Article, Emergency Medicine

The association of hemodialysis and survival in intubated salicylate-poisoned patients

a b s t r a c t

Introduction: Salicylate poisonings are common due to their multiple uses and wide availability. The variation of presenting symptoms contributes to inconsistent treatments in the emergency department. Patients with severe salicylate overdose require a high minute ventilation. Early in the course of an overdose, a patient will require hy- perventilation. If they become too fatigued to compensate, mechanical ventilation may be needed. It can be im- possible to recreate such a high minute ventilation with mechanical ventilation. This places patients at a high risk for decompensation and death. Hemodialysis is an effective elimination technique for salicylate overdose and should be considered early.

Methods: All salicylate cases reported to the Illinois Poison Center were reviewed from 2003-2014. All intubated patients with a Salicylate level N 50 mg/dl were included for analysis. Survival was compared to measured serum salicylate level and the administration of hemodialysis.

Results: 56 Cases were identified with an overall survival rate of 73.2% in patients with a serum salicylate level N 50 mg/dl. When patients did not receive hemodialysis, a peak salicylate level N 50 mg/dl had a 56% survival rate and 0% survival when the level was N 80 mg/dl. In the patients who received hemodialysis, a peak salicylate level N 50 mg/dl had a 83.9% survival rate and 83.3% survival when the level was N 80 mg/dl.

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.

(C) 2017

Introduction

Salicylates have long been used for multiple medical conditions due to their antipyretic, antithrombotic, and analgesic properties. They are acces- sible to the public, come in various formulations, and considered safe when taken in the proper dosage. The most commonly used salicylate is aspirin. Over 24,700 aspirin and salicylate exposures were reported to poi- son centers in the United States in 2014 with over 200 major exposures [1]. The ubiquitous nature of salicylates makes them an easily available method of overdose whether intentionally or unintentionally. Salicylate poisoning cases can become very complex due to the erratic absorption, distribution, metabolism, and elimination of the drug. Due to these drug characteristics, any medical provider who cares for a salicylate-toxic pa- tient should appreciate how quickly their clinical status can deteriorate.

The pathophysiology associated with Salicylate toxicity has been well- documented: early respiratory alkalosis from hyperventilation due to di- rect sensitization of the medullary respiratory center and metabolic acido- sis due to uncoupling of oxidative phosphorylation which shifts cellular

* Corresponding author at: Department of Emergency Medicine, Cook county hospital, 10th Floor, 1900 West Polk, Chicago, IL 60612, United States.

E-mail address: [email protected] (D.J. McCabe).

metabolism from aerobic to anaerobic which increases lactate production and accumulation which creates a loss of bicarbonate. The body’s natural response to salicylates includes hyperventilating which decreases PCO2 and increases serum pH. It also increases the renal excretion of bicarbon- ate, which decreases serum pH. In an acidemic patient, salicylates easily enter the central nervous system. Expelling carbon dioxide is an essential mechanism to alkalinize the blood and becomes even more apparent when sodium bicarbonate is required for Urine alkalinization [2-10].

The patient with salicylate poisoning should be considered unstable until the clinical manifestations of hyperventilation and any Mental status changes have returned to baseline along with a decreasing serum salicy- late level to minimal levels. If a patient has any clinical manifestations of toxicity in the setting of an elevated or increasing serum salicylate level, there is a high risk of clinical deterioration. The provider should be vigilant to foresee this decline by attempting gastrointestinal decontamination with activated charcoal as well as urinary alkalinization with sodium bicar- bonate and aggressive potassium replacement [3,4,11-13].

A patient’s mental and respiratory status should be closely moni- tored for fatigue, which could signal a decompensation created by a metabolic acidosis. If a patient becomes too fatigued to compensate, they may need Endotracheal intubation and mechanical ventila- tion. In severe salicylate toxicity, the exact roles of hypoventilation,

http://dx.doi.org/10.1016/j.ajem.2017.04.017

0735-6757/(C) 2017

hypercapnea, and worsening acidosis are unclear and optimal Ventilator management may be extremely difficult to attain. In ETI patients with severe salicylate intoxication, it may be difficult to provide the high minute ventilation necessary to maintain adequate hyperventilation and acid-base equilibrium [5,6,14].

