In this episode we discuss two articles about fluid resuscitation. Recorded on 6/25/20.

Presenters: Alex Pizarro, MD and Ivana Margi, MD, Wellspan York Hospital Emergency Medicine Department
Hosts: Giselle Aerni, MD and Sonya Del Tredici, MD
Producer: Robert Stuntz, MD 

Article 1: Balanced Crystalloids versus Saline in Critically Ill Adults. Semler, Et. Al. N Engl J Med 2018 Mar 1;378(9):829-839. The SMART Investigators and the Pragmatic Critical Care Research Group. Notes By Dr. Pizarro.

Question: In critically ill patients does the use of balanced crystalloids compared to normal reduce a 30-day composite outcome of death, new renal replacement therapy, and renal dysfunction?

Background: Historically normal saline has been the most commonly administered IV fluid; however, its safety has been questioned. Normal saline is a hypertonic, acidotic fluid so far from “normal”.  Balanced crystalloid solutions (such as LR and Plasma-Lyte A) have electrolyte compositions closer to that of plasma which is why they make an excellent alternative! Normal saline causes hyperchloremic metabolic acidosis.  Several studies suggest that normal saline is associated with higher rates of acidosis, acute kidney injury, use of renal replacement therapy, and death. 

Evidence that normal saline is associated with:

Hemodynamic instability
§  Kellum (2004): Septic rats who received normal saline had more profound hemodynamic dysfunction as compared to LR.
§  Orbegozo (2016): Sheep who received normal saline had reduced cardiac index, reduced tissue oxygen levels, impaired microcirculatory perfusion, more coagulopathy, earlier development of oliguria, and earlier death. 
§  Potura (2015): Retrospective control study on patients undergoing renal transplantation randomized to receive normal saline vs. Elomel Isoton solution (an acetate-buffered balanced crystalloid).  Patients receiving saline required vasopressors more frequently (30% vs 15%; p=0.03)

Increased inflammation
§  Kellum (2006):  Used hydrochloric acid in septic rats to induce a hyperchloremic acidosis resulting in increased levels of pro-inflammatory cytokines.
§  Zhou (2014): In a rat sepsis model, resuscitation with saline produced higher levels of interleukin-6 compared to Plasmalyte.
§  Wu (2011): Randomized control trial of patients with pancreatitis comparing LR to normal saline.  Normal saline had higher levels of C-reactive protein one day after the initiation of fluid resuscitation.  Normal saline also seemed to delay resolution of clinical features of systemic inflammation (SIRS criteria).  Based on this study, LR is generally recommended as the fluid of choice for pancreatitis resuscitation by the American College of Gastroenterology guidelines.
§  de-Madaria (2018): Replicated Wu (2011) results.  Patients treated with normal saline had a nonsignificant trend towards more SIRS criteria (p=0.06) and increased level of C-reactive protein.

Increased risk of acute kidney injury (Theory: hyperchloremia causes renal vasoconstriction which in turn decreases renal cortical blood flow leading to AKI thus increasing the need for renal replacement therapy and risk of death)
§  Zhou (2014): In septic rats, saline resuscitation increased the rate of kidney injury compared to Plasmalyte.
§  Chawdhury (2012): Patients who received two-liter saline bolus had reduced blood flow to the renal cortex compared to two-liter Plasmalyte.
§  Yunos (2012): Before-after study which involved avoiding chloride-rich resuscitative fluids in an ICU.  Following this intervention, the rate of acute kidney injury decreased. 

Debunked myths about LR:
1. It is cheap – LR is only $0.25 more expensive than normal saline. 
2. LR worsens hyperkalemia – Evidence suggests the exact opposite.  In fact, normal saline causes hyperchloremic acidosis which may exacerbate a hyperkalemic state due to shift of H+ intracellularly in exchange for K+.
§  Martini (2013): Pig model for hemorrhagic shock found that normal saline is more likely to cause hyperkalemia when compared to LR.
§  O’Malley (2005), Khajavi (2008), Modi (2012), and Weinberg (2017): Randomized control trials performed during renal transplant surgery showed that normal saline more frequently causes hyperkalemia when compared to LR or Plasmalyte.

