Study Group NEJM, 2008, 358: 111-124.

  47. CORTICUS • Multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of low-dose hydrocortisone (HC) therapy in septic shock. • 52 European and Israeli ICUs took part between March 2002 and November 2005. • Inclusion criteria: age >=18 with onset of septic shock within the previous 72 hrs and hypoperfusion or organ dysfunction due to sepsis. • Exclusion criteria: underlying disease with poor prognosis, moribund (life expect < 24hrs), immunosuppression, Rx with long-term CS within 6 months, or short-term CS within 4 weeks.

  48. CORTICUS • Protocol: 50 mg IVP q6h x 5days, then q12h x 3 days, and then q24h x 3 days (both HC and placebo) • Primary end-point was rate of death at 28-days in pts who DID NOT have a response to ACTH • Secondary end-points: 28-day mortality in pts who HAD a response to ACTH, and in all pts, ICU-mortality, 1 year mortality, reversal of organ failure and shock, ICU LOS, Hospital LOS. • 500 pts enrolled: 252 (HC) and 248 (placebo) • 233 (46.7%) did not respond to ACTH – 125(HC), 108(plac) • 254 (50.9%) DID respond to ACTH – 118(HC), 136(plac)

  49. CORTICUS • Results: No significant difference between the 2 study grps in the primary outcome – 28 day mortality in ACTH non-responders. • HC grp: 49/125 (39.2%) died • Placebo grp: 39/108 (36.1%) died; p=0.69 • Likewise, there was no significant difference in 28 day mortality in the ACTH responders • HC grp: 34/118 (28.8%) died • Placebo grp: 39/136 (28.7%) died; p=1.00 • Overall, there were 86/252 (34.3%) deaths in HC grp and 78/248 (31.5%) deaths in Placebo grp ; p=0.51 • Of those patients who had reversal of their shock, those who rec’d HC took less days to do so ( 3.3 vs 5.8 days)

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