The dependence upon such a high minute ventilation is difficult to recreate on an artificially ventilated patient and an increase in pulmo- nary permeability combined with the high amount of fluid needed to al- kalinize the urine with sodium bicarbonate puts these patients at high risk of worsening respiratory status [3,5].

When someone is unable to expel carbon dioxide due to intubation without appropriate hyperventilation there is going to be an expected decrease in serum pH. The kidneys continue to excrete bicarbonate, which contributes further to the acidemia. This relatively acidic envi- ronment changes aspirin to its nonionized form which can easily cross membranes including the blood brain barrier contributing to Neurologic deterioration. The shift of salicylates into the central nervous system due to worsening acidosis has been attributed to Peri-intubation cardiac arrest in these patients [2,6,15-17]. All of these complicated and integral factors place a patient at an extremely high risk for further decompen- sation and death [4-10].

Hemodialysis (HD) is an effective mechanism for eliminating salicy- lates (ASA) as well as correcting the associated acid-base disturbances in salicylate-toxic patients but must be considered in a timely fashion [4-6,11,12,18]. Many patients do not receive HD despite having general- ly accepted indications for hemodialysis including severe metabolic ac- idosis, end-organ injury (seizures, renal failure, pulmonary edema, altered mental status), and ETI [19]. Timely hemodialysis may be a life-saving therapy in these cases.

The purpose of this study was to describe the impact of hemodialysis on survival rates in salicylate-poisoned intubated patients as well as to contribute to the surprisingly limited data related to this group of criti- cal patients.

Methods

This is a retrospective observational study. Illinois Poison Center cases from 1/1/2003-12/31/2014 with National Poison Data System (NPDS) generic substance code 041000 (ASPIRIN UNKNOWN IF

ADULT OR PEDIATRIC FORMULATION) or 041703 (ASPIRIN PEDIATRIC FORMULATION) or 041701 (ASPIRIN ADULT FORMULATION) or 201064 (ASPIRIN WITH CARISOPRODOL) or 041700 (ASPIRIN WITH CODEINE) or 041706 (ASPIRIN WITH OXYCODONE) or 041718 (ASPI- RIN WITH PROPOXYPHENE) or 041707 (ASPIRIN WITH OTHER OPIOID) or 041708 (ASPIRIN WITH OTHER DRUG: ADULT COMBINATION FOR- MULATION) or 041717 (ASPIRIN WITH OTHER DRUG: PEDIATRIC COM-

BINATION) and NPDS treatment code of INTUBATION were included. Intubated patients with a serum salicylate level N 50 mg/dl were includ- ed for analysis. This level could be reached at any time before or after initiation of mechanical ventilation. Subjects of all ages and with polysubstance ingestions were included but were only eligible if the units of measure were recorded. Fig. 1 illustrates the cases studied.

The serum salicylate level was compared to survival. If sequential sa- licylate levels were recorded, a peak measured salicylate level was com- pared to survival. Particular attention was paid to implementation of hemodialysis and if it occurred before or after intubation.

Exclusions

Eight patients were excluded from analysis due to clear lack of asso- ciation with salicylate intoxication (Fig. 1).

Results

56 Cases were identified with an overall survival rate of 73.2% (41/56). In 73.3% (11/15) of the fatal cases, patients did not receive HD. Of all the patients who did receive HD, all thirty-one had ETI prior to HD

implementation.

ASA level was compared to survival.

Salicylate serum concentration compared to survival without HD

In patients that did not receive HD, an ASA level N 50 mg/dl had a 56% survival rate (14/25) compared to 0% survival (0/9) when the level was N 80 mg/dl.

Fig. 1. All cases considered eligible for analysis.

Fig. 2. Measured serum salicylate levels compared to mortality with or without implementation of hemodialysis. Total cases in each salicylate group represented as bars compared to percentage of survival within each group represented with lines.

Salicylate serum concentration compared to survival when received HD

When patients received HD, an ASA level N 50 mg/dl had an 83.9% survival rate (26/31) and 83.3% survival (15/18) when the level was N 80 mg/dl.

The survival of patients compared to ASA levels are shown in Figs. 2 and 3. Fig. 2 compares the survival in the different serum ASA levels (10 mg/dl groups). This allows systematic analysis of the cases and survival within each group; the groups were deter- mined arbitrarily. Fig. 3 illustrates survival when pooling all cases

Fig. 3. Measured serum salicylate levels compared to mortality with or without implementation of hemodialysis. All cases above each salicylate level are pooled together. Total cases in each salicylate group represented as bars compared to percentage of survival within each group represented with lines.

