Acute Salicylate Toxicity, Mechanical Ventilation, and Hemodialysis

Background: Salicylates are common substances that can be purchased over the counter. They are readily available, and in the setting of an overdose, can be fatal [1]. Initially, as salicylates are metabolized, they can induce a respiratory alklalosis. This is then followed by an anion gap metabolic acidosis.

Due to the metabolic derangements induced by salicylates as well as salicylate’s direct stimulation on the respiratory centers of the brain, patients can present with profound tachypnea, fever and even altered mental status. As the severity of toxicity increases, the need for airway protection through intubation and mechanical ventilation becomes more profound.

Intubation has unique implications in patients with acute salicylate toxicity [1]. Patients with  tachypnea are able to compensate for the profound metabolic acidosis that can develop from salicylate poisoning. Once intubated, the peri-intubation minute ventilation, typically, cannot be matched by the ventilator, thus taking away the patient’s physiologic mechanism of compensation for the metabolic abnormalities associated with salicylate toxicity leading to further clinical deterioration. Despite this, intubation in many cases of severe salicylate toxicity is necessary.

In addition to ventilation management, other therapeutic options to help manage acute salicylate toxicity include alkalization of the serum to prevent conversion of salicylates to its non-ionized form, which easily crosses the blood brain barrier and can lead to cerebral edema and end organ damage. Hemodialysis is another option in management of salicylate toxicity to help correct acid-base abnormalities and directly remove salicylates from the blood stream [3].

What They Did:

  • Retrospective observational study
  • Identified cases of salicylate toxicity (level >50 mg/dl) from the Illinois Poison Center associated with the National Poison Data System (NPDS) treatment code of ASPIRIN and INTUBATION
  • Of those cases, investigators noted which patients received hemodialysis as part of their management

Outcomes:

  • Mortality

Inclusion:

  • Patients of all ages recorded as having ingested salicylate and salicylate containing medications resulting in intubation
  • Patents were included if salicylate levels >50mg/dl

Exclusion:

  • Lack of association with salicylate intoxication

Results:

  • 56 Cases Identified
  • 41 of those 56 patients survived (73.2%)
  • Of the 15 fatal cases, 11 patients (73.3%) did not receive hemodialysis
  • 6 patients did not complete HD, all suffering cardiac arrest

Strengths:

  • Addresses an important option in managing salicylate poisoning
  • Queries a nationally established and reputable data base
  • Measures an important, clinically relevant endpoint (i.e. survival)

Limitations:

  • Retrospective nature of study (i.e. Can only demonstrate association, not causation)
  • Small patient population
  • Inclusion of patients that ingested multiple medications
  • Unable to distinguish acute vs chronic salicylate toxicity
  • Extracted data may have been incomplete
  • Inconsistent poison center data acquisition (i.e. May have missed some cases of salicylate toxicity)

Discussion:

  • Measured serum salicylate levels can be erratic due to multiple factors. In this study, there were 9 cases of patients with an initial serum salicylate level of <50mg/dL and subsequently increased to a level above toxic thresholds.  Two of these patients died and four had HD performed.  This fact should emphasize the importance of checking serial levels of salicylate poisoning cases.
  • In patients with worsening clinical status, intubation maybe a necessary evil. The issue with intubation is the inability to keep up with the hyperventilation necessary to avoid hypercapnia and worsening acidosis, both of which can lead to cardiac arrest. It is therefore important to consider bicarbonate therapy and hemodialysis in these situations.
  • As this paper is limited due to the size of the population and its retrospective nature, consultation with your local poison center is strongly encouraged to help guide management.

Author Conclusion:

“Survival was decreased in these patients if hemodialysis was not performed.  Mortality increases with the measured serum salicylate level.  Timely hemodialysis for intubated salicylate overdose patients decreases mortality.”

Clinical Take Home Point: In patients requiring intubation from acute salicylate toxicity, hemodialysis should be considered as part of management, as this is associated with decreased mortality.