Design: Pragmatic, unblinded, cluster-randomized, multiple-crossover trial

Setting: Location: Conducted in 5 ICUs at a single US academic center (Vanderbilt in Nashville, TN): Medical (34 beds), Neurologic (22 beds), Cardiac (27 beds), Trauma (31 beds), Surgical (22 beds).
Dates: From June 1st 2015 to April 30th 2017

Population:
Inclusion: All adult patients admitted to the ICU
Exclusion: Age < 18 yrs
Sample Size: 15,802 adults
Median age: 58-years-old
Gender: 57.6% male
No significant differences in baseline characteristics between groups

How were they assigned?
For every month of the trial, each ICUs was randomized to use saline or balanced crystalloids.  They then alternated at the beginning of each calendar month. Patients were enrolled at time of ICU admission and assigned to receive either the control (normal saline) or the intervention (balanced crystalloids: LR or plasma-lyte A) according to the unit where they were admitted to. They coordinated with ED and OR so that fluid administered in the ED or OR was the same as that assigned to the ICU they were being admitted to. This was not true for the post cardiac surgery patients. Physicians completed a questionnaire at time of admission to determine if the patient had the relative contraindication of hyperkalemia or traumatic brain injury.  If so, then 0.9% sodium chloride could be used in preference to balanced crystalloid at the physician’s discretion.

Groups
Intervention
-7942 patients were allocated to the balanced crystalloid group
Median volume of balanced crystalloid administered between ICU admission and hospital discharge or 30 days: 1000ml (IQR 0-3210).

Control
-7860 patients were allocated to saline
Median volume of normal saline administered between ICU admission and hospital discharge or 30 days: 1020ml (IQR 0-3500)

Management of both groups
Volumes and rates were prescribed by the treating physicians
All other management was at the discretion of the treating physician

Outcomes: Primary outcome: Proportion of patients who met one or more criteria for a Major Adverse Kidney Event at hospital discharge or 30 days whichever came first (MAKE 30) – mortality, new receipt of renal-replacement therapy, or persistent renal dysfunction (defined as final inpatient creatinine of >200% baseline). MAKE 30 was significantly greater in normal saline group (15.4% vs 14.3%; p = 0.04). Number needed to treat was 94.
Secondary outcomes:
-In hospital death before ICU discharge or within 30 days of ICU admission was greater in normal saline group (11.1% (875) vs 10.3% (818); p = 0.06).
-Receipt of new RRT was greater in normal saline group (2.9% (220) vs 2.5% (189); p = 0.08).
-Persistent renal dysfunction was greater in normal saline group (6.6% vs 6.4%; p = 0.60).
-However, there was no significant difference in ICU free days, ventilator free days, vasopressor free days, and Stage 2 (or higher) AKI developing after enrolment!
Sub-group analysis:
-In-hospital mortality was significantly greater in normal saline group for sepsis (29.4% vs 25.2%; p = 0.02) and chronic dialysis (18.4% vs 12.2%; p = 0.01)

Strengths: -Important question helping guide fluid resuscitation to improve morbidity and mortality in critically-ill patients
-Large sample size providing adequate power to detect even slight difference in clinical outcomes.
-Balanced population of both medical and surgical critically ill patients thus generalizable.
-Median fluid volume was approximately the same between the normal saline and balanced cr.
-Separation between groups of fluids received indicating that the allocation was largely successful.

Weaknesses: -Single center trial may not be generalizable. Although, population was fairly balanced.
-Unblinded
-Raises question of Plasmalyte vs LR. Currently no good evidence.
-Physicians could exclude patients if they felt that there was a relative contraindication to the assigned fluid.
-Used small volumes of fluid.