Fig. 4. All cases with initial [ASA] b 50 mg/dl and subsequent [ASA] N 50 mg/dl.

above each ASA level. This provides the clinician with the total cases and survival above each ASA level.

Cases with initial low salicylate serum level with subsequent level

N 50 mg/dl

There were nine cases of initial ASA levels b 50 mg/dl but the level in- creased to N 50 mg/dl upon repeat testing. Fig. 4 describes all nine of these cases. There were a total of two deaths; one received HD and one did not.

There were five cases of initial ASA levels b 50 mg/dl and subsequent measurements increased to N 50 mg/dl but HD was not performed. One of these cases had an ASA level N 70 mg/dl and that patient did not survive. There were four cases of initial ASA level b 50 mg/dl but the patient went on to receive HD. All four of these cases had an ASA N 70 mg/dl.

One of these patients did not survive.

Cases of incomplete HD

There were four patients in whom HD was attempted but it was ini- tiated after the patients had cardiac arrest with return of spontaneous circulation; none survived hospitalization. There were two additional patients in whom HD was initiated but they suffered cardiac arrest dur- ing the initial HD session and were unable to be resuscitated. Since these patients did not complete a full HD session, these six patients were in- cluded in the group that did not receive HD.

Discussion

Measured serum salicylate levels have long been known to be erratic due to variable absorption and dynamic shifts from serum into tissues based on serum acid-base status. The total body salicylate burden can be quite a bit higher due to changes of volume of distribution based on acid-base status. The mechanism for elimination can be altered based on changes in electrolyte and acid-base base status. This can make interpretation of serum salicylate levels difficult for the clinician [4-6,14]. Our results are consistent with the well-described phenome- non of erratic serum salicylate measurements due to the variable ab- sorption and redistribution throughout the body. This can be quite alarming, as demonstrated by two cases in our study with a drastic in- crease from a salicylate level b 15 mg/dl to over 120 mg/dl. A similar case was described by Herres et al. about a patient who presented with an undetectable salicylate level that increased to 35 mg/dl at seven hours post-ingestion and was medically cleared; unfortunately

the patient died after the salicylate level subsequently increased to 128 mg/dl [10]. In our study, there were nine cases that had initial serum salicylate level b 50 mg/dl and subsequently surpassed this arbi- trary threshold. Two of these patients did not survive and four had HD performed. This should reinforce the necessity of performing serial measurements.

In some cases, a patient may need to be mechanically ventilated due to deteriorating clinical status. Multiple cases of cardiac arrest occurring soon after endotracheal intubation of severely salicylate poisoned pa- tients have been reported [15,20]. Worsening acidosis and hypercapnea associated with mechanical ventilation have been implicated as possible contributing factors, due to reliance on hyperventilation to keep acid- base homeostasis [2-4,14-17]. While intubation may be unavoidable, salicylate-elimination techniques including bicarbonate therapy and hemodialysis comprise key roles in the Management strategy [4-6,11, 12,18].

It has been said that mortality rates are three-fold higher if the salic- ylate ingestion is not identified in the emergency department but in- stead has a delayed diagnosis [4,6,16,21,22]. Chalasani et al. found a 70% survival rate when salicylate toxicity was identified and treated within the first 24 h of presentation [22]. In these 56 cases, we did not find any patients that required endotracheal intubation after they had received hemodialysis. With this in mind, it is a reasonable recommen- dation to initiate hemodialysis for all intubated aspirin overdose pa- tients without delay to decrease the salicylate level and improve overall chances of patient survival [4-6,17,21].

In this study on mechanically ventilated salicylate-toxic patients, we found alarmingly high rates of mortality if hemodialysis was not per- formed. These patients did not have an increase in mortality with in- creasing serum salicylate levels if they received hemodialysis. This study provides reinforcement to the emergency medicine provider about the importance of Emergent hemodialysis in salicylate toxic pa- tients. If a salicylate-toxic patient requires endotracheal intubation, im- mediate action should be performed to complete hemodialysis. We feel this is an important topic for an emergency medicine physician to rec- ognize, as they are the providers that can consult for emergent hemodi- alysis, transfer to a center that can provide this treatment, and place a hemodialysis catheter to expedite this life saving intervention.

Limitations

Some limitations of this study include the retrospective nature of the extracted poison center data. A retrospective study can only demon- strate association, not causation. Cases involving co-ingestions were

not excluded unless they were an obvious primary reason for intubation or death. However, co-ingestions may impact salicylate absorption/ elimination kinetics, even though they also represent real overdose sit- uations. We were not able to distinguish acute versus chronic salicylate toxicity with the available data. Other limitations include incomplete clinical data and inconsistent poison center data acquisition.

Conclusion

In salicylate-Poisoned patients who require mechanical ventilation emergent hemodialysis is associated with a Mortality benefit. In this ret- rospective observational study, when hemodialysis was started after a worsening of hemodynamic status there were very poor outcomes. He- modialysis should be initiated as soon as possible. An emergency physi- cian should make arrangements for emergent hemodialysis or transfer the patient to a facility with these capabilities.

Funding

None.

Conflicts of interest

Neither author has a financial or academic conflict of interest preventing neutral assessment of the data presented in the study.

IRB

This study was provided an exemption by the Institutional Review Board at Cook County Health & Hospitals System.

Acknowledgements

We would like to thank Carol DesLauriers of the Illinois Poison Cen- ter for assistance with case search.

References

  1. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 annual report of the American Association of Poison control centers‘ National Poison Data System (NPDS): 32nd annual report. Clin Toxicol 2015;53(10):962-1147.
  2. Stolbach AI, et al. Mechanical ventilation was associated with Acidemia in a case se- ries of salicylate-poisoned patients. Acad Emerg Med 2008;15(9):866-9.
  3. Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch In-

    tern Med 1981;141:364-9.

    Pearlman BL, Gambhir R. Salicylate intoxication: a clinical review. Postgrad Med 2015;121(4):162-8.

  4. Fertel BS, et al. The underutilization of hemodialysis in patients with salicylate poi- soning. Kidney Int 2009;75:134-1353.
  5. O’Malley GF. Emergency department management of the salicylate-poisoned pa- tient. Emerg Med Clin North Am 2007;25(2):333-46.
  6. Proudfoot AT. Toxicology of salicylates. Am J Med 1983;75:99-103.
  7. Mukerji V, et al. Cardiac Conduction abnormalities and Atrial arrhythmias associated with salicylate toxicity. Pharmacotherapy 1986;6(1):41-3.
  8. Chyka PA, et al. Salicylate poisoning: an evidence-based consensus guideline for out- of-hospital management. Clin Toxicol 2007;45(2):95-131.
  9. Herres J, et al. Delayed salicylate toxicity with undetectable initial levels after large- dose aspirin ingestion. Am J Emerg Med 2009;27(9):1173.e1-3.
  10. McGuigan MA. Death due to salicylate poisoning in Ontario. Can Med Assoc J 1986; 135:891-4.
  11. Higgins RM. Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient. Clin Nephrol 1998;50(3):178-83.
  12. Yip L, et al. Concepts and controversies in salicylate toxicity. Emerg Med Clin North Am 1994;12(2):351-64.
  13. Bora K, Aaron C. Pitfalls in salicylate toxicity. Am J Emerg Med 2010;28(3):383-4.
  14. Greenberg MI. Deleterious effects of endotracheal intubation in salicylate poisoning. Ann Emerg Med 2003;41(4):583-4.
  15. Thisted S, et al. Acute salicylate self-poisoning in 177 consecutive patients treated in ICU. Acta Anaesthesiol Scand 1987;31:312-6.
  16. Guidance document: management priorities in salicylate toxicity, J Med Toxicol 2015;11(1):149-52.
  17. Winchester JF, et al. Extracorporeal treatment of salicylate or acetaminophen poi- soning-is there a role? Arch Intern Med 1981;141:370-4.
  18. Minns AB, et al. Death due to acute salicylate intoxication despite dialysis. J Emerg Med 2011;40(5):515-7.
  19. Krause, et al. Acute aspirin overdose: mechanisms of toxicity. Ther Drug Monit 1992;

    14:441-51.

    Anderson RJ, et al. Unrecognized adult salicylate intoxication. Ann Intern Med 1976; 85(6):745-8.

  20. Chalasani N, et al. Systemic inflammatory response syndrome caused by chronic sa- licylate intoxication. South Med J 1996;89(5):479-82.

Leave a Reply

Your email address will not be published. Required fields are marked *