Guest Post By:

Patrick C Ng
Chief Resident- San Antonio Military Medical Center- PGY 3
Next Year: to Rocky Mountain Poison and Drug Center, Denver CO Toxicology Fellowship

References:

  1. Chyka PA, et al. Salicylate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2007;45(2):95-131. PMID: 17364628
  2. Fernando SM, et al. Hypercapnea and Acidemia despite Hyperventilation following Endotracheal Intubation in a Case of Unknown Severe Salicylate Poisoning. Case Rep Crit Care 2017; 2017: 6835471. PMID: 28465843
  3. Reingardiene D, Lazauskas R. Acute Salicylate Poisoning. Medicina (Kaunas). 2006; 42(1): 79-83. PMID: 16467617

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Post Peer Reviewed By: Anand Swaminathan (Twitter: @EMSwami) and Salim Rezaie (Twitter: @srrezaie)

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The WOMAN Trial: Early TXA in Post-Partum Hemorrhage

Background: Post-partum hemorrhage (PPH) is the leading cause of maternal death worldwide. It is typically defined as > 500 ml of blood loss within 24 hours of giving birth. However, PPH encompasses a broad spectrum of disease from mild oozing over hours to rapid exsanguination and death. The burden of mortality from PPH is shouldered mainly by developing countries thus requiring cost-effective treatment modalities. Tranexamic acid (TXA) is one such possibly modality. TXA works by inhibiting the breakdown of fibrinogen and fibrin by plasmin. In essence, it stabilizes clot that the body naturally forms. TXA has a well established role in reducing death in trauma patients as demonstrated in the CRASH-2 trial (CRASH-2 2010) and is already used by many performing resuscitations in resource strapped locations due to its availability and low cost. Whether early TXA in post-partum hemorrhage reduces mortality while avoiding significant clotting complications (DVT, PE, ACS, CVA) is unknown.

Article: WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with postpartum hemorrhage (WOMAN) – an international, randomised, double-blind, placebo-controlled trial. Lancet 2017. PMID: 28456509

Clinical Question: Does early administration of TXA reduce death and hysterectomy rate in patients with PPH when compared to placebo.

Population: Women > 16 years of age diagnosed with PPH after a vaginal or caesarean section in 193 hospitals in 21 countries. Clinicians enrolling patients had to be uncertain about whether TXA should be used in a particular case or not.

Intervention: TXA 1 gm slow IV injection (1 ml/min of 10 mg/ml solution). A second dose could be administered if bleeding continued after 30 minutes or stopped and restarted anytime within the 1st 24 hours

Control: Placebo with identical packaging, volume and instructions

Outcomes:

  • Original Primary Outcome: All-cause mortality or hysterectomy within 42 days of giving birth
  • Final Primary Outcome: Death from post-partum hemorrhage

Design: Multicenter, multinational, Randomized, double-blind, placebo-controlled trial

Exclusion Criteria: Clinician was certain that TXA would either clearly be beneficial or clearly would not be appropriate

Primary Results:

  • Initial Plan
    • Enroll 15,000 patients
    • Primary endpoint: all-cause mortality or hysterectomy
    • 90% power to detect a 25% relative reduction
  • Revised Plan
    • Enroll 20,000 patients
    • Primary endpoint: death from PPH
    • 90% power to detect a 25% relative reduction
  • Ultimately, enrolled 20,060 women and randomized to TXA or placebo
    • TXA group: 10,036/10,051 patients included for analysis
    • Placebo group: 9,985/10,009 patients included for analysis

Critical Results:

  • Death from all causes or hysterectomy (original primary endpoint)
    • No statistically significant difference
    • TXA 5.3% vs. Placebo 5.5%
    • RR = 0.97 (CI 0.87 – 1.09, p = 0.65)
  • Death due to PPH (revised primary outcome)
    • Statistically significant benefit to TXA
    • TXA 1.5% (155/10,036) vs Placebo 1.9% (191/9,985)
    • Risk Ratio (RR): 0.81 (CI 0.65 – 1.00, p = 0.045)
    • Absolute risk reduction = 0.4%
    • NNT = 267 (Fragility Index = 0)
  • No difference in adverse events including thromboembolic events
  • Secondary Outcomes
    • Death due to PPH (TXA given < 3 hours)
      • TXA 1.2% vs. Placebo 1.7%
      • RR = 0.69 (CI 0.62 – 0.91, p = 0.008)
    • Death due to PPH (TXA given > 3 hours)
      • TXA 2.6% vs. Placebo 2.5%
      • RR = 1.07 (CI 0.76 – 1.51 , p = 0.70)
    • Hysterectomy rate
      • TXA 3.6% vs. Placebo 3.5%
      • RR = 1.02 (CI 0.88 – 1.07, p = 0.84)

Strengths:

  • Study asks a clinically important, patient centered question
  • Large, multicenter, multinational trial
  • Randomization and blinding was appropriately performed to minimize the risk of bias
  • Follow up was excellent (99.74%)
  • Pharma (Pfizer) did help fund the study but had no role in study design, data collection, data analysis, data interpretation or writing of the report

Limitations:

  • Patients were only enrolled in the study if clinicians were uncertain if they would benefit from TXA or not. This may act to underestimate the benefit of TXA in PPH
  • The primary endpoint was altered after initiation of the trial (see details below)
  • Diagnosis of PPH made clinically and no assessment of inter-rater reliability in making this determination

Other Issues:

  • Primary endpoint was changed during study. Investigators learned that the decision to perform hysterectomy was most commonly made at the time of randomization and, thus, could not be affected by the intervention
  • The change in the primary endpoint was performed prior to any data analysis or unmasking of data
  • As with the CRASH-2 study, the data show a consistent association of delayed administration of TXA with harm

Authors Conclusions:

Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.”

Our Conclusions:

TXA may be a beneficial intervention in preventing death from bleeding in patients with post-partum hemorrhage without increasing the risk of VTE. Unfortunately, we cannot offer a definitive bottom line due to methodology issues mainly revolving around alteration of the primary outcome. Even after forgiving the methodological issues, the NNT was large (267) with a fragility index of 0.

Potential to Impact Current Practice:

PPH is a complicated disease and it was unlikely that a single medication was going to significantly change outcomes. Although the benefit of TXA in PPH was modest at best, the absence of increased VTE or other complications is reassuring for proponents of it’s use and may empower others to employ the drug.

Clinical Bottom Line:

The WOMAN study demonstrated that TXA confers a small but significant decrease in death from bleeding in patients with PPH without an increase in thromboembolic events. It is reasonable to consider using TXA, an inexpensive medication, in the treatment of this life-threatening disorder.

For More on This Topic Checkout:

References:

  1. CRASH-2 trial collaborators. Effects of tanexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a ransomised placebo-controlled trial. Lancet 2010; 376: 23-32. PMID: 20554319

Post Peer Reviewed By: Salim Rezaie (Twitter: @srrezaie)

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Local Anesthetic Systemic Toxicity (LAST)

Definition: A life-threatening adverse reaction resulting from local anesthetic reaching significant systemic circulating levels. Local Anesthetic Systemic Toxicity (LAST) is rare and almost always occurs within minutes of injection of the local anesthetic.

Causes:

  • Injection of local anesthetic into the systemic circulation (either errantly as part of a regional block i.e. Bier block)
  • Rapid absorption of local anesthetic injected into a highly vascular area
  • Use of local anesthetic doses in excess of the maximum dose (typically occurs with multiple subcutaneous injections)
  • Common implicated procedures: bronchoscopy, circumcision, tumescent liposuction. Consider diagnosis in any patient coming from outpatient surgical center with cardiac arrest

Commonly Used Local Anesthetics

Mechanism of Action

  • All of the local anesthetic agents are sodium channel blockers
  • Lidocaine
    • Class IB antidysrhythmic
    • Gains rapid entry to the brain thus producing CNS symptoms early on