Conclusion: This is a large and strong study that adds further evidence to avoid normal saline in critically ill patients because it is associated with increased mortality, new receipt of renal-replacement therapy, or persistent renal dysfunction.  There is a lot of evidence to suggest that normal saline can worsen acidosis, inflammatory markers, and AKI.  In addition, a lot of the myths about LR have been debunked. First, LR is not much more expensive than normal saline.  Second, LR is less likely to cause hyperkalemia or worsen acidosis.

Article 2: Fluid resuscitation in patients with end-stage renal disease on hemodialysis presenting with severe sepsis or septic shock: A case control study. Rajdev, K., Et. Al. J Crit Care. 2020 Feb;55:157-162. Notes By. Dr. Marji.

Question: Among patients diagnosed with severe sepsis and septic shock, what percentage of patients with end-stage renal disease (ESRD) on hemodialysis (HD) received an initial fluid resuscitation of ≥30mL/kg compared to non-ESRD patients?

Facts: In ESRD patients HD, infection is the second most common cause of mortality after cardiovascular disease (Sarnik 2000).

General sepsis guidelines:
-Due to systemic inflammation and increased capillary permeability, septic patients have significant risk of fluid imbalances and frequently require large volumes of IV fluids.
-The Surviving Sepsis Campaign guidelines provide a strong recommendation for administering a 30mL/kg fluid bolus within 3 hours but have limited evidence (Rhodes 2016).
-Fluid administration should be guided by hemodynamic assessment

However, treatment of ESRD patients is inconsistent due to…
-Lack of studies
-ESRD patients appear volume overloaded on physical exam but may be intravascularly deplete
-Hesitation to administer a large fluid bolus in ESRD due to risk of cardiogenic shock, pulmonary edema, and respiratory failure

Design: Retrospective case-control chart review study
Location: A single center in Staten Island, New York

Population:
Inclusion Criteria:
-Adult patients who met criteria for severe sepsis or septic shock based on Surviving Sepsis Campaign definitions admitted from 2015 to 2018
-Severe Sepsis: 2 SIRS criteria + sepsis-induced organ dysfunction or tissue hypoperfusion (SBP ≤ 90mmHg or MAP ≤ 70mmHg or fall of > 40mmHg from baseline or lactate ≥ 4mmol/L)
-Septic shock = Sepsis-induced hypotension persisting despite a 30mL/kg fluid bolus
Exclusion Criteria
-Patients < 18-years-old
-Pregnant patients
-Incomplete or illegible documentation

Dates: 715 patient records were screened from 2015 to 2018

Sample Size: 215 met criteria for severe sepsis and septic shock

How were they assigned?
-Included patients were assigned to one of two groups
Case: ESRD patients (104)
Control: Non-ESRD patients (111)

Outcomes: Primary outcome: Percentage of patients who received initial fluid resuscitation of ≥30mL/kg presenting to the hospital with severe sepsis or septic shock.

Percentage of patients who received ≥ 30mL/kg within the first 6 hours
Case (ESRD): 23.08%
Control (Non-ESRD): 60.36%
P < 0.001

Mean fluids received
Case (ESRD): 21.38mL/kg (1643.3mL)
Control (Non-ESRD): 36.28mL/kg (2669.8mL)
P < 0.001

Secondary outcomes:
ICU admission rate was higher in Control (Non-ESRD) group
Case (ESRD): 66.35%
Control (Non-ESRD): 80.18%
P = 0.03

Need for vasopressors was higher in Control (Non-ESRD) group
Case (ESRD): 53.85%
Control (Non-ESRD): 69.37%
P = 0.025

Rate of intubation for respiratory distress (within 24 hours of presentation), length of mechanical ventilation, mean time to ordering antibiotics, need for urgent dialysis for volume overload, and in-hospital mortality were not significantly different between groups!

Source of infection
Most common cause of severe sepsis/septic shock in both groups was pneumonia
Case (ESRD): 45.19%
Control (Non-ESRD): 47.75%

UTIs were more common in the control (Non-ESRD) group
Case (ESRD): 6.73%
Control (Non-ESRD): 27.93%

Skin/Soft tissue/IV line infections were more common in the case (ESRD) group
Case (ESRD): 19.23%)
Control (Non-ESRD): 3.60%

Multivariate logistic regression analysis
Age was significantly associated with mortality (p = 0.044); for every year, mortality increased by 2.9%
Higher lactic acid levels were associated with higher mortality (p < 0.01)
Fluid administration was independently associated with lower mortality in patients with severe sepsis/septic shock (p = 0.035)

Subgroup analysis: Compared ESRD patients who received < 30mL/kg (80 patients) to those who received ≥ 30mL/kg (24 patients)
No statistically significant difference in need for vasopressor support, number of vasopressors required, rate of ICU admission, ICU LOS, hospital LOS, rate of intubation, rate of urgent dialysis, and mortality. However, there was a trend towards worse outcomes with larger fluid boluses!

Vasopressor use
< 30mL/kg: 51.25%
≥ 30mL/kg: 62.50%

Rate of ICU admission
< 30mL/kg: 65%
≥ 30mL/kg: 70.83%

Intubation rate within 24h of presentation for respiratory distress
< 30mL/kg: 6.35%
≥ 30mL/kg: 16.67%

Length of mechanical ventilation (in days)
< 30mL/kg: 4
≥ 30mL/kg: 6

In-hospital mortality
<30mL/kg: 38.75%
≥30mL/kg: 41.67% 

Author’s conclusion: “Our study indicates that initial fluid resuscitation of 30mL/kg may be safe, or at least not harmful, in patients with ESRD on HD and can potentially be incorporated in the sepsis triage bundle in the ED.”

Strengths: -ESRD group was relatively similar to the control group
-Subgroup analysis focused on the outcomes of ESRD patients only

Limitations: -Single-center retrospective study design.
-Population predominantly Caucasian males in Staten Island, NY limits generalizability.
-Small sample size.
-Type of crystalloid and use of blood products or albumin was not recorded. Volumes and characteristics of these other products could have affected outcomes.
-Primary objective looked at percentage of ESRD patients with severe sepsis and septic shock who received ≥ 30mL/kg fluid bolus compared to non-ESRD patients. This has already been demonstrated by Lowe (2018), Truong (2019), and Dagher (2015).
-Secondary outcomes raised more questions. Does ≥ 30mL/kg vs <30mL/kg fluid resuscitation lead to higher rates of intubation, urgent dialysis, hospital LOS, ICU LOS, need for vasopressors, in-hospital mortality, and other outcomes in patients with ESRD?
-Only looked at intubation within the first 24 hours
-The Non-ESRD group had higher lactic acid, heart rate, ICU admission rate, and need for vasopressors. Was the non-ESRD group sicker at baseline?
-Early administration of appropriate antibiotics which has been shown to reduce mortality was not documented.
-Subgroup analysis comparing ESRD patients who received < 30 mL/kg vs ≥ 30 mL/kg, intubation rate is more than 2x patients who received ≥ 30mL/kg.  Larger sample size may make this statistically significant.

Conclusion: This is not a practice changing study. Overall, the sample size was fairly low and homogenous, examined primarily Caucasian males but as we know, significant number of patients with end-stage renal disease are African-American males. In the future, it would be interesting to examine how serial fluid assessments that impact mortality rate inpatient care in patients with severe sepsis or septic shock. For example using things like CVP, ultrasound of the IVC, or passive leg raise to further evaluate fluid status would be more beneficial and could guide fluid resuscitation and hypotensive patient with ESRD more effectively. Overall, this study did not necessarily demonstrate any harm or benefit from a 30 cc/kg bolus.