Signs + Symptoms

  • CNS Symptoms
    • Minor Signs/Symptoms
      • Tongue and perioral numbness
      • Parasthesias
      • Restlessness
      • Tinnitus
      • Muscle fasciculations + tremors
    • Major Signs/Symptoms
      • Tonic-clonic seizures
      • Global CNS depression
      • Decreased level of consciousness
      • Apnea
    • Neurologic symptoms typically precede cardiovascular symptoms in lidocaine toxicity
  • Cardiovascular Symptoms
    • Early Signs: Hypertension and tachycardia
    • Late Signs
      • Peripheral vasodilation + profound hypotension
      • Sinus bradycardia, AV blocs
      • Conduction defects (Prolonged PR, Prolonged QRS)
      • Ventricular dysrhythmias
      • Cardiac arrest
    • Cardiovascular symptoms typically present first in bupivacaine toxicity

Differential Diagnosis

  • Anaphylaxis (rare with amide anesthetics)
  • Effect of other sodium channel blockers (i.e. antihistamines, TCAs, cocaine, antimalarials)
  • Anxiety

Management

  • Prevention of toxicity
    • Know + calculate maximum doses of local anesthetic agent prior to use
    • Always aspirate prior to injection to ensure drug is not delivered intra-arterial or intravenous
    • Ask patient about symptoms after injection
    • Consider serial repairs of large or multiple wounds to minimize chance for toxicity
  • Basic Management
    • Institute basic management if ANY sign/symptom is present after local anesthetic use (i.e. new perioral numbness; don’t wait for CV findings!)
    • Stop injection or infusion of agent
    • Establish IV access if not already present
    • Continuous cardiac monitor
  • Aggressive Supportive Care
    • Airway/Breathing
      • Toxicity worsened by hypercapnea, hypoxia and acidosis
      • Use 100% FiO2
      • Hyperventilate
    • Cardiovascular Collapse
      • Consider epinephrine to augment cardiac output and improve peripheral vascular tone
      • Consider bicarbonate infusion for severe acidosis
      • Initiate high-quality CPR in arrest
    • Manage seizures with benzodiazepines over propofol as propofol is a cardiac depressant (Goldfrank’s 2015)
  • Lipid Emulsion Therapy (20% Intralipid)
    • Mechanism of action: unclear. May act as lipid sink, may facilitate redistribution of local anesthetic from target organs
    • Utility in lidocaine vs. bupivacaine
      • Due to lidocaine short 1/2 life, may be unnecessary. CPR alone typically adequate
      • Bupivacaine has longer 1/2 life making intralipid more useful in this form of LAST
    • Dosing (Neal 2012, Cao 2015)
      • Bolus: 1 – 1.5 ml/kg over 1 min
        • Can repeat bolus every 3 minutes up to a total dose of 3 ml/kg
      • Infusion: 0.25 ml/kg/min
        • Continue infusion until hemodynamically stable for at least 10 minutes
        • Can increase infusion to 0.5 ml/kg/min if BP worsens
    • Continue CPR during infusion to circulate drug

Take Home Points

  • The key in managing LAST is prevention. Know your dose, know your maximum dose, always aspirate prior to injection and ask patient about symptoms
  • Lidocaine toxicity CV complications are typically preceded by neurological signs/symptoms. If these develop, stop administration, place patient on monitor and ready your antidote
  • Bupivacaine toxicity can be sudden and catastrophic. If you are using the drug, undershoot your max dose and know where your antidote is
  • Intralipid has been shown to be effective in LAST. Administer the drug anytime there are signs of hemodynamic compromise

For More on This Topic Checkout:

References:

  1. Schwartz DR, Kaufman B. Local Anesthetics. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank’s Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. Link
  2. Neal JM et al, American Society of Regional Anesthesia and Pain Medicine. American Society of Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2012 version. Reg Anesth Pain Med 2012;37:16–8. PMID: 22189574
  3. Cao D et al. Intravenous lipid emulsion in the emergency department: a systematic review. J Emerg Med 2015; 48(3): 387-97. PMID: 25534900

Post Peer Reviewed By: Salim Rezaie (Twitter: @srrezaie